Novel EP4 antagonist

Abstract

The purpose of the present invention is to provide a novel compound having an EP4 antagonistic activity.　The present invention relates to a compound represented by formula (I) [wherein each symbol is as defined in the description] or a pharmaceutically acceptable salt thereof, which has an EP4 antagonistic activity. The present invention also relates to: an EP4 antagonist comprising the compound; and a pharmaceutical composition containing the compound. One embodiment of the present invention is, for example, a medicine for preventing and / or treating cancer.

Description

Novel EP4 antagonists

[0001] The present invention relates to novel heterocyclic compounds that have prostaglandin E2 (PGE2) receptor EP4 antagonistic activity and are useful as agents for preventing or treating cancer, particularly lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, or leukemia, and to pharmaceuticals containing the same as an active ingredient.

[0002] Prostaglandin E2 (PGE2) is a bioactive lipid that can induce a wide range of biological effects related to inflammation and cancer. PGE2 belongs to the prostanoid receptor family of lipids. Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of biological mediators called prostanoids, which consist of prostaglandins PGD2, PGE2, PGF2α, prostacyclin PGI2, and thromboxane TXA2. Prostanoids function through the activation of seven transmembrane G-protein-coupled receptors (GPCRs), of which EP1, EP2, EP3, and EP4 are receptors for PGE2. Activation of EP4 by PGE2 stimulates adenyl cyclase, leading to an increase in cytosolic cAMP levels and initiating numerous downstream events via its typical effector, protein kinase A. In addition, PGE2 can also signal through PI3K / AKT and Ras-MAPK / ERK signaling.

[0003] Cancer is a leading cause of death worldwide. Tumors consist not only of abnormally proliferating malignant cancer cells but also of a functionally supportive microenvironment. This tumor microenvironment is composed of a complex arrangement of cells, extracellular matrix components, and signaling molecules, and is established by altered communication between the stroma and tumor cells. As tumors grow in size, they induce the production of various factors that can aid tumor growth, such as angiogenic factors (which promote blood vessel growth), or help tumors evade attack from the host's immune response. PGE2 is one such immunomodulatory factor produced in tumors.

[0004] It is well established that COX-2 promotes overall tumor growth, primarily via PGE2, and that upregulation correlates with clinical outcomes in many common cancers, particularly lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumors, malignant lymphomas, and leukemias. High expression levels of COX-2 and PGE2 are associated with neoplastic transformation, cell proliferation, angiogenesis, invasiveness, metastasis, and immune evasion.

[0005] Patent Documents 1 to 5 and Non-Patent Document 1 each disclose compounds useful as modulators of EP4, one of the prostaglandin E2 (PGE2) receptors.

[0006] International Publication No. WO 2014 / 086739 International Publication No. WO 2010 / 123049 International Publication No. WO 2012 / 039972 International Publication No. WO 2015 / 094902 International Publication No. WO 2016 / 111347

[0007] Baurle, S. et al., J. Med. Chem., 2019, 62, 2541-2563

[0008] An object of the present invention is to provide novel compounds which have an antagonistic effect on EP4, one of the prostaglandin E2 (PGE2) receptors, and which are useful as agents for preventing or treating cancer.

[0009] As a result of intensive investigations aimed at solving the above problems, the present inventors have discovered that a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an excellent EP4 antagonistic effect, and have thus completed the present invention.

[0010] That is, the present invention includes the following exemplary embodiments.

[0011] [1] The following formula (I):

[0012]

[0013] [In the formula, R １ , R ２ , and R ３are each independently a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group, C １－４ Alkoxy group or mono- or di-C １－４ represents an alkylamino group; ４ is a hydrogen atom, C optionally substituted with one or more substituents selected from the substituent group a １－４ Alkyl group, C １－６ an alkylsulfonyl group, a halogen atom, or C １－６ C optionally substituted with an alkoxy group １－６ represents an alkyl-carbonyl group; １ａ , X １ｂ , and X ２ are each independently a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group or C １－４ represents an alkoxy group; １ is NR ５ , O, or S; Y ２ is CR ６ or N; ５ represents a hydrogen atom or a C optionally substituted with one or more substituents selected from the substituent group a １－４ represents an alkyl group; ６ C may be substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a. １－４ Alkyl group or C １－４ represents an alkoxy group; L represents a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ -, -OCH ２ - or -CH ２ and Z represents a carboxy group, a hydroxy group, or a group biologically equivalent to a carboxy group. (hereinafter, also abbreviated as "compound (I)") or a pharmaceutically acceptable salt thereof. (Substituent group a): a halogen atom; a cyano group; a hydroxy group; a carboxy group; a nitro group; C １－４C optionally substituted with an alkoxy group １－６ Alkoxy group; C １－６ haloalkoxy group; C １－６ Alkylsulfonyl group; C １－６ haloalkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; C ６－１４ Aryl-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a diC １－６ an alkylamino group, (iv) C １－６ an alkoxy group, and (v) C １－６ haloalkoxy group, and one or two C optionally substituted with a substituent selected from the group consisting of １－６ a carbamoyl group optionally substituted with an alkyl group; １－６ Alkylamino group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ Aryl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６(viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ Aryloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ６－１４ Arylsulfonyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ alkoxy-carbonyl group, (x) C １－６(xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８Cycloalkyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８ Cycloalkyloxy group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; and (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and a nitro group;

[0014] [1'] R １ , R ２ , and R ３ are each independently substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group, C １－４ Alkoxy group or mono- or di-C １－４ is an alkylamino group, R ４ C optionally substituted with a hydrogen atom or one or more substituents selected from the substituent group a １－４ is an alkyl group, １ａ , X １ｂ , and X ２ are each independently substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group or C １－４ is an alkoxy group, １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom or C optionally substituted with one or more substituents selected from the substituent group a １－４ is an alkyl group, R ６ each of which may be substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; １－４Alkyl group or C １－４ an alkoxy group, and L is a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ -, -OCH ２ - or -CH ２ The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof, wherein Z is a carboxy group, a hydroxy group, or a group biologically equivalent to a carboxy group.

[0015] [2] R １ , R ２ , and R ３ are independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ Alkoxy group, C １－４ Fluoroalkoxy group, or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; １－４ Fluoroalkyl group; (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４(vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group; １－６ an alkylsulfonyl group; or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group;１－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, R ６ is a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ an alkoxy group, or C １－４ L is a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ - or -OCH ２ - or a pharmaceutically acceptable salt thereof,

[0016] [2'] R １ , R ２ , and R ３ are independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ Alkoxy group, C １－４ Fluoroalkoxy group, or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; １－４ Fluoroalkyl group; (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, R ６ is a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ an alkoxy group, or C １－４ L is a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ - or -OCH ２ - or a pharmaceutically acceptable salt thereof,

[0017] [3] Y １ But NR ５ The compound according to the above [1], [1'], [2] or [2'], or a pharmaceutically acceptable salt thereof,

[0018] [4] Y １ But NR ５ And Y ２ But, CR ６ The compound according to the above [1], [1'], [2] or [2'], or a pharmaceutically acceptable salt thereof,

[0019] [5] X １ａ and / or X １ｂ is a fluorine atom, or a pharmaceutically acceptable salt thereof.

[0020] [6] X ２ , R ２ , and R ３are all hydrogen atoms, or a pharmaceutically acceptable salt thereof.

[0021] [7] R １ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

[0022] [8] X １ａ and X １ｂ and are both fluorine atoms, or a pharmaceutically acceptable salt thereof,

[0023] [9] The compound according to any one of the above-mentioned [1] to [8], wherein L is a single bond, or a pharmaceutically acceptable salt thereof.

[0024]

[10] The compound according to any one of the above-mentioned [1] to [9], wherein Z is a carboxy group, or a pharmaceutically acceptable salt thereof.

[0025]

[11] R ４ is a hydroxy group or C １－４ C optionally substituted with an alkoxy group １－４

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

[11] or a pharmaceutically acceptable salt thereof, wherein the compound is an alkyl group;

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

[12] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0026]

[13] The pharmaceutical composition according to the above-mentioned

[12] for the prevention and / or treatment of a disease whose symptoms can be alleviated by EP4 antagonism.

[0027]

[14] The pharmaceutical composition according to the above-mentioned

[13] , wherein the disease whose symptoms can be alleviated by EP4 antagonism is cancer.

[0028]

[15] The pharmaceutical composition according to the above-mentioned

[14] , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0029]

[16] An EP4 antagonist comprising the compound according to any one of the above [1] to

[11] or a pharmaceutically acceptable salt thereof.

[0030]

[17] A medicament for preventing and / or treating cancer, comprising a compound according to any one of the above-mentioned [1] to

[11] or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor.

[0031]

[18] The medicine according to the above-mentioned

[17] , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0032]

[19] The medicine according to the above-mentioned

[17] or

[18] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or anti-PD-L1 antibody selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, atezolizumab, avelumab, and durvalumab.

[0033]

[20] A preventive or therapeutic agent for cancer, comprising the compound according to any one of the above [1] to

[11] or a pharmaceutically acceptable salt thereof.

[0034]

[21] The preventive or therapeutic agent according to the above-mentioned

[20] , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0035]

[22] The compound according to any one of the above-mentioned [1] to

[11] or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer.

[0036]

[23] The compound according to the above-mentioned

[22] or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0037]

[24] A method for inhibiting EP4 in a mammal, comprising administering to the mammal an effective amount of the compound according to any one of the above-mentioned [1] to

[11] or a pharmaceutically acceptable salt thereof.

[0038]

[25] A method for preventing or treating cancer in a mammal, comprising administering to the mammal an effective amount of the compound according to any one of the above-mentioned [1] to

[11] or a pharmaceutically acceptable salt thereof.

[0039]

[26] The method for preventing or treating cancer according to the above-mentioned

[25] , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0040]

[27] Use of the compound according to any one of the above [1] to

[11] or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for cancer; and

[0041]

[28] The use according to the above-mentioned

[27] , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0042] According to the present invention, it is possible to provide a compound that has an excellent antagonistic effect against EP4, which is one of the prostaglandin E2 (PGE2) receptors, and is useful as an agent for preventing and / or treating diseases whose symptoms can be alleviated by EP4 antagonism, such as cancers selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0043] The graph shows the time course of relative tumor volume in the group administered with the compound of Example 3 alone, the group administered with the anti-mouse PD-1 antibody alone, the group administered with the compound of Example 3 in combination with the anti-mouse PD-1 antibody, and the control (vehicle) group.

[0044] The definitions of groups used in the present specification are explained in detail below. Unless otherwise specified, groups have the following definitions.

[0045] In the present specification, compounds represented by a formula are referred to as "compound" followed by the number of the formula. For example, a compound represented by formula (I) is referred to as "compound (I)." In the present specification, a numerical range represented by "to" or "-" means a numerical range with the numbers before and after "to" or "-" as the lower or upper limit (for example, when the range includes [1'], [2'], etc., these are also included in the range). In the present specification, when a numerical range is indicated by the element symbol "C" followed by numbers before and after "-" and is indicated in the name of an arbitrary group, it indicates each of the arbitrary groups having an integer number of carbon atoms with the numbers before and after "-" as the lower or upper limit. For example, an alkyl group having 1 to 4 carbon atoms is referred to as "C １－４ The alkyl group is sometimes referred to as an alkyl group. ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ The same applies to other groups.

[0046] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0047] In this specification, "C １－６ The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. １－６ Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0048] In this specification, "C １－４ The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. １－４The "alkyl group" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0049] In this specification, "C １－６ An "alkoxy group" is an alkoxy group of the formula R'O-, where R' is C １－６ represents an alkyl group. １－６ Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.

[0050] In this specification, "C １－４ An "alkoxy group" is an alkoxy group of the formula R'O-, where R' is C １－４ represents an alkyl group. １－４ The "alkoxy group" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0051] In this specification, "C １－４ Alkoxy-C １－４ An "alkoxy group" is an alkoxy group of the formula R'O-R''O-, where R' is C １－４ represents an alkyl group, and R" is C １－４ represents an alkylene group. １－４ Alkoxy-C １－４ Examples of the "alkoxy group" include methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy, sec-butoxymethoxy, tert-butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxyethoxy, butoxyethoxy, isobutoxyethoxy, sec-butoxyethoxy, tert-butoxyethoxy, and the like.

[0052] In this specification, "C １－４ The "alkylene group" refers to the C １－４"C" means a divalent, linear or branched saturated hydrocarbon group derived from an alkyl group. １－４ Examples of the alkylene group include methylene, ethylene, propylene, butylene, etc.

[0053] In this specification, "C １－６ The term "haloalkyl group" refers to "C １－６ "C" means a group in which one or more hydrogen atoms in the "alkyl group" are substituted with halogen atoms. １－６ Examples of the "haloalkyl group" include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0054] In this specification, "C １－４ The term "fluoroalkyl group" refers to a group having a C １－４ "C" means a group in which one or more hydrogen atoms in the "alkyl group" are substituted with a fluorine atom. １－４ Examples of the "fluoroalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, and perfluoroisopropyl.

[0055] In this specification, "C １－６ An "alkylsulfonyl group" is a group represented by the formula R'S(=O) ２ - (where R' is C １－６ represents an alkyl group. １－６Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, isohexylsulfonyl, 1,1-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 2-ethylbutylsulfonyl, and the like.

[0056] In this specification, "C １－６ A "haloalkylsulfonyl group" is a group represented by the formula R'S(=O) ２ - (where R' is C １－６ represents a haloalkyl group. １－６ Examples of the "haloalkylsulfonyl group" include fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl, 2-iodoethylsulfonyl, 2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl, 2,2,3,3-tetrafluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, 4,4,4-trifluorobutylsulfonyl, 5,5,5-trifluoropentylsulfonyl, and 6,6,6-trifluorohexylsulfonyl.

[0057] In this specification, "C １－６ An "alkyl-carbonyl group" is a group of the formula R'C(O)-, where R' is C １－６ represents an alkyl group. １－６ Examples of the "alkyl-carbonyl group" include methylcarbonyl (acetyl), ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.

[0058] In this specification, "C １－６ The term "haloalkoxy group" refers to a group consisting of "C １－6 "Alkoxy group" means a group in which one or more hydrogen atoms are substituted with halogen atoms. １－６ Examples of the "haloalkoxy group" include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy.

[0059] In this specification, "C １－４ The term "fluoroalkoxy group" refers to a group １－４ "C" means a group in which one or more hydrogen atoms in the "alkoxy group" are substituted with a fluorine atom. １－４ Examples of the "fluoroalkoxy group" include fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, and perfluoroisopropoxy.

[0060] In this specification, "C １－６ An "alkoxy-carbonyl group" is an alkoxy group of the formula R'OC(O)-, where R' is C １－６ represents an alkyl group. １－６ Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, and the like.

[0061] In this specification, "C ３－８"Cycloalkyl group" means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. ３－８ The "cycloalkyl group" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0062] In this specification, "C ３－８ The term "cycloalkyloxy group" refers to a group consisting of "C ３－８ "Cycloalkyl group" means a group bonded to an oxygen atom. ３－８ Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0063] In this specification, "C ６－１４ "Aryl (group)" means a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity. ６－１４ Examples of the aryl (group) include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, and fluorenyl.

[0064] In this specification, "C ６－１４ The term "aryloxy group" refers to a group consisting of "C ６－１４ "Aryl" means a group bonded to an oxygen atom. ６－１４ Examples of the "aryloxy group" include phenyloxy, 1-naphthyloxy, 2-naphthyloxy, biphenylyloxy, and 2-anthryloxy.

[0065] In this specification, "C ７－１８ "Aralkyl (group)" means "C １－４ "Alkyl group" to "C ６－１４ "Aryl group" means a substituted group. ７－１８ Examples of the "aralkyl (group)" include benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl)methyl, (naphthyl-2-yl)methyl, 1-(naphthyl-1-yl)ethyl, 1-(naphthyl-2-yl)ethyl, 2-(naphthyl-1-yl)ethyl, 2-(naphthyl-2-yl)ethyl, biphenylylmethyl, and the like.

[0066] In this specification, "C ７－１８ The term "aralkyloxy group" refers to "C ７－１８ "Aralkyl (group)" means a group bonded to an oxygen atom. ７－１８ Examples of the "aralkyloxy group" include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, and the like.

[0067] In the present specification, "one or two C １－６ The term "carbamoyl group which may be substituted with an alkyl group" refers to a carbamoyl group (-CONH ２ ) one or two hydrogen atoms are each independently selected from "C １－６ "One or two C alkyl groups" means a group which may be substituted with "C １－６ Examples of the "carbamoyl group which may be substituted with an alkyl group" include methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, and the like.

[0068] As used herein, "diC １－６ The "alkylamino group" is an amino group (-NH ２ ) are each independently denoted by "C １－６ "DiC" means a group substituted with an "alkyl group." １－６ Examples of the "alkylamino group" include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, and the like. １－４ Examples of the "alkylamino group" include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, and the like.

[0069] As used herein, "diC １－４ Alkoxy-C １－４ The "alkylamino group" is an amino group (-NH ２ ) are each independently denoted by "C １－４ Alkoxy-C １－４ "DiC" means a group substituted with an "alkyl group." １－４ Alkoxy-C １－４Examples of the "alkylamino group" include di(methoxymethyl)amino, di(methoxyethyl)amino, di(ethoxymethyl)amino, di(ethoxyethyl)amino, and the like.

[0070] In the present specification, examples of the "aromatic heterocyclic group" include 5- to 14-membered aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0071] Preferable examples of the "5- to 14-membered aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, and pyrazolopyridyl; Examples thereof include 8- to 14-membered fused aromatic heterocyclic groups (fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups) such as oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0072] In the present specification, examples of the "non-aromatic heterocyclic group" include 3- to 14-membered non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0073] Preferable examples of the "3- to 14-membered non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl. 3- to 10-membered monocyclic non-aromatic heterocyclic groups (preferably 5- to 8-membered monocyclic non-aromatic heterocyclic groups) such as zolyl, piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl;Tetrahydrotriazolopyridyl, tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrazinyl, dihydropyrazolopyrrolyl, dihydropyrazolopyrazinyl, tetrahydropyrazolopyridyl, tetrahydroimidazolopyridyl, dihydroimidazolopyridyl, dihydroimidazolopyrrolyl, tetrahydroimidazolopyrazinyl, dihydropyrimidopyrrolyl, dihydropyridopyrrolyl, tetrahydropyridopyridyl, tetrahydrooxazolopyrazinyl, tetrahydropyridopyridyl, tetrahydrotriazolodiazepinyl, octahydro-1,4-oxazinopyrazinyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, dihydroisoquinolyl 8- to 14-membered fused non-aromatic heterocyclic groups (fused polycyclic (preferably bicyclic) non-aromatic heterocyclic groups) such as tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, dihydrothiazolo[4,5-c]pyridyl, dihydrothiazolo[5,4-c]pyridyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, dihydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl;

[0074] In the present specification, the term "cyclic ether group" refers to, for example, a 3- to 14-membered non-aromatic heterocyclic group containing at least one oxygen atom as a ring-constituting atom in addition to carbon atoms. Examples of the "cyclic ether group" include oxiranyl, oxetanyl, tetrahydrofuryl, and tetrahydropyranyl.

[0075] In this specification, the term "bioisostere" refers to "a functional group that exhibits broadly similar biological effects and has chemical and physical similarities" proposed by Thornber in 1979 in the field of medicinal chemistry. The "group bioequivalent to a carboxy group" represented by Z in the formula (I) refers to a chemical functional group that can be used as a substitute for a carboxy group and can change the physicochemical properties of a drug (e.g., solubility, metabolic stability, etc.). One embodiment of the "group bioequivalent to a carboxy group" is, for example, C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group which may be substituted with an alkyl group; a cyano group; a group represented by the following formula:

[0076]

[0077] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group), or a tautomeric group thereof.

[0078] In addition to the above, other embodiments of the "group biologically equivalent to a carboxy group" also include ester groups that can be converted into a carboxy group in a living body by a reaction with an enzyme, gastric acid, or the like (e.g., phenoxycarbonyl, carboxymethoxycarbonyl, dimethylaminomethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1-{(ethoxycarbonyl)oxy}ethoxycarbonyl, phthalidyloxycarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, 1-{[(cyclohexyloxy)carbonyl]oxy}ethoxycarbonyl, etc.).

[0079] In the present specification, the term "optionally substituted" means that the group is unsubstituted or substituted with a specific substituent at any substitutable position (any hydrogen atom is replaced with a substituent). When not otherwise specified, the "substituent" may be a substituent selected from the following (substituent group a).

[0080] (Substituent group a): halogen atoms; cyano groups; hydroxy groups; carboxy groups; nitro groups; C １－４ C optionally substituted with an alkoxy group １－６ Alkoxy group; C １－６ haloalkoxy group; C １－６ Alkylsulfonyl group; C １－６ haloalkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; C ６－１４ Aryl-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a diC １－６ an alkylamino group, (iv) C １－６ an alkoxy group, and (v) C １－６ haloalkoxy group, and one or two C optionally substituted with a substituent selected from the group consisting of １－６ a carbamoyl group optionally substituted with an alkyl group; １－６ Alkylamino group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ Aryl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６(vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ Aryloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ６－１４ Arylsulfonyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group;１－６ alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group; １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８Cycloalkyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８ Cycloalkyloxy group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; and (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group.

[0081] The number of substituents is not particularly limited as long as it is a substitutable number, but is usually 1 to 5, and preferably 1 to 3. When multiple substituents are present, the respective substituents may be the same or different.

[0082] In the present specification, the term "a pharmaceutically acceptable salt thereof" means a salt that can be used as a medicine. When the compound (I) of the present invention has an acidic or basic group, it can be converted into a basic salt or an acid salt by reacting it with a base or an acid, and therefore the term "a pharmaceutically acceptable salt thereof" refers to such a salt.

[0083] Examples of the pharmaceutically acceptable "basic salt" of compound (I) of the present invention include alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt, etc.; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, aspartic acid salt, etc., and the like, and alkali metal salts are preferred.

[0084] Examples of the pharmaceutically acceptable "acid salt" of compound (I) of the present invention include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, etc.; and the like, and preferably hydrohalides (particularly hydrochloride).

[0085] As used herein, "prevention" includes prevention of disease onset and delay of disease onset. An "effective amount" (also referred to as a "prophylactically effective amount") refers to the dose of compound (I) of the present invention or a pharmaceutically acceptable salt thereof sufficient to achieve the purpose of prevention.

[0086] As used herein, "treatment" includes curing a disease, ameliorating the pathological condition of a disease (e.g., one or more symptoms), and inhibiting the progression of a disease (or its severity). An "effective amount" (also referred to as a "therapeutically effective amount") refers to the dose of compound (I) of the present invention or a pharmaceutically acceptable salt thereof that is sufficient to achieve the therapeutic purpose.

[0087] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" may be a human or a non-human animal, particularly a mammal (e.g., a human, a mouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey, etc.).

[0088] As used herein, the term "EP4 antagonist" refers to a drug comprising a compound having the effect of inhibiting EP4-mediated PGE2 signaling, which suppresses innate and adaptive immunity and induces tumor progression. In particular, compound (I) of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent antagonistic activity (antagonist activity) against EP4, a PGE2 receptor. The EP4 antagonist activity can be measured, for example, by the method described in Test Example 1 below.

[0089] As used herein, examples of "diseases whose symptoms can be alleviated by EP4 antagonism" include cancers (particularly lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, leukemia, etc.), since tumor progression is suppressed by EP4 antagonism.

[0090] (Compound of the Present Invention (Compound (I))) Hereinafter, each group in the above formula (I) of compound (I) will be explained.

[0091] R １ , R ２ , and R ３ are each independently a hydrogen atom, a halogen atom, or one or more substituents selected from the above (substituent group a), C １－４ Alkyl group, C １－４ Alkoxy group or mono- or di-C １－４ represents an alkylamino group.

[0092] R １ , R ２ , and R ３ are preferably each independently a hydrogen atom; a halogen atom; １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ alkylamino group, and more preferably, each independently represents a hydrogen atom; a halogen atom;１－４ alkyl group; １－４ Fluoroalkyl group; or mono- or di-C １－４ Alkoxy-C １－４ alkylamino group, and more preferably R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), and R ２ and R ３ are both hydrogen atoms.

[0093] R ４ is a hydrogen atom, C optionally substituted with one or more substituents selected from the above (substituent group a) １－４ Alkyl group, C １－６ an alkylsulfonyl group, a halogen atom, or C １－６ C optionally substituted with an alkoxy group １－６ It represents an alkyl-carbonyl group.

[0094] R ４ is preferably a hydrogen atom; １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４(vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ alkyl-carbonyl group, more preferably C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ alkyl group, C １－４an alkylsulfonyl group, or a halogen atom or C １－４ C optionally substituted with an alkoxy group １－４ alkyl-carbonyl group, more preferably a hydroxy group or C １－４ C optionally substituted with an alkoxy group (e.g., a methoxy group) １－４ alkyl group, and even more preferably a hydroxy group or C １－４ It is an ethyl group which may be substituted with an alkoxy group (for example, a methoxy group).

[0095] X １ａ , X １ｂ , and X ２ are each independently a hydrogen atom; a halogen atom; or C which may be substituted with one or more substituents selected from the above (substituent group a). １－４ Alkyl group or C １－４ Represents an alkoxy group.

[0096] X １ａ , X １ｂ , and X ２ are preferably each independently a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ X is a fluoroalkoxy group, and more preferably, X is a fluoroalkoxy group. １ａ and / or X １ｂ is a fluorine atom, and X ２ is a hydrogen atom, and more preferably, X １ａ and X １ｂ are both fluorine atoms, and X ２ is a hydrogen atom.

[0097] Y １ is NR ５ , O, or S.

[0098] Y １ is preferably NR ５ is.

[0099] Y ２ is CR ６, or N.

[0100] Y ２ is preferably CR ６ is.

[0101] R ５ represents a hydrogen atom; or represents a C optionally substituted with one or more substituents selected from the above (substituent group a). １－４ represents an alkyl group.

[0102] R ５ is preferably a hydrogen atom; １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ alkyl group, more preferably C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ alkyl group, more preferably C １－４ an alkoxy group (e.g., a methoxy group), or C １－４ Alkoxy-C １－４ It is an ethyl group substituted with an alkoxy group (e.g., a methoxyethoxy group).

[0103] R ６ each of which may be substituted with a hydrogen atom; a halogen atom; or one or more substituents selected from the above (substituent group a), １－４ Alkyl group or C １－４ Represents an alkoxy group.

[0104] R ６ is preferably a hydrogen atom; a halogen atom; １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, and more preferably a hydrogen atom; a fluorine atom; １－４ an alkyl group; or C １－４ A fluoroalkyl group is preferable, and a hydrogen atom is more preferable.

[0105] L is a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ -, -OCH ２ - or -CH ２ Represents O-.

[0106] L is preferably a single bond, —CH ２ -, -CH=CH-, -CH ２ CH ２ - or -OCH ２ -, more preferably a single bond, -CH ２ - or -CH=CH-, and more preferably a single bond.

[0107] Z represents a carboxy group, a hydroxy group, or a group bioisosteric to a carboxy group.

[0108] Z is preferably a carboxy group; １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0109]

[0110] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ and a fluoroalkyl group; or a tautomeric group thereof, more preferably a carboxy group; １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); carbamoyl group (—CONH ２ a cyano group; or a group represented by the following formula:

[0111]

[0112] (wherein each symbol has the same meaning as defined above) or a tautomeric group thereof, and more preferably a carboxy group; a carbamoyl group (—CONH ２), a cyano group; or a group of the formula:

[0113]

[0114] or a tautomeric group thereof, and particularly preferably a carboxy group.

[0115] The following compound is suitable as compound (I): [Compound (IA)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C１－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0116]

[0117] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0118] [Compound (IA')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C１－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0119]

[0120] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0121] [Compound (IB)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C１－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0122]

[0123] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0124] [Compound (IB')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C１－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0125]

[0126] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0127] [Compound (IC)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C１－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0128]

[0129] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0130] [Compound (IC')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0131]

[0132] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0133] [Compound (ID)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C１－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６(c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0134]

[0135] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0136] [Compound (ID')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group;１－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５, O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0137]

[0138] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0139] [Compound (IE)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0140]

[0141] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0142] [Compound (IE')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C１－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0143]

[0144] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0145] [Compound (IF)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C１－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６(c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0146]

[0147] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0148] [Compound (IF′)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂis a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－６ Alkoxy-carbonyl group; 1 or 2 C １－６ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0149]

[0150] (In the formula, the wavy line represents the bonding position with L in the formula (I), and R ０ is C １－４ Alkyl group or C １－４ represents a fluoroalkyl group, or a tautomeric group thereof (preferably a carboxy group),

[0151] [Compound (IG)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C１－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C１－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0152]

[0153] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0154] [Compound (IG')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0155]

[0156] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0157] [Compound (IH)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C１－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８(v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0158]

[0159] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0160] [Compound (IH')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４(iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0161]

[0162] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0163] [Compound (IJ)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C１－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２-; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0164]

[0165] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0166] [Compound (IJ')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８(v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and X １ｂ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ a fluoroalkoxy group, ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group,１－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0167]

[0168] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0169] [Compound (IK)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４(iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom and C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６(c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0170]

[0171] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0172] [Compound (IK′)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５, O, or S; Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0173]

[0174] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0175] [Compound (IL)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６(c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0176]

[0177] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0178] [Compound (IL')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４(iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0179]

[0180] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0181] [Compound (IM)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group, １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ and / or X １ｂis a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２-; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0182]

[0183] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0184] [Compound (IM')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４(vi) an alkoxy group, and (vii) a cyclic ether group, １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ is a hydrogen atom; C １－４ a fluoroalkyl group; or (i) C １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ haloalkyl group, (d) C １－６ an alkoxy group, and (e) C １－６ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C１－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0185]

[0186] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0187] [Compound (IN)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group;１－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ alkyl group, C １－６ an alkylsulfonyl group, or a halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C１－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0188]

[0189] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0190] [Compound (IN')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0191]

[0192] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0193] [Compound (IO)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ alkyl group, C １－４ an alkylsulfonyl group, or C １－４ C optionally substituted with an alkoxy group １－４ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C１－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２- (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0194]

[0195] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0196] [Compound (IO')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0197]

[0198] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0199] [Compound (IP)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ Alkyl group C １－４ an alkylsulfonyl group, or C １－４ C optionally substituted with an alkoxy group １－４ an alkyl-carbonyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0200]

[0201] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0202] [Compound (IP')] R １ , R ２ , and R ３are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ , X １ｂ , and X ２ are independently a hydrogen atom, a halogen atom, or C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0203]

[0204] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0205] [Compound (IQ)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ is an alkyl group, and X １ａ and / or X １ｂis a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0206]

[0207] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0208] [Compound (IQ')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ , O, or S; Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C１－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0209]

[0210] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0211] [Compound (IR)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0212]

[0213] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0214] [Compound (IR')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C１－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ , or N, R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0215]

[0216] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0217] [Compound (IS)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0218]

[0219] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0220] [Compound (IS')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, a halogen atom, C １－４ alkyl group, C １－４ fluoroalkyl group, C １－４ an alkoxy group, or C １－４ is a fluoroalkoxy group, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group;１－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４ an alkoxy group; or C １－４ a fluoroalkoxy group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; C １－４ Alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl); 1 or 2 C １－４ a carbamoyl group optionally substituted with an alkyl group; a cyano group; or a group represented by the following formula:

[0221]

[0222] (wherein the symbols have the same meanings as defined above) or a tautomeric group thereof (preferably a carboxy group), Compound (I) or a pharmaceutically acceptable salt thereof.

[0223] [Compound (IT)] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４ Fluoroalkyl group; C １－４Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C１－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a fluorine atom; C １－４ an alkyl group; or C １－４ fluoroalkyl group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; a carbamoyl group (-CONH ２ ), a cyano group; or a group of the formula:

[0224]

[0225] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0226] [Compound (IT')] R １ , R ２ , and R ３ are each independently a hydrogen atom; a halogen atom; C １－４ alkyl group; １－４Fluoroalkyl group; C １－４ Alkoxy group; C １－４ Fluoroalkoxy group; or mono- or di-C １－４ Alkoxy-C １－４ an alkylamino group, R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; C １－４ an alkyl group; or C １－４ fluoroalkyl group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; a carbamoyl group (-CONH ２ ), a cyano group; or a group of the formula:

[0227]

[0228] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0229] [Compound (IU)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group optionally substituted with a halogen atom or a trifluoromethyl group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a hydroxy group, and a carboxy group; １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; a fluorine atom; C １－４ an alkyl group; or C １－４ fluoroalkyl group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; a carbamoyl group (-CONH ２ ), a cyano group; or a group of the formula:

[0230]

[0231] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0232] [Compound (IU')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ aralkyloxy groups (e.g., benzyloxy groups optionally substituted with a halogen atom or a trifluoromethyl group), and C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group). １－４ is an alkyl group, and X １ａ and / or X １ｂ is a fluorine atom (preferably, X １ａ and X １ｂ are both fluorine atoms), X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But, C １－４ Alkoxy group (e.g., methoxy group), (a) halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４ an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ６－１４ an aryloxy group (e.g., a phenoxy group), (a) a halogen atom, (b) C １－４ (c) an alkyl group; １－４ haloalkyl group, (d) C １－４an alkoxy group, and (e) C １－４ haloalkoxy group, C optionally substituted with 1 to 3 substituents selected from the group consisting of ７－１８ an aralkyloxy group (e.g., a benzyloxy group), C １－４ Alkoxy-C １－４ C optionally substituted with a substituent selected from the group consisting of an alkoxy group (e.g., a methoxyethoxy group), a cyclic ether group (e.g., a tetrahydropyranyl group), and a 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group). １－４ is an alkyl group, and R ６ is a hydrogen atom; C １－４ an alkyl group; or C １－４ fluoroalkyl group, wherein L is a single bond; ２ -; -CH=CH-; -CH ２ CH ２ -; or -OCH ２ - (preferably a single bond), and Z is a carboxy group; a carbamoyl group (-CONH ２ ), a cyano group; or a group of the formula:

[0233]

[0234] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0235] [Compound (IV)] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ is a hydroxy group, or C １－４ an ethyl group optionally substituted with an alkoxy group (e.g., a methoxy group), １ａ and X １ｂ are both fluorine atoms, and X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R５ But C １－４ an alkoxy group (e.g., a methoxy group), or C １－４ Alkoxy-C １－４ an ethyl group substituted with an alkoxy group (e.g., a methoxyethoxy group), R ６ is a hydrogen atom, L is a single bond, and Z is a carboxy group; a carbamoyl group (—CONH ２ ), a cyano group; or a group of the formula:

[0236]

[0237] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0238] [Compound (IV')] R １ is a hydrogen atom; or C １－４ an alkyl group (e.g., a methyl group), R ２ and R ３ are both hydrogen atoms, and R ４ But C １－４ an ethyl group optionally substituted with an alkoxy group (e.g., a methoxy group), １ａ and X １ｂ are both fluorine atoms, and X ２ is a hydrogen atom, and Y １ But NR ５ and Y ２ But, CR ６ and R ５ But C １－４ an alkoxy group (e.g., a methoxy group), or C １－４ Alkoxy-C １－４ an ethyl group substituted with an alkoxy group (e.g., a methoxyethoxy group), R ６ is a hydrogen atom, L is a single bond, and Z is a carboxy group; a carbamoyl group (—CONH ２ ), a cyano group; or a group of the formula:

[0239]

[0240] or a tautomeric group thereof (preferably a carboxy group) selected from the group consisting of:

[0241] Specific examples of suitable compound (I) include the compounds of Examples 1 to 64 described below, or pharmaceutically acceptable salts thereof.

[0242] When compound (I) of the present invention has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or a mixture thereof is encompassed in the compound of the present invention. Furthermore, when compound (I) has optical isomers, optical isomers resolved from the racemate are also encompassed in compound (I). Compound (I) may be a solvate (e.g., hydrate, ethanol solvate, dimethyl sulfoxide solvate, etc.) or a non-solvate, and both are encompassed in compound (I).

[0243] Compound (I) of the present invention may contain an isotope (e.g., ２ H. ３ H. １３ C. １４ C. １５ N. １８ F. ３２ P. ３５ S. １２３ I, １２５ I, １３１ The compound may be a compound labeled or substituted with an isotope (e.g., I), and a compound labeled or substituted with an isotope can be used as a tracer (PET tracer) used in, for example, Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.

[0244] The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be crystalline, and may be in a single crystalline form or a mixture of multiple crystalline forms.

[0245] (Method for producing compound (I) of the present invention) Hereinafter, a method for producing compound (I) of the present invention or a pharmaceutically acceptable salt thereof will be described. As an example of a method for producing compound (I), a representative production method (A) will be described below, but the production method is not limited to this. Compound (I) can be produced by the following production method (A), Examples 1 to 64 described below, or methods similar thereto.

[0246] The raw materials and reagents used in each step of the following production method (A), as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those described above (pharmaceutically acceptable salts). When the compound obtained in each step is a free compound, it can be converted into the desired salt by a known method. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a known method. The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, or chromatography, according to a conventional method.

[0247] The contents of all patent, non-patent, or literature references expressly cited in this specification are hereby incorporated by reference in their entirety.

[0248] [Production Method (A)] In this production method, compound (1) shown in the following scheme is used as a starting material, and is subjected to reactions in (Step 1) to (Step 8) to obtain compound (I) (group Y in formula (I)). １ NR ５ Compound (1) may be a commercially available product or may be synthesized by a method known per se.

[0249]

[0250] (In the formula, X represents a leaving group (e.g., a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, etc.), and the other symbols are as defined above.)

[0251] (Step 1) In this step, compound (1) and alkylamine (R ５ -NH ２ ) to produce compound (2).

[0252] Alkylamine (R ５ -NH ２ The amount of the compound (1) used is 1 to 2 moles, preferably 1.1 to 1.5 moles, per mole of compound (1).

[0253] The reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Among these, dimethyl sulfoxide is preferred.

[0254] The reaction temperature is usually 0° C. to 100° C., preferably room temperature to 60° C., and the reaction time is usually 4 to 24 hours.

[0255] (Step 2) This step is a step of converting compound (2) to compound (3) by reducing the nitro group of compound (2). A method of hydrogenating in a solvent under a hydrogen atmosphere in the presence of a palladium catalyst, or a method of reducing with a metal such as zinc, iron, or tin in the presence of an acid is used.

[0256] Examples of the palladium catalyst used in the hydrogenation reaction include 10% palladium on carbon and palladium hydroxide, with 10% palladium on carbon being preferred. The reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples include alcohols such as methanol and ethanol; and ethers such as tetrahydrofuran. Of these, methanol is preferred. The amount of the palladium catalyst used is 0.01 mol to 0.2 mol, preferably 0.05 mol to 0.1 mol, per mol of compound (2). The reaction temperature is usually 0°C to 60°C, preferably room temperature, and the reaction time is usually 2 hours to 12 hours.

[0257] In the method of reduction with a metal such as zinc, iron, or tin, zinc, iron, or tin is preferred, with zinc or iron being particularly preferred. Examples of the acid include hydrochloric acid, acetic acid, and ammonium chloride, with ammonium chloride or hydrochloric acid being preferred. Examples of the solvent used include alcohols such as methanol, ethanol, and 2-propanol; water; acetic acid; or a mixed solvent thereof. Among these, methanol or water is preferred, and a mixed solvent of methanol and water is more preferred. The reaction temperature is usually 0°C to 100°C, preferably room temperature to 80°C, and the reaction time is usually 2 hours to 24 hours.

[0258] (Step 3) This step is a step of producing a precursor of compound (6) (a compound in which the methoxycarbonyl group in compound (6) is replaced with a carboxy group) by heating compound (4) and compound (5) in the presence of an acid. This step can be carried out according to the Fischer indole synthesis method.

[0259] Examples of the acid to be used include Bronsted acids such as sulfuric acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, p-toluenesulfonic acid, and perchloric acid, and Lewis acids such as zinc chloride, aluminum trichloride, titanium tetrachloride, and boron trifluoride. Among these, preferred are sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid, and zinc chloride, and particularly preferred are sulfuric acid and acetic acid.

[0260] The amount of the acid used varies depending on the type of acid, but is 0.1 to 100 moles, preferably 1 to 10 moles, per mole of compound (4).

[0261] The amount of compound (4) used is 1 mole to 1.5 moles, preferably 1 mole to 1.2 moles, per mole of compound (5).

[0262] This step can be carried out using an acid as a solvent (no solvent) or in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples include alcohols such as methanol, ethanol, isopropanol, etc.; water; ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as toluene, xylene, chlorobenzene, etc.; and mixed solvents thereof. Among these, no solvent, or water, methanol, or ethanol is preferred.

[0263] The reaction temperature is usually 70 to 120°C, preferably 90 to 110°C, and the reaction time is usually 0.5 to 4 hours.

[0264] (Step 4) This step is a step of producing compound (6) by heating the precursor of compound (6) obtained in the above (Step 3) under reflux in methanol in the presence of an acid.

[0265] The acid to be used includes concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, etc., and among these, concentrated sulfuric acid is preferred.

[0266] The reaction time is usually 1 to 4 hours.

[0267] (Step 5) This step is carried out by reacting compound (6) with alkyl halide (R ４ -X'; where X' represents a halogen atom) to produce compound (7).

[0268] Examples of the base to be used include sodium hydride, triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, cesium fluoride, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, potassium tert-butoxide, and the like. Of these, sodium hydride is preferred.

[0269] The amount of the base used is 1 to 2 moles, preferably 1.1 to 1.5 moles, per mole of compound (6).

[0270] Alkyl halide (R ４ The amount of —X′) used is 1 to 5 moles, preferably 1.5 to 3 moles, per mole of compound (6).

[0271] The reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include ethers such as tetrahydrofuran, 1,2-dimethoxymethane, and 1,4-dioxane; and amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. Among these, tetrahydrofuran is preferred.

[0272] The reaction temperature is usually 0° C. to 60° C., preferably room temperature, and the reaction time is usually 2 to 24 hours.

[0273] (Step 6) This step is a step of producing compound (8) by reacting compound (7) with a reducing agent in a solvent.

[0274] The reducing agent used may be a boron-based hydride or an aluminum-based hydride, etc. Specific examples of the reducing agent include, but are not limited to, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium tri(tert-butoxy)aluminum hydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, sodium borohydride / iodine, sodium borohydride / trifluoroacetic acid, etc., and among these, lithium aluminum hydride is preferred.

[0275] The amount of the reducing agent used is 1 to 5 moles, preferably 1.5 to 3 moles, per mole of compound (7).

[0276] The solvent to be used is not particularly limited, but examples thereof include ethers such as triglyme, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane, and among these, tetrahydrofuran is preferred.

[0277] The reaction temperature is usually 0° C. to 60° C., preferably room temperature, and the reaction time is usually 2 to 24 hours.

[0278] (Step 7) This step is a step of producing compound (9) by reacting compound (8) with an oxidizing agent in a solvent.

[0279] The oxidizing agent used is not particularly limited, but may be appropriately selected from known oxidizing agents described in, for example, "Experimental Chemistry Lectures, 4th Edition (21. Organic Synthesis III: Aldehydes, Ketones, and Quinones)," Maruyama Kazuhiro et al., Chemical Society of Japan, Maruzen Co., Ltd., 1990, and the like, and this step is carried out in accordance with such an oxidizing agent. Specific examples include oxidation reactions using chromic acid such as chromic anhydride, chromium (VI) oxide-pyridine complex (Collins reagent), pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC); oxidation reactions using activated manganese dioxide; oxidation reactions using a combination of dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or oxalyl chloride and dimethyl sulfoxide (DMSO); oxidation reactions using sodium hypochlorite; and oxidation reactions using a hyperatomic iodine compound (Dess-Martin reagent). Among these, oxidation reactions using a combination of a sulfur trioxide-pyridine complex and dimethyl sulfoxide are preferred.

[0280] The amount of the oxidizing agent used is 1 to 5 moles, preferably 2 to 3 moles, per mole of compound (8).

[0281] The solvent to be used is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the above organic solvents in any ratio, among which acetonitrile is preferred.

[0282] The reaction temperature is usually 0° C. to 60° C., preferably 0° C. to room temperature, and the reaction time is usually 0.5 to 12 hours.

[0283] (Step 8) This step is a step of producing compound (I) by reacting compound (9) with compound (3) in a solvent in the presence of sodium disulfite.

[0284] The amount of compound (3) used is 0.5 to 1.5 moles, preferably 0.6 to 1 mole, per mole of compound (9).

[0285] The amount of sodium disulfite used is 2 to 3 moles, preferably 2 to 2.5 moles, per mole of compound (9).

[0286] The solvent to be used is not particularly limited, but examples thereof include ethers such as triglyme, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane, and among these, tetrahydrofuran is preferred.

[0287] The reaction temperature is usually 0° C. to 60° C., preferably 0° C. to room temperature, and the reaction time is usually 0.5 to 12 hours.

[0288] When the group Z in the compound (I) obtained by the above production method is a group other than a carboxy group, it can be converted to the corresponding carboxylic acid by a known conversion method, for example, by subjecting it to hydrolysis reaction or the like.

[0289] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means, such as solvent extraction, liquid conversion, resolving, crystallization, recrystallization, chromatography, etc. When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also contained in compound (I), and each can be obtained as a single product by known synthesis and separation methods. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I).

[0290] (Medicine (Pharmaceutical Composition) of the Present Invention) The medicament of the present invention is a medicament for preventing and / or treating a disease whose symptoms can be alleviated by EP4 antagonism, which contains compound (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "the compound of the present invention") as an active ingredient. Specifically, the medicament of the present invention is at least one of a medicament for preventing the onset of a disease whose symptoms can be alleviated by EP4 antagonism, and a medicament for ameliorating the symptoms of the disease, which contains the active ingredient.

[0291] The pharmaceutical of the present invention may be either a pharmaceutical consisting of the compound of the present invention alone, or a pharmaceutical composition containing the compound of the present invention and a pharmaceutically acceptable carrier, etc. (hereinafter also referred to as the "pharmaceutical composition of the present invention.") The pharmaceutical of the present invention can be administered in an effective amount (a prophylactically effective amount or a therapeutically effective amount) to a subject (e.g., a human, a mouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey, etc.).

[0292] As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as formulation materials are used, and are incorporated as excipients, lubricants, binders, disintegrants in solid formulations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can also be used as needed.

[0293] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose. Suitable examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Suitable examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate. Suitable examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates; and polyoxyethylene hydrogenated castor oil.Suitable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates. Suitable examples of soothing agents include benzyl alcohol. Suitable examples of preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acid. Suitable examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, and Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.

[0294] Dosage forms of the pharmaceutical composition of the present invention include, for example, oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions, and films (e.g., orally disintegrating films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. These can each be safely administered orally or parenterally (e.g., topically, rectally, or intravenously). These preparations may be immediate-release preparations or controlled-release preparations such as sustained-release preparations (e.g., sustained-release microcapsules).

[0295] The pharmaceutical composition of the present invention can be produced by a method conventionally used in the field of formulation technology, for example, a method described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the formulation. When producing an oral formulation, coating may be performed, if necessary, for the purposes of taste masking, enteric coating, or sustained release.

[0296] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. Sugar coating bases include sucrose, which may be used in combination with one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. Examples of water-soluble film coating bases include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based polymers such as methacrylic acid copolymer L (Eudragit L (trade name)), methacrylic acid copolymer LD (Eudragit L-30D55 ​​(trade name)), and methacrylic acid copolymer S (Eudragit S (trade name)); and natural products such as shellac. Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)). Two or more of the above-mentioned coating bases may be mixed in an appropriate ratio. Furthermore, a light-shielding agent such as titanium oxide or iron sesquioxide may be used during coating.

[0297] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent or a diagnostic agent for various diseases in mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0298] The dose of the compound of the present invention can be appropriately selected depending on the subject (the subject's age, body weight, general health condition, sex, severity of symptoms, etc.), the administration route, the type of disease, the type of concomitant medication, etc. The dose of the compound of the present invention, for example, in the case of humans, when administered orally or parenterally to an adult patient, is usually about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, more preferably 0.5 to 20 mg / kg body weight per dose, and this amount is desirably administered once to three times a day. The administration time may be before, after, or between meals. The administration period is not particularly limited.

[0299] The compound of the present invention is useful for the prevention and / or treatment of diseases whose symptoms can be alleviated by EP4 antagonism.

[0300] The compounds of the present invention exhibit their activity as antagonists of the prostaglandin E2 receptor, EP4, in a biological environment (i.e., in the presence of one or more enzymes capable of cleaving the covalent bond attached to the carbonyl group, such as an amidase, esterase, or any suitable equivalent thereof capable of removing the prodrug group from the carboxylic acid group).

[0301] The compound of the present invention is useful for preventing the onset of or treating diseases whose symptoms can be alleviated by EP4 antagonism, particularly cancer, including cancers selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

[0302] The compounds of the present invention can be used as a single therapeutic agent for diseases, particularly cancer, whose symptoms can be alleviated by EP4 antagonism, or in combination with one or more chemotherapeutic agents and / or radiation therapy and / or targeted therapy that can complement and / or enhance the therapeutic effect of the compounds of the present invention, so long as the efficacy of the compounds is not impaired. Such combined treatments may be carried out simultaneously, separately, or over a period of time.

[0303] Accordingly, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and: a compound of the invention; and one or more cytotoxic chemotherapeutic agents.

[0304] Therefore, the present invention also relates to a kit comprising a pharmaceutically acceptable carrier and: a pharmaceutical composition comprising a compound of the invention; and instructions on how to use said pharmaceutical composition for the prevention or treatment of cancer in combination with chemotherapy and / or radiotherapy and / or targeted therapy.

[0305] The term "radiotherapy" (or "radiation therapy" or "radiation oncology") means the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer; includes external and internal radiation therapy.

[0306] The term "targeted therapy" refers to the prevention (adjuvant therapy) and / or treatment of cancer with one or more anti-neoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapy); or inhibit angiogenesis, the growth and formation of new blood vessels within tumors; or deliver toxic substances directly to cancer cells to kill them. An example of a targeted therapy that is particularly suitable for combination with the compounds of the present invention is immunotherapy, in particular immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Zelenay et al., 2015, Cell 162, 1-14; Yongkui Li et al., Oncoimmunology 2016, 5(2): e1074374).

[0307] The term "targeted therapy" when used in combination with the compounds of the present invention refers, inter alia, to the following agents: a) epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (e.g., Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab, and Cetuximab); b) RAS / RAF / MEK pathway inhibitors (e.g., vemurafenib, sorafenib, dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304, trametinib (GSK1120212), cobimetinib (GDC-0973 / XL518), binimetinib (MEK162, ARRY-162), selumetinib (AZD6244)); c) aromatase inhibitors (e.g. Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole); d) angiogenesis inhibitors, in particular VEGF signaling inhibitors such as Bevacizumab (Avastin), Ramucirumab, Sorafenib or Axitinib; e) immune checkpoint inhibitors (e.g., anti-PD-1 antibodies such as pembrolizumab, lambrolizumab, MK-3475, nivolumab, pidilizumab (CT-011), AMP-514 / MED10680, PDR001, SHR-1210, REGN2810, and BGBA317;Fusion proteins that target PD-1, such as AMP-224, small molecule anti-PD-1 agents such as the compounds disclosed in WO2015 / 033299, WO2015 / 044900, and WO2015 / 034820; BMS-936559, atezolizumab (MPDL3280A, RG7446), MEDI4736, Abel Anti-PD-L1 antibodies such as avelumab (MSB0010718C) and durvalumab (MEDI4736); anti-PD-L2 antibodies such as AMP224; anti-CTLA-4 antibodies such as ipilimumab and tremilmumab; BMS-986016, IMP701, MK-4280, ImmuFact anti-lymphocyte-activated gene 3 (LAG-3) antibodies such as IMP321; anti-T cell immunoglobulin mucin-3 (TIM-3) antibodies such as MBG453; anti-CD137 / 4-1BB antibodies such as BMS-663513 / urelumab and PF-05082566; anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibodies such as RG6058 (anti-TIGIT, MTIG7192A); f) vaccine therapy approaches (e.g., dendritic cell vaccine therapy, peptide or protein vaccine therapy (e.g., using gp100 peptides or MAGE-A3 peptides); g) reintroduction of patient-derived or allogenic (non-autologous) cancer cells genetically modified to secrete immunomodulatory factors, such as granulocyte monocyte colony-stimulating factor (GMCSF) gene-transfected tumor cell vaccine (GVAX) or Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX) or Toll-like receptor-enhanced GM-CSF tumor-based vaccine (TEGVAX); h) T-cell-based adoptive immunotherapy, such as chimeric antigen receptor (CAR)-modified T-cells (e.g., CTL019); i) cytokine or immunocytokine-based treatments (e.g., interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 15);j) Toll-like receptor (TLR) agonists (e.g., resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodeoxynucleotides); k) thalidomide analogs (e.g., lenalidomide, pomalidomide); l) indoleamine-2,3-dioxygenase (IDO) and / or tryptophan-2,3-dioxygenase (TDO) inhibitors (e.g., RG6078 / NLG919 / GDC-0919; Indoximod / 1MT (1-methyltryptophan), INCB024360 / Epacadostat, PF-06840003 (EOS200271), F001287); m) activators of T cell costimulatory receptors (e.g., anti-OX40 / CD134 (tumor necrosis factor receptor superfamily member 4, such as RG7888 (MOXR0916), 9B12, MEDI6469, GSK3174998, MEDI0562); anti-OX40-ligand / CD252; anti-glucocorticoids (such as TRX518, MEDI1873, MK-4166, BMS-986156) Coid-induced TNFR family-related gene (GITR); anti-CD40 (TNF receptor superfamily member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122, CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40-ligand antibodies (such as BG9588); anti-CD27 antibodies (such as Varlilumab); n) molecules that bind to tumor-specific antigens and T-cell surface markers, such as bispecific antibodies (e.g., RG7802 targets CEA and CD3) or antibody fragments, antibody mimetic proteins (e.g., designed ankyrin repeat proteins (DARPINS), bispecific T-cell engagers (BITEs, e.g., AMG103, AMG330));o) antibodies or low molecular weight inhibitors targeting colony-stimulating factor 1 receptor (CSF-1R) (e.g., emactuzumab (RG7155), cabiralizumab (FPA-008), PLX3397); p) agents targeting immune cell checkpoints on natural killer cells, such as antibodies against killer cell immunoglobulin-like receptors (KIR) (e.g., lirilumab (IPH2102 / BMS-986015)); q) agents targeting adenosine receptors or the ectonucleases CD39 and CD73 that convert ATP to adenosine (MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (adenosine A2a receptor antagonist);

[0308] Immune checkpoint inhibitors such as those listed under e) and, in particular, those that target programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 are preferred when used in combination with the compounds of the invention.

[0309] The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapeutic agents"). Chemotherapy is often combined with other cancer treatments, such as radiation therapy or surgery. The term specifically refers to traditional cytotoxic chemotherapeutic agents that act by killing rapidly dividing cells, which is one of the main characteristics of most cancer cells. Chemotherapy can use one drug at a time (single-agent chemotherapy) or several drugs at a time (combination chemotherapy or polychemotherapy). Chemotherapy that uses drugs that are converted to cytotoxic activity only by exposure to light is called photochemotherapy or photodynamic therapy.

[0310] As used herein, the term "cytotoxic chemotherapeutic agent" or "chemotherapeutic agent" refers to an active anti-neoplastic agent that causes cell death or cell necrosis. When used in combination with the compounds of the present invention, this term specifically refers to conventional cytotoxic chemotherapeutic agents such as: a) alkylating agents (e.g., mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, dacarbazine, temozolomide, fotemustine, thiotepa, or altretamine; in particular, cyclophosphamide, carmustine, melphalan, dacarbazine, or temozolomide); b) platinum agents (especially cisplatin, carboplatin or oxaliplatin); c) antimetabolites (e.g., 5-fluorouracil, folic acid / leucovorin, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, or pemetrexed; in particular, 5-fluorouracil, folic acid / leucovorin, capecitabine, methotrexate, gemcitabine, or pemetrexed); d) antitumor antibiotics (e.g. daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone; especially doxorubicin);e) mitotic inhibitors (e.g., paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine; in particular, paclitaxel, docetaxel, ixabepilone or vincristine); f) topoisomerase inhibitors (e.g. etoposide, teniposide, topotecan, irinotecan, diflomotecan or eromotecan; in particular etoposide or irinotecan);

[0311] Preferred cytotoxic chemotherapeutic agents for use in combination with the compounds of the present invention are the alkylating agents mentioned above (particularly fotemustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine and their prodrugs, such as temozolomide, in particular; or pharmaceutically acceptable salts of these compounds; especially temozolomide); mitotic inhibitors (particularly paclitaxel, docetaxel, ixabepilone; or pharmaceutically acceptable salts of these compounds; especially paclitaxel); platinum agents (particularly cisplatin, oxaliplatin or carboplatin); and etoposide and gemcitabine.

[0312] Chemotherapy may be administered with curative intent or with the aim of prolonging life or ameliorating symptoms.

[0313] - Combined modality chemotherapy is the use of drugs in conjunction with other cancer treatments such as radiation therapy or surgery.

[0314] - Induction chemotherapy is the first-line treatment of cancer with chemotherapeutic drugs. This type of chemotherapy is used for curative purposes.

[0315] Consolidation chemotherapy is administered after remission with the goal of improving overall disease-free interval and overall survival. The drugs administered are the same drugs that produced remission.

[0316] - Intensification chemotherapy is the same as consolidation chemotherapy, but different drugs are used than induction chemotherapy.

[0317] Combination chemotherapy involves treating patients with many different drugs at the same time. These drugs have different mechanisms and side effects. The biggest advantage is that it minimizes the chance of developing resistance to any one drug. Also, lower doses of drugs are often used, reducing toxicity.

[0318] Neoadjuvant chemotherapy is given prior to local treatment such as surgery with the aim of shrinking the primary tumor. It is also given for cancers at high risk of micrometastatic disease.

[0319] - Adjuvant chemotherapy is given after local treatment (radiation therapy or surgery). It can be used when there is little evidence of cancer, but there is a risk of recurrence. It is also useful for killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy, reducing the chance of recurrence from these disseminated cells.

[0320] - Maintenance chemotherapy is repeated low dose treatment to prolong remission.

[0321] - Salvage or palliative chemotherapy is not intended to cure, but is given simply to reduce tumor burden and increase life expectancy. A better toxicity profile is generally required for such regimens.

[0322] The term "concurrently," when used in connection with a dosage form, means in this patent application that the dosage form in question is for near-simultaneous administration of two or more active ingredients and / or treatments; by simultaneous administration, it is understood that the subject is exposed to two or more active ingredients and / or treatments at the same time. When administered simultaneously, the two or more active ingredients may be administered as a fixed dose combination, or as an equivalent non-fixed dose combination (e.g., by using two or more different pharmaceutical compositions to be administered at near-simultaneous times via the same route of administration), or as a non-fixed dose combination using two or more different routes of administration, which results in the subject being exposed to two or more active ingredients and / or treatments essentially at the same time. For example, the EP4 antagonists of the present invention would optionally be used "concurrently" when used in combination with chemotherapy and / or an appropriate targeted therapy.

[0323] "Fixed-dose combination," when referring to a dosage form, means in this application that the dosage form is the administration of a single pharmaceutical composition having two or more active ingredients.

[0324] The term "separately" in connection with a dosage form means in this patent application that the dosage form in question is the administration of two or more active ingredients and / or treatments at different times; separate administration leads to a treatment phase in which a subject is simultaneously exposed to two or more active ingredients and / or treatments (e.g., for at least 1 hour, particularly at least 6 hours, and especially at least 12 hours), but it is understood that separate administration may also lead to a treatment phase in which a subject is exposed to only one of two or more active ingredients and / or treatments for a certain period of time (e.g., for at least 12 hours, particularly at least one day). Separate administration particularly refers to situations in which at least one of the active ingredients and / or treatments is administered at a periodicity substantially different from daily administration (e.g., once or twice daily) (e.g., one active ingredient and / or treatment is administered once or twice daily, and another is administered, for example, every other day, once a week, or at longer intervals). For example, when used in combination with radiation therapy, the EP4 antagonists of the present invention will sometimes be administered "separately."

[0325] Administration "over a period of time" in this patent application refers to the sequential administration of two or more active ingredients and / or treatments at different times. This term particularly refers to administration methods in which the administration of one active ingredient and / or treatment is completed before the administration of one or more other active ingredients and / or treatments begins. In this case, it is possible to administer one active ingredient and / or treatment for several months before administering the other or other active ingredient and / or treatment.

[0326] Administration "over a period of time" also encompasses situations in which the compounds of the invention are used in treatment beginning after completion of an initial chemotherapy (e.g., induction chemotherapy) and / or radiotherapy treatment and / or targeted therapy treatment, optionally in combination with further / ongoing chemotherapy and / or radiotherapy treatment and / or targeted therapy treatment (e.g., in combination with consolidation chemotherapy, intensification chemotherapy, adjuvant chemotherapy or maintenance chemotherapy; or radiotherapy as well); and such further / ongoing chemotherapy and / or radiotherapy treatment and / or targeted therapy treatment may be administered simultaneously, separately, or over a period of time, which is what is meant by "not administered in the same cycle."

[0327] The dosage of the other drug (active ingredient) used in the combination therapy can be appropriately selected based on the clinically used dose. The mixing ratio of the compound of the present invention to the other drug is not particularly limited and can be appropriately selected depending on the subject of administration (subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of other drug, etc.

[0328] The compounds of the invention are also useful in a method of modulating the immune response in a tumor-bearing subject, comprising administering an effective amount of a compound of the invention, which effective amount reactivates the immune system in the tumor of the subject; in particular, said effective amount: - prevents the localization of tumor-associated macrophages into tumor-promoting M2 macrophages; and / or - downregulates the activation, proliferation and / or effector function of immunosuppressive cells accumulated in the tumor (particularly regulatory T cells (Treg) and / or myeloid-derived suppressor cells (MDSC)); and / or - upregulates IFN-γ and / or TNF-α and / or IL-12 and / or IL-2 expression in immune cells such as natural killer cells, T-cells, dendritic cells and macrophages (inducing tumor cell apoptosis and / or suppression of tumorigenesis); and / or - directly or indirectly prevents the activation of cytotoxic T-cells, IL-2 response and suppression of proliferation (thereby reducing local immunosuppression).

[0329] The compounds of the present invention are also useful in a method for attenuating tumor growth and / or reducing tumor size in a tumor-bearing subject, comprising administering an effective amount of a compound of the present invention; which downregulates tumor angiogenesis (particularly by reducing endothelial cell motility and / or survival and / or by reducing VEGF (vascular endothelial growth factor) expression); and / or which attenuates tumor cell survival and / or induces tumor cell apoptosis (particularly through inhibition of PI3K / AKT and MAPK signaling).

[0330] The compounds of the present invention are also useful in a method of modulating the immune response in a tumor-bearing subject, comprising administering an effective amount of a compound of the present invention; said effective amount reactivating the immune system in the tumor of said subject; said effective amount activating the cytotoxicity and cytokine production of natural killer cells and / or cytotoxic T-cells.

[0331] The present invention will be described below with reference to examples, test examples and formulation examples, but the present invention is not limited to these. Nuclear magnetic resonance spectroscopy (NMR) was measured using a JEOL ECZ400S FT-NMR. １ H-NMR was performed at 400 MHz using tetramethylsilane as the reference. １９ F-NMR was performed using CCl ３ Measurement was performed at 376 MHz using F as the standard. Mass spectrometry (LC-MS) was performed using a liquid chromatograph mass spectrum system (Quadrupole, LCMS6120) manufactured by Agilent Technologies. Reagents, devices, and materials used in the present invention are commercially available unless otherwise specified.

[0332] % indicates mol / mol% for yield, and % by weight for other values ​​unless otherwise specified. Furthermore, room temperature indicates a temperature between 15°C and 30°C unless otherwise specified. Other abbreviations used in the text have the following meanings: THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMF: N,N-dimethylformamide MTBE: methyl tert-butyl ether DBU: 1,8-diazabicyclo[5.4.0]-7-undecene HOBt: 1-hydroxybenzotriazole DIEA: N,N-diisopropylethylamine HBSS: Hank's balanced salt solution BSA: bovine serum albumin IBMX: 3-isobutyl-1-methylxanthine HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Ac: acetyl

[0333] Example 1 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0334]

[0335] Step 1: Methyl 4-[(2-methoxyethyl)amino]-3-nitrobenzoate

[0336]

[0337] Methyl 4-chloro-3-nitrobenzoate (3 g, 13.9 mmol) was added to DMSO (15 mL), and 2-methoxyethanamine (1.7 g, 22.3 mmol) was added, and the mixture was heated at 60°C for 5 hours and then stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution (15 mL), and the resulting precipitate was filtered off and washed with water (10 mL). The precipitate was dried to give the title compound (2.9 g) as yellow crystals. 1H-NMR (400MHz, CDCl3) δ: 8.88 (1H, d, J = 2.3 Hz), 8.58 (1H, br s), 8.06-8.03 (1H, m), 6.89 (1H, d, J = 9.1 Hz), 3.80 (3H, s), 3.69 (2H, t, J = 5.3 Hz), 3.54 (2H, q, J = 5.3 Hz), 3.43 (3H, d, J = 2.7 Hz); LC-MS[M+1] = 255.2.

[0338] Step 2: Methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate

[0339]

[0340] Methyl 4-[(2-methoxyethyl)amino]-3-nitrobenzoate (2.9 g, 13.9 mmol) was dissolved in methanol (66 mL), 10% palladium / carbon (0.3 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give the title compound (0.8 g) as pale purple crystals. 1 H-NMR (400 MHz, CDCl3) δ: 7.57 (1H, dd, J = 8.5, 2.1 Hz), 7.41 (1H, d, J = 1.8 Hz), 6.60 (1H, d, J = 8.7 Hz), 3.85 (3H, s), 3.67 (2H, t, J = 5.3 Hz), 3.40 (3H, s), 3.35 (2H, t, J = 5.3 Hz); LC-MS[M+1] = 225.1.

[0341] Step 3: 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid

[0342]

[0343] 4,4-Difluorocyclohexanone (2.79 g, 20.8 mmol) and 4-hydrazinobenzoic acid hydrochloride (3.55 g, 23.4 mmol) were mixed, and then 25% aqueous sulfuric acid solution (28 mL) was added, and the mixture was heated at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated solid was washed with water and 50% aqueous ethanol solution and then dried to obtain the title compound (2.79 g) as a pale pink solid. 1 H-NMR (400 MHz, CD3OD) δ:8.16 (1H, s), 7.81 (1H, d, J = 8.7 Hz), 7.31 (1H, d, J = 8.7 Hz), 3.24 (2H, t, J = 14.0 Hz), 2.99 (2H, t, J = 6.6 Hz), 2.29-2.40 (2H, m); 19 F-NMR (CD3OD) δ: -97.8 (2F, m); LC-MS[M+1] = 252.2.

[0344] Step 4: Methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0345]

[0346] 3,3-Difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid (1.6 g, 6.3 mmol) was dissolved in methanol (23 mL), concentrated sulfuric acid (1.8 mL) was added, and the mixture was heated to reflux for 2.5 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, poured into a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.7 g) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ:8.19 (1H, s), 8.06 (1H, br s), 7.88 (1H, d, J = 8.7 Hz), 7.31 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.28 (2H, t, J = 14.0 Hz), 2.99 (2H, t, J = 6.6 Hz), 2.37 (2H, m); 19 F-NMR (CDCl3) δ: -98.9 (2F, m); LC-MS[M+1] = 266.2.

[0347] Step 5: 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate methyl

[0348]

[0349] Methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (175.9 mg, 0.7 mmol) synthesized in Step 4 of Example 1 was dissolved in THF (2 mL) and added to a suspension of sodium hydride (46.6 mg, 1.2 mmol) in THF (5 mL). After stirring at room temperature for 30 minutes, iodoethane (246 mg, 1.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (166.4 mg) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ:8.20 (1H, s), 7.90 (1H, d, J = 8.7 Hz), 7.28 (1H, d, J = 8.7 Hz), 4.11 (2H, q, J = 7.2 Hz), 3.93 (3H, s), 3.29 (2H, t, J = 14.0 Hz), 2.97 (2H, t, J = 6.6 Hz), 2.44-2.34 (2H, m), 1.36 (3H, t, J = 7.1 Hz); 19 F-NMR (CDCl3) δ: -97.8 (2F, m); LC-MS[M+1] = 294.1.

[0350] Step 6 (9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0351]

[0352] Lithium aluminum hydride (124.4 mg, 3.3 mmol) was suspended in THF (1.2 mL), and a solution of methyl 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (463.3 mg, 1.6 mmol) in THF (8 mL) was added at -20°C over 10 minutes. After 30 minutes, the temperature was returned to room temperature and the mixture was stirred overnight. A saturated ammonium chloride solution was added to the reaction mixture, which was then filtered through Celite and washed with ethyl acetate. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (420 mg) as a colorless amorphous substance. 1 H-NMR (400 MHz, CDCl3) δ: 7.44 (1H, s), 7.28 (1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.7 Hz), 4.77 (2H, d, J = 5.5 Hz), 4.09 (2H, q, J = 7.3 Hz), 3.26 (2H, t, J = 14.0 Hz), 2.96 (2H, t, J = 6.6 Hz), 2.42-2.32 (2H, m), 1.34 (3H, t, J = 7.3 Hz); LC-MS[M+1] = 266.1.

[0353] Step 7 9-Ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0354]

[0355] (9-Ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (420 mg, 1.6 mmol) was dissolved in acetonitrile (7 mL), DIEA (1.3 g, 9.5 mmol) was added, and the mixture was cooled to 0°C. A solution of sulfur trioxide pyridine complex (755 mg, 4.8 mmol) in DMSO (2.4 mL) was added dropwise to the reaction mixture at 0°C, and the mixture was stirred for an additional 30 minutes. The mixture was diluted with ethyl acetate, saturated sodium bicarbonate solution was added, and the mixture was returned to room temperature. The reaction mixture was extracted three times with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (320 mg) as pale yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 10.02 (1H, s), 7.98 (1H, d, J = 1.4 Hz), 7.75 (1H, dd, J = 8.5, 1.6 Hz), 7.37 (1H, d, J = 8.7 Hz), 4.14 (2H, q, J = 7.3 Hz), 3.30 (2H, t, J = 13.7 Hz), 2.98 (2H, t, J = 6.6 Hz), 2.45-2.35 (2H, m), 1.38 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -97.8(2F, m); LC-MS[M+1] = 264.2.

[0356] Step 8: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0357]

[0358] 9-Ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (68 mg, 0.26 mmol) synthesized in Step 7 was dissolved in THF (0.5 mL), and 2.3 M aqueous sodium disulfite solution (0.23 mL, 0.52 mmol) was added and stirred. A solution of methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (39 mg, 0.17 mmol) synthesized in Step 2 in THF (0.5 mL) was added to the reaction mixture, and the mixture was heated to reflux for 3 hours and then stirred at room temperature for 19 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (72 mg). 1 H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, s), 8.03 (1H, dd, J = 8.7, 1.4 Hz), 7.93 (1H, s), 7.59 (1H, dd, J = 8.5, 1.6 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 8.7 Hz), 4.46 (2H, t, J = 5.7 Hz), 4.15 (2H, q, J = 7.3 Hz), 3.96 (3H, s), 3.77 (2H, t, J = 5.5 Hz), 3.29 (3H, s), 3.29 (2H, d, J = 13.7 Hz), 3.00 (2H, t, J = 6.4 Hz), 2.45-2.35 (2H, m), 1.39 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 468.2.

[0359] Step 9 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0360]

[0361] Methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (63.1 mg, 0.14 mmol) was dissolved in THF (2.5 mL) and methanol (1.3 mL). 1N aqueous sodium hydroxide solution (1.3 mL) was added thereto, and the mixture was stirred at 70°C for 1 hour. The reaction mixture was returned to room temperature, neutralized with 1N hydrochloric acid, and the resulting solid was collected by filtration and washed with water to obtain the title compound (39.8 mg) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.16 (1H, d, J = 1.4 Hz), 7.86 (1H, s), 7.82 (1H, dd, J = 8.7, 1.4 Hz), 7.67 (1H, d, J = 8.7 Hz), 7.56-7.51 (2H, m), 4.46 (2H, t, J = 5.0 Hz), 4.14 (2H, q, J = 6.9 Hz) 3.61 (2H, t, J = 5.3 Hz), 3.26-3.22 (2H, m), 3.06 (3H, s), 2.95 (2H, t, J = 6.2 Hz), 2.38-2.30 (2H, m), 1.22 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6)δ:-94.8 - -94.9 (2F, m); LC-MS[M+1] = 454.2.

[0362] Example 2 Synthesis of 2-(9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0363]

[0364] Step 1: 3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid

[0365]

[0366] To a solution of 4-hydrazinobenzoic acid (612 mg, 4.03 mmol) in acetic acid (7.5 mL), 4,4-dimethylcyclohexan-1-one (508 mg, 4.03 mmol) was added portionwise over 30 minutes, and the mixture was then heated to reflux for 8 hours. The reaction mixture was cooled and poured into crushed ice. The solid product was collected by filtration, washed with water, and dried to give the title compound (1.2 g) as a brown solid. LC-MS [M+1] = 244.2.

[0367] Step 2: Methyl 3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0368]

[0369] The title compound (637 mg) as a pale brown solid was obtained from 3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid in the same manner as in Step 4 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.21 (1H, d, J = 1.4 Hz), 7.93-7.90 (1H, br m), 7.83 (1H, dd, J = 8.2, 1.8 Hz), 7.27 (1H, d, J = 8.2 Hz), 3.92 (3H, s), 2.72 (2H, t, J = 6.4 Hz), 2.53 (2H, s), 1.68 (2H, t, J = 6.4 Hz), 1.05 (6H, s).

[0370] Step 3: Methyl 9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0371]

[0372] Using methyl 3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (382.5 mg, 1.49 mmol), iodoethane (1.2 g, 7.47 mmol), and sodium hydride (77.3 mg, 1.93 mmol), in the same manner as in Step 5 of Example 1, the title compound (308 mg) was obtained as white crystals. 1H-NMR (400 MHz, CDCl3) δ: 8.21 (1H, d, J = 1.8 Hz), 7.85 (1H, dd, J = 8.1, 1.5 Hz), 7.26 (1H, d, J = 8.1 Hz), 4.10 (2H, q, J = 7.3 Hz), 3.92 LC-MS[M+1] = 286.2.

[0373] Step 4 (9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0374]

[0375] Using methyl 9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (285.9 mg, 1.01 mmol), and in the same manner as in Step 6 of Example 1, the title compound (258.7 mg) was obtained as a pale yellow viscous oil. 1 H-NMR (400 MHz, CDCl3) δ: 7.45 (1H, d, J = 0.9 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 8.2, 1.8 Hz), 4.75 (2H, s), 4.08 (2H, q, J = 7.1 Hz), 2.69 (2H, t, J = 6.4 Hz), 2.52 (2H, d, J = 1.4 Hz), 1.70 (2H, t, J = 6.4 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.04 (6H, s).

[0376] Step 5 9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0377]

[0378] Using (9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (258.9 mg, 1.01 mmol), and in the same manner as in Step 7 of Example 1, the title compound (110.4 mg) was obtained as a pale yellow viscous oil. 1 H-NMR (400 MHZ, CDCl3) δ: 10.00 (1H, s), 7.99 (1H, d, J = 1.4 Hz), 7.71 (1H, dd, J = 8.5, 1.6 Hz), 7.33 (1H, d, J = 8.2 Hz), 4.12 (2H, q, J LC-MS[M+1] = 256.2.

[0379] Step 6: 2-(9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0380]

[0381] Using 9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (59.2 mg, 0.23 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (40 mg, 0.18 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (80 mg) was obtained as white crystals. 1H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 1.4 Hz), 8.02 (1H, dd, J = 8.7, 1.4 Hz), 7.90 (1H, d, J = 1.4 Hz), 7.54-7.50 (2H, m), 7.39 (1H, d, J = 8.2 Hz), 4.48 (2H, t, J = 5.7 Hz), 4.14 (2H, q, J = 7.2 Hz), 3.96 (3H, s), 3.77 (2H, t, J = 5.7 Hz), 3.30 (3H, s), 2.74 (2H, t, J = 6.4 Hz), 2.55 (2H, s), 1.73 (2H, t, J = 6.4 Hz), 1.37 (3H, t, J = 7.1 Hz), 1.06 (6H, s); LC-MS[M+1] = 460.1.

[0382] Step 7 2-(9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0383]

[0384] Using methyl 2-(9-ethyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (79.8 mg, 0.17 mmol), in the same manner as in Step 9 of Example 1, the title compound (41.3 mg) was obtained as pale purple crystals. 1H-NMR (400 MHz, DMSO-d6) δ: 8.27 (1H, s), 7.94 (1H, d, J = 8.2 Hz), 7.90 (1H, s), 7.74 (1H, d, J = 8.7 Hz), 7.63-7.58 (2H, m), 4.57 (2H, t, J = 5.3 Hz), 4.24 (2H, q, J = 7.2 Hz), 3.77 (2H, t, J = 5.5 Hz), 3.21 (3H, s), 2.82 (2H, t, J = 5.9 Hz), 2.25-2.23 (2H, m), 1.74 (2H, t, J = 6.4 Hz), 1.34 (3H, t, J = 7.1 Hz), 1.10 (6H, s); LC-MS[M+1] = 446.2.

[0385] Example 3 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0386]

[0387] Step 1: Methyl 4-[(2-methoxyethyl)amino]-2-methyl-3-nitrobenzoate

[0388]

[0389] Using methyl 4-chloro-2-methyl-3-nitrobenzoate (2.5 g, 10.93 mmol), 2-methoxyethan-1-amine (1.5 g, 19.7 mmol), and triethylamine (3.1 mL, 22.0 mmol), the title compound was obtained as yellow crystals in DMSO in the same manner as in Step 1 of Example 1. The product was used in the next step without purification. 1H-NMR (400 MHz, CDCl3) δ: 7.92 (1H, d, J = 8.7 Hz), 6.64 (1H, d, J = 9.1 Hz), 5.79 (1H, s), 3.86 (3H, s), 3.61 (2H, t, J = 5.6 Hz), 3.40 (3H, s), 3.39 (2H, t, J = 5.6 Hz), 2.57 (3H, s).

[0390] Step 2: Methyl 3-amino-4-[(2-methoxyethyl)amino]-2-methylbenzoate

[0391]

[0392] Using methyl 4-[(2-methoxyethyl)amino]-2-methyl-3-nitrobenzoate and in the same manner as in Step 2 of Example 1, the title compound (2.9 g) was obtained as pale yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 7.49 (1H, d, J = 8.2 Hz), 6.52 (1H, d, J = 8.2 Hz), 4.17 (1H, br s), 3.83 (3H, s), 3.67-3.64 (2H, m), 3.40 (3H, s), 3.38-3.31 (4H, m), 2.49 (3H, s).

[0393] Step 3: Methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxylate

[0394]

[0395] Using methyl 3-amino-4-[(2-methoxyethyl)amino]-2-methylbenzoate (765.2 mg, 3.21 mmol) obtained in Step 2 and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (1.01 g, 4.17 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (1.1 g) was obtained as white crystals. 1H-NMR (400 MHz, CDCl3) δ: 7.95 (1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 1.4 Hz), 7.58 (1H, dd, J = 8.5, 1.6 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 8.7 Hz), 4.42 (2H, t, J = 5.7 Hz), 4.16 (2H, q, J = 7.3 Hz), 3.95 (3H, s), 3.74 (2H, t, J = 5.7 Hz), 3.31 (2H, t, J = 14.0 Hz), 3.28 (3H, s), 3.04-3.00 (5H, m), 2.47-2.37 (2H, m), 1.40 (3H, t, J = 7.3 Hz). 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 482.2.

[0396] Step 4 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0397]

[0398] Using methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxylate (1.1 g, 2.27 mmol), and following a method similar to that in Step 9 of Example 1, the title compound (0.56 g) was obtained as flesh-colored crystals. 1H-NMR (400 MHz, DMSO-d6) δ: 7.88 (1H, s), 7.75 (1H, d, J = 8.2 Hz), 7.61-7.55 (2H, m), 7.42 (1H, d, J = 8.2 Hz), 4.46 (2H, t, J = 5.5 Hz), 4.21 (2H, q, J = 7.0 Hz), 3.66 (2H, t, J = 5.3 Hz), 3.31 (2H, t, J = 14.0 Hz), 3.12 (3H, s), 3.02 (2H, t, J = 6.2 Hz), 2.84 (3H, s), 2.46-2.36 (2H, m), 1.30 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.8 (2F, m); LC-MS[M+1] = 468.2.

[0399] Example 4 Synthesis of 4-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0400]

[0401] Step 1: tert-butyl 2,4-dichloro-3-nitrobenzoate

[0402]

[0403] 2,4-Dichloro-3-nitrobenzoic acid (100 mg, 0.42 mmol) was dissolved in dichloromethane (1.5 mL) at room temperature, and 4-dimethylaminopyridine (25.9 mg, 0.21 mmol) and tert-butyl alcohol (82 mg, 1.06 mmol) were added and stirred. The mixture was cooled to 0°C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91.8 mg, 0.46 mmol) was added. The reaction mixture was stirred at the same temperature for 2 hours and then further stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and ethyl acetate was added again to the residue. The resulting solution was washed twice each with saturated aqueous sodium carbonate and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (76 mg) as yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 7.83 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.7 Hz), 1.61 (9H, s).

[0404] Step 2 tert-butyl 2-chloro-4-[(2-methoxyethyl)amino]-3-nitrobenzoate

[0405]

[0406] The title compound (30 mg) as a yellow solid was obtained from tert-butyl 2,4-dichloro-3-nitrobenzoate (76 mg, 0.26 mmol) in the same manner as in Step 1 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.56 (1H, s), 7.87 (1H, d, J = 8.7 Hz), 6.66 (1H, d, J = 8.7 Hz), 3.57 (2H, t, J = 5.2 Hz), 3.40 (3H, s), 3.23 (2H, t, J = 5.0 Hz), 1.58 (9H, s).

[0407] Step 3: tert-butyl 3-amino-2-chloro-4-[(2-methoxyethyl)amino]benzoate

[0408]

[0409] Methanol (0.45 mL), water (0.05 mL), and ammonium chloride (10 mg) were added to tert-butyl 2-chloro-4-[(2-methoxyethyl)amino]-3-nitrobenzoate (21 mg, 0.06 mmol). The mixture was heated to 80°C, and zinc powder (38 mg) was added portionwise over 10 minutes while stirring. The reaction mixture was stirred at 80°C for 5 hours and then reacted at room temperature for an additional 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (8.8 mg) as a yellow solid. 1 H-NMR (400 MHz, CDCl3) δ: 7.20 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 4.48 (2H, s), 3.49 (2H, t, J = 5.0 Hz), 3.39 (3H, s), 3.22 (2H, t, J = 5.0 Hz), 1.58 (9H, s).

[0410] Step 4 tert-butyl 4-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate

[0411]

[0412] Using tert-butyl 3-amino-2-chloro-4-[(2-methoxyethyl)amino]benzoate (8.8 mg, 0.03 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (12.3 mg, 0.05 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (5.5 mg) was obtained as white crystals. 1H-NMR (400 MHz, CDCl3) δ: 7.85 (1H, d, J = 0.9 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.52 (1H, dd, J = 8.5, 1.6 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 4.85 (2H, t, J = 5.3 Hz), 4.14 (2H, q, J = 7.3 Hz), 3.36 (2H, t, J = 5.3 Hz), 3.29 (2H, t, J = 14.0 Hz), 3.01 (3H, s), 2.99 (2H, t, J = 6.2 Hz), 2.45-2.35 (2H, m), 1.65 (9H, s), 1.38 (3H, t, J = 7.3 Hz); LC-MS[M+1] = 544.2.

[0413] Step 5: 4-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0414]

[0415] Tert-butyl 4-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (5.5 mg, 0.011 mmol) was dissolved in acetonitrile (0.2 mL), 1N hydrochloric acid (0.1 mL) was added, and the mixture was stirred at 40° C. until the raw materials disappeared. The reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration and washed successively with water and a mixed solvent of hexane / ethyl acetate (1 / 1) to obtain the title compound (3 mg) as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 8.12 (1H, d, J = 8.2 Hz), 8.06-8.04 (1H, m), 7.78 (1H, d, J = 8.2 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.64 (1H, dd, J = 8.5, 1.1 Hz), 5.14 (2H, t, J = 4.8 Hz), 4.30 (2H, q, J = 7.2 Hz), 3.59-3.57 (2H, m), 3.35-3.33 (2H, m), 3.09 (2H, t, J = 6.8 Hz), 3.07 (3H, s), 2.48-2.41 (2H, m), 1.39 (3H, t, J = 7.1 Hz); 19 F-NMR (MeOH-d4) δ: -95.9 (2F, m); LC-MS[M+1] = 488.2.

[0416] Example 5 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0417]

[0418] Step 1: Methyl 5-amino-4-[(2-methoxyethyl)amino]-2-methylbenzoate

[0419]

[0420] The title compound (58.4 mg) was obtained as pale purple crystals in the same manner as in Step 2 of Example 1 from methyl 4-[(2-methoxyethyl)amino]-2-methyl-5-nitrobenzoate (63 mg, 0.24 mmol), which was synthesized from methyl 4-chloro-2-methyl-5-nitrobenzoate in the same manner as in Step 1 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 7.40 (1H, s), 6.41 (1H, s), 4.28 (1H, br s), 3.83 (3H, s), 3.66 (2H, t, J = 5.2 Hz), 3.41 (3H, s), 3.37-3.33 (2H, m), 3.18 (2H, br s), 2.54 (3H, s); LC-MS[M+1] = 239.1.

[0421] Step 2: Methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-methyl-1H-benzo[d]imidazole-5-carboxylate

[0422]

[0423] Using methyl 5-amino-4-[(2-methoxyethyl)amino]-2-methylbenzoate (37.3 mg, 0.16 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (53.3 mg, 0.2 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (70 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3)δ: 8.43 (1H, s), 7.92 (1H, br s), 7.59 (1H, dd, J = 8.5, 1.6 Hz), 7.40 (1H, d, J = 8.7 Hz), 7.28 (1H, s), 4.42 (2H, t, J = 5.7 Hz), 4.15 (2H, q, J = 7.3 Hz), 3.93 (3H, s), 3.76 (2H, t, J = 5.7 Hz), 3.30 (3H, s), 3.29 (2H, t, J = 13.7 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.77 (3H, s), 2.45-2.35 (2H, m), 1.39 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -97.6 (2F, m); LC-MS[M+1] = 482.2.

[0424] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0425]

[0426] The title compound (42.4 mg) was obtained as beige crystals from methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-methyl-1H-benzo[d]imidazole-5-carboxylate (70.7 mg, 0.15 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 7.89 (2H, d, J = 16.9 Hz), 7.59-7.53 (2H, m), 7.33 (1H, s), 4.42 (2H, t, J = 5.5 Hz), 4.19 (2H, q, J = 7.2 Hz), 3.66 (2H, t, J = 5.5 Hz), 3.29 (2H, t, J = 14.0 Hz), 3.13 (3H, s), 3.01 (2H, t, J = 6.2 Hz), 2.63 (3H, s), 2.45-2.35 (2H, m), 1.28 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.8 (2F, m); LC-MS[M+1] = 468.2.

[0427] Example 6 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-N,1-bis(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxamide

[0428]

[0429] 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazole-5-carboxylic acid (27 mg, 0.058 mmol) synthesized in Example 3 was dissolved in THF (0.8 mL) and methanol (0.5 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (18.7 mg, 0.68 mmol) was added thereto and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (26.6 mg) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.13 (1H, t, J = 5.5 Hz), 7.85 (1H, d, J = 1.4 Hz), 7.58 (1H, d, J = 8.7 Hz), 7.53 (1H, dd, J = 8.2, 1.4 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.23 (1H, d, J = 8.2 Hz), 4.45 (2H, t, J = 5.3 Hz), 4.19 (2H, q, J = 7.0 Hz), 3.62 (2H, t, J = 5.3 Hz), 3.47 (2H, t, J = 6.2 Hz), 3.41 (2H, t, J = 5.3 Hz), 3.29 (2H, t, J = 13.6 Hz), 3.28 (3H, s), 3.08 (3H, s), 3.00 (2H, t, J = 6.4 Hz), 2.61 (3H, s), 2.44-2.33 (2H, m), 1.27 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.7 (2F, m); LC-MS[M+1] = 525.2.

[0430] Example 7 Synthesis of 6-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0431]

[0432] Step 1: Methyl 2-chloro-4-[(2-methoxyethyl)amino]-5-nitrobenzoate

[0433]

[0434] DMSO (1 mL) was added to methyl 2-chloro-4-fluoro-5-nitrobenzoate (190 mg, 0.81 mmol), and 2-methoxyethanamine (78 mg, 1.04 mmol) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution, and the resulting precipitate was filtered off and washed successively with water and hexane. The residue was dried in vacuo to obtain the title compound (155.7 mg) as yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.87 (1H, s), 8.43 (1H, br s), 6.93 (1H, s), 3.90 (3H, s), 3.69 (2H, t, J = 5.3 Hz), 3.52 (2H, t, J = 5.3 Hz), 3.44 (3H, s); LC-MS[M+1] = 289.2.

[0435] Step 2: Methyl 5-amino-2-chloro-4-[(2-methoxyethyl)amino]benzoate

[0436]

[0437] Methanol (2 mL), water (0.22 mL), and ammonium chloride (56 mg) were added to methyl 2-chloro-4-[(2-methoxyethyl)amino]-5-nitrobenzoate (90.6 mg, 0.31 mmol), and the mixture was heated to 80°C. While stirring, zinc powder (199 mg) was added portionwise over 30 minutes. The reaction mixture was stirred at 80°C for 5 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (104.7 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 7.33 (1H, s), 6.60 (1H, s), 3.86 (3H, s), 3.66 (2H, t, J = 5.0 Hz), 3.41 (3H, s), 3.31 (2H, t, J = 5.0 Hz); LC-MS[M+1] = 259.2.

[0438] Step 3: 6-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0439]

[0440] Using methyl 5-amino-2-chloro-4-[(2-methoxyethyl)amino]benzoate (40.5 mg, 0.16 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (51.3 mg, 0.19 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (46.5 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.36 (1H, s), 7.95 (1H, d, J = 1.4 Hz), 7.63-7.61 (2H, m), 7.45 (1H, d, J = 8.2 Hz), 4.46 (2H, t, J = 5.5 Hz), 4.20 (2H, q, J = 7.3 Hz), 4.01 (3H, s), 3.80 (2H, t, J = 5.5 Hz), 3.37-3.29 (2H, m), 3.35 (3H, s), 3.05 (2H, t, J = 6.8 Hz), 2.50-2.40 (2H, m), 1.44 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 502.1.

[0441] Step 4 6-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0442]

[0443] The title compound (22.1 mg) was obtained as pink crystals from methyl 6-chloro-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (46.5 mg, 0.093 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.01 (1H, s), 7.88 (2H, d, J = 18.8 Hz), 7.61-7.56 (2H, m), 4.51 (2H, t, J = 5.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.64 (2H, t, J = 5.0 Hz), 3.27-3.25 (2H, m), 3.11 (3H, s), 3.01 (2H, t, J = 6.4 Hz), 2.46-2.32 (2H, m), 1.28 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.9(2F, m); LC-MS[M+1] = 488.2.

[0444] Example 8 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-[(2-methoxyethyl)amino]-1H-benzo[d]imidazole-5-carboxylic acid

[0445]

[0446] Step 1: Methyl 2,4-bis[(2-methoxyethyl)amino]-5-nitrobenzoate

[0447]

[0448] Methyl 2-chloro-4-fluoro-5-nitrobenzoate (441.1 mg, 1.89 mmol), 2-methoxyethanamine (226.8 mg, 3.02 mmol), and DMSO (2 mL) were mixed, and a reaction was carried out under the same reaction conditions as in Step 1 of Example 1. The reaction mixture was worked up and then purified by silica gel column chromatography (ethyl acetate / hexane; 30% to 50%) to obtain the title compound (376.1 mg) as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.92 (1H, s), 8.57-8.55 (2H, m), 5.67 (1H, s), 3.85 (3H, s), 3.68 (4H, q, J = 5.6 Hz), 3.46 (2H, t, J = 5.5 Hz), 3.44 (3H, s), 3.44 (3H, s), 3.40 (2H, q, J = 5.5 Hz); LC-MS[M+1] = 328.2.

[0449] Step 2: Methyl 5-amino-2,4-bis[(2-methoxyethyl)amino]benzoate

[0450]

[0451] The title compound (337.5 mg) was obtained as pale purple crystals from methyl 2,4-bis[(2-methoxyethyl)amino]-5-nitrobenzoate (372.1 mg, 1.14 mmol) in the same manner as in Step 2 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.37 (1H, br s), 5.82 (1H, s), 3.78 (3H, s), 3.67-3.63 (4H, m), 3.46-3.33 (5H, m), 3.42 (3H, s), 3.40 (2H, s); LC-MS[M+1] = 298.1.

[0452] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-[(2-methoxyethyl)amino]-1H-benzo[d]imidazole-5-carboxylate methyl

[0453]

[0454] Using methyl 5-amino-2,4-bis[(2-methoxyethyl)amino]benzoate (39 mg, 0.12 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (44.9 mg, 0.17 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (47 mg) was obtained as pale yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.40 (1H, d, J = 1.4 Hz), 7.92 (1H, br s), 7.87 (1H, d, J = 1.4 Hz), 7.55 (1H, dd, J = 8.5, 1.6 Hz), 7.38 (1H, d, J = 8.7 Hz), 6.58 (1H, s), 4.34 (2H, t, J = 5.7 Hz), 4.17-4.09 (2H, m), 3.90 (3H, s), 3.76-3.72 (4H, m), 3.47 (3H, s), 3.45 (2H, t, J = 5.5 Hz), 3.30 (3H, s), 3.28 (2H, t, J = 13.6 Hz), 2.99 (2H, t, J = 6.6 Hz), 2.43-2.36 (2H, m), 1.38 (3H, t, J = 7.1 Hz); 19 F-NMR (CDCl3) δ: -97.6 (2F, m); LC-MS[M+1] = 541.2.

[0455] Step 4: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-[(2-methoxyethyl)amino]-1H-benzo[d]imidazole-5-carboxylic acid

[0456]

[0457] The title compound (38.1 mg) was obtained as a yellow powder from methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-6-[(2-methoxyethyl)amino]-1H-benzo[d]imidazole-5-carboxylate (45.8 mg, 0.085 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.08 (1H, s), 7.84 (1H, s), 7.57-7.50 (2H, m), 6.70 (1H, s), 4.37 (2H, t, J = 5.0 Hz), 4.19 (2H, q, J = 6.9 Hz), 3.67-3.61 (4H, m), 3.37 (2H, t, J = 5.3 Hz), 3.33 (3H, s), 3.29 (2H, t, J = 14.0 Hz), 3.14 (3H, s), 3.00 (2H, t, J = 5.9 Hz), 2.45-2.36 (2H, m), 1.28 (3H, t, J = 7.1 Hz); LC-MS[M+1] = 527.2.

[0458] Example 9 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0459]

[0460] Step 1: Methyl 4-[(2-methoxyethyl)amino]-3-nitro-5-(trifluoromethyl)benzoate

[0461]

[0462] The title compound (230.8 mg) as a yellow solid was obtained from methyl 4-chloro-3-nitro-5-(trifluoromethyl)benzoate (257 mg, 0.91 mmol) in the same manner as in Step 1 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.92 (1H, s), 8.57-8.55 (2H, br m), 3.85 (3H, s), 3.71-3.66 (4H, m), 3.44 (3H, s); 19 F-NMR (CDCl3) δ: -58.4 (3F, s); LC-MS[M+1] = 323.2.

[0463] Step 2: Methyl 3-amino-4-[(2-methoxyethyl)amino]-5-(trifluoromethyl)benzoate

[0464]

[0465] The crude product of the title compound was obtained using methyl 4-[(2-methoxyethyl)amino]-3-nitro-5-(trifluoromethyl)benzoate (105.2 mg, 0.33 mmol) in the same manner as in Step 2 of Example 7. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane; 10% to 50%) to obtain the title compound (36.6 mg) as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 7.64-7.64 (1H, m), 7.51-7.51 (1H, m), 4.40-3.99 (2H, br m), 3.88 (3H, s), 3.56 (2H, t, J = 4.8 Hz), 3.43 (3H, s), 3.23 (2H, t, J = 4.8 Hz); 19 F-NMR (CDCl3) δ: -60.5 (3F, m); LC-MS[M+1] = 293.2.

[0466] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate

[0467]

[0468] Using methyl 3-amino-4-[(2-methoxyethyl)amino]-5-(trifluoromethyl)benzoate (36.6 mg, 0.13 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (55.3 mg, 0.21 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (68 mg) was obtained as a pale yellow solid. 1 H-NMR (400 MHz, CDCl3)δ: 8.68 (1H, d, J = 1.4 Hz), 8.37 (1H, d, J = 0.9 Hz), 7.81 (1H, d, J = 1.4 Hz), 7.50 (1H, dd, J = 8.2, 1.8 Hz), 7.43 (1H, d, J = 8.2 Hz), 4.70 (2H, t, J = 5.9 Hz), 4.19-4.11 (2H, m), 3.99 (3H, s), 3.38 (2H, t, J = 6.2 Hz), 3.30 (2H, t, J = 13.7 Hz), 3.01 (2H, t, J = 7.3 Hz), 2.99 (3H, s), 2.46-2.36 (2H, m), 1.40 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -57.0 (3F, s), -97.7 (2F, m); LC-MS[M+1] = 536.2.

[0469] Step 4: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0470]

[0471] The title compound (46 mg) was obtained as white crystals from methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (68 mg, 0.13 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz,DMSO-d6) δ: 8.46 (1H, s), 8.19 (1H, s), 7.87 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.51 (1H, d, J = 8.2 Hz), 4.64 (2H, t, J = 5.5 Hz), 4.21 (2H, q, J = 7.0 Hz), 3.31-3.26 (4H, m), 3.02 (2H, t, J = 5.9 Hz), 2.81 (3H, s), 2.46-2.35 (2H, m), 1.29 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -55.1 (3F, s), -94.9 (2F, m); LC-MS[M+1] = 522.1.

[0472] Example 10 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0473]

[0474] Step 1: Methyl 6-[(2-methoxyethyl)amino]-5-nitronicotinate

[0475]

[0476] Using methyl 6-chloro-5-nitronicotinate (1 g, 4.62 mmol) and 2-methoxyethan-1-amine (0.62 g, 8.31 mmol), and in the same manner as in Step 1 of Example 1, the title compound (0.98 g) was obtained as yellow crystals. 1H-NMR (400 MHz, CDCl3) δ: 8.99 (2H, dd, J = 7.3, 2.3 Hz), 8.74 (1H, s), 3.94-3.89 (2H, m), 3.93 (3H, s), 3.65 (2H, t, J = 5.3 Hz), 3.42 (3H, s).

[0477] Step 2: Methyl 6-[(2-methoxyethyl)amino]-5-nitronicotinate

[0478]

[0479] Using methyl 6-[(2-methoxyethyl)amino]-5-nitronicotinate (987.1 mg, 3.87 mmol), and in the same manner as in Step 2 of Example 1, the title compound (822.1 mg) was obtained as pale yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.43 (1H, d, J = 1.8 Hz), 7.41 (1H, d, J = 2.3 Hz), 5.11 (1H, br s), 3.86 (3H, s), 3.71 (2H, t, J = 4.8 Hz), 3.63 (2H, t, J = 4.8 Hz), 3.39 (3H, s), 3.27 (2H, br s).

[0480] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate methyl

[0481]

[0482] Using methyl 5-amino-6-[(2-methoxyethyl)amino]nicotinate (34.5 mg, 0.15 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (52.4 mg, 0.20 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (37.2 mg) was obtained as pale yellow crystals. 1H-NMR (400 MHz, CDCl3) δ: 9.06 (1H, d, J = 1.8 Hz), 8.65 (1H, d, J = 1.8 Hz), 8.08 (1H, d, J = 1.4 Hz), 7.73 (1H, dd, J = 8.5, 1.6 Hz), 7.43 (1H, d, J = 8.7 Hz), 4.64 (2H, t, J = 5.5 Hz), 4.15 (2H, q, J = 7.3 Hz), 3.99 (3H, s), 3.91 (2H, t, J = 5.7 Hz), 3.30 (2H, t, J = 14.0 Hz), 3.28 (3H, s), 3.00 (2H, t, J = 6.4 Hz), 2.45-2.35 (2H, m), 1.39 (3H, t, J = 7.3 Hz); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 469.2.

[0483] Step 4 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0484]

[0485] Using 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate methyl (70.9 mg, 0.15 mmol), the title compound (32.6 mg) was obtained as a beige solid in the same manner as in Step 9 of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ: 8.86 (1H, d, J = 1.4 Hz), 8.36 (1H, d, J = 1.4 Hz), 7.98 (1H, d, J = 0.9 Hz), 7.66-7.60 (2H, m), 4.56 (2H, t, J = 5.7 Hz), 4.21 (2H, q, J = 7.1 Hz), 3.74 (2H, t, J = 5.5 Hz), 3.27-3.25 (2H, m), 3.11 (3H, s), 3.01 (2H, t, J = 6.4 Hz), 2.44-2.37 (2H, m), 1.29 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.8 (2F, m); LC-MS[M+1] = 455.1.

[0486] Example 11 Synthesis of 2-(9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0487]

[0488] Step 1: 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid

[0489]

[0490] The title compound (4.7 g) was obtained as pink crystals from cyclohexanone (3.7 g, 37.0 mmol) and 4-hydrazinobenzoic acid (4.0 g, 26.3 mmol) in the same manner as in Step 3 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 12.25 (1H, s), 7.98 (1H, s), 7.60 (1H, dd, J = 8.5, 1.6 Hz), 7.25 (1H, d, J = 8.7 Hz), 2.69-2.60 (4H, m), 1.84-1.74 (4H, m); LC-MS[M+1] = 216.2.

[0491] Step 2: Methyl 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0492]

[0493] Using 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid (1.1 g, 4.95 mmol), and following a method similar to that of Step 4 of Example 1, the title compound (1.02 g) was obtained as pale yellow crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.23 ​​(1H, s), 7.91(1H, br s), 7.83 (1H, d, J = 8.4 Hz), 7.27 (1H, d, J = 8.0 Hz), 3.93 (3H, s), 2.75-2.72 (4H, m), 1.96-1.85 (4H, m); LC-MS[M+1] = 230.2.

[0494] Step 3: Methyl 9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0495]

[0496] Using methyl 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (1.1 g, 4.95 mmol) synthesized in Step 2, iodoethane (0.65 mL, 8.08 mmol), and sodium hydride (309.2 mg, 7.73 mmol), in the same manner as in Step 5 of Example 1, the title compound (1.27 g) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.23 ​​(1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.4 Hz), 4.08 (2H, q, J = 7.3 Hz), 3.92 (3H, s), 2.76-2.70 (4H, m), 1.99-1.84 (4H, m), 1.33 (3H, t, J = 7.1 Hz); LC-MS[M+1] = 258.2.

[0497] Step 4 (9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0498]

[0499] Using methyl 9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (1.3 g, 4.94 mmol) and lithium aluminum hydride (380 mg, 1.66 mmol), in the same manner as in Step 6 of Example 1, the title compound (414 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 7.47 (1H, s), 7.26 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 8.2 Hz), 4.75 (2H, s), 4.07 (2H, q, J = 7.3 Hz), 2.73-2.70 (4H, m), 1.98-1.83 (4H, m), 1.53 (1H, br s), 1.31 (3H, t, J = 7.1 Hz); LC-MS[M+1] = 230.2.

[0500] Step 5 9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0501]

[0502] Using methyl 9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (70 mg, 0.31 mmol), and in the same manner as in Step 7 of Example 1, the title compound (44.3 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 10.01 (1H, s), 8.21 (1H, s), 7.71 (1H, d, J = 8.8 Hz), 7.34 (1H, d, J = 8.4 Hz), 4.11 (2H, q, J = 7.2 Hz), 2.78-2.63 (4H, m), 1.99-1.82 (4H, m), 1.33 (3H, t, J = 7.2 Hz); LC-MS[M+1] = 228.2.

[0503] Step 6: 2-(9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0504]

[0505] Using 9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (44.3 mg, 0.20 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (83.4 mg, 0.37 mmol) synthesized in Step 2 of Example 1, and following a procedure similar to that in Step 8 of Example 1, the title compound (58.4 mg) was obtained as pale yellow crystals. LC-MS [M+1] = 432.1.

[0506] Step 7 2-(9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0507]

[0508] The title compound (29 mg) was obtained as white crystals from methyl 2-(9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (51.7 mg, 0.12 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.27 (1H, s), 7.88-7.85 (2H, m), 7.58 (1H, d, J = 8.3 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 8.3 Hz), 4.47 (2H, t, J = 5.4 Hz), 4.10 (2H, q, J = 7.1 Hz), 3.71 (2H, t, J = 5.4 Hz), 3.12 (3H, s), 2.70-2.64 (6H, m), 1.87-1.76 (4H, m), 1.23 (3H, t, J = 7.0 Hz); LC-MS[M+1] = 418.2.

[0509] Example 12 Synthesis of 1-(2-methoxyethyl)-2-(9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1H-benzo[d]imidazole-5-carboxylic acid

[0510]

[0511] Step 1: Methyl 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0512]

[0513] Methyl 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (454.8 mg, 1.98 mmol) synthesized in Step 2 of Example 11 was dissolved in THF (11 mL), and the solution was added to a suspension of sodium hydride (158.7 mg, 3.97 mmol) in THF (4.5 mL). The mixture was stirred for 30 minutes, and then 1-bromo-2-methoxyethane (246 mg, 1.6 mmol) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (311.9 mg) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ: 8.22 (1H, d, J = 1.4 Hz), 7.85 (1H, dd, J = 9.1, 1.4 Hz), 7.27 (1H, t, J = 9.1 Hz), 4.20 (2H, t, J = 5.9 Hz), 3.92 (3H, s), 3.63 (2H, t, J = 5.9 Hz), 3.29 (3H, s), 2.76-2.72 (4H, m), 1.98-1.83 (4H, m); LC-MS[M+1] = 288.2.

[0514] Step 2: 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0515]

[0516] The title compound (249 mg) was obtained as white crystals from methyl 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (311.9 mg, 1.09 mmol) in the same manner as in Step 6 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.46 (1H, s), 7.26 (1H, d, J = 8.2 Hz), 7.15 (1H, dd, J = 8.2, 1.4 Hz), 4.75 (2H, d, J = 5.5 Hz), 4.18 (2H, t, J = LC-MS[M+1] = 260.2.

[0517] Step 3: 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0518]

[0519] The title compound (58.2 mg) was obtained as a yellow oil from methyl 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (104.6 mg, 0.40 mmol) by a method similar to that in Step 7 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 10.01 (1H, s), 8.01 (1H, s), 7.70 (1H, dd, J = 8.2, 1.4 Hz), 7.36 (1H, d, J = 8.7 Hz), 4.22 (2H, t, J = 5.9 Hz), 3.64 (2H, t, J = 5.7 Hz), 3.29 (3H, s), 2.77-2.73 (4H, m), 1.97-1.85 (4H, m); LC-MS[M+1] = 258.2.

[0520] Step 4: Ethyl 1-(2-methoxyethyl)-2-(9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1H-benzo[d]imidazole-5-carboxylate

[0521]

[0522] The title compound (61.7 mg) was obtained as white crystals from 9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (58.5 mg, 0.23 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (34 mg, 0.15 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.53 (1H, d, J = 1.4 Hz), 8.03 (1H, dd, J = 8.7, 1.4 Hz), 7.92 (1H, s), 7.54-7.50 (2H, m), 7.41 (1H, d, J = 8.7 Hz), 4.47 (2H, t, J = 5.7 Hz), 4.25 (2H, t, J = 5.7 Hz), 3.96 (3H, s), 3.76 (2H, t, J = 5.7 Hz), 3.68 (2H, t, J = 5.7 Hz), 3.32 (3H, s), 3.29 (3H, s), 2.79-2.74 (4H, m), 1.98-1.86 (4H, m); LC-MS[M+1] = 462.2.

[0523] Step 5: 1-(2-methoxyethyl)-2-(9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1H-benzo[d]imidazole-5-carboxylic acid

[0524]

[0525] The title compound (34.7 mg) was obtained as a white powder from methyl 1-(2-methoxyethyl)-2-(9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1H-benzo[d]imidazole-5-carboxylate (61.7 mg, 0.13 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.16 (1H, s), 7.82-7.79 (2H, m), 7.67 (1H, d, J = 8.7 Hz), 7.50-7.44 (2H, m), 4.45 (2H, t, J = 5.3 Hz), 4.23 (2H, t, J = 5.0 Hz), 3.63 (2H, t, J = 5.3 Hz), 3.55 (2H, t, J = 5.3 Hz), 3.16 (3H, s), 3.07 (3H, s), 2.72-2.70 (2H, m), 2.64-2.61 (2H, m), 1.84-1.74 (4H, m); LC-MS[M+1] = 448.2.

[0526] Example 13 Synthesis of 2-(3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0527]

[0528] Step 1: Methyl 3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0529]

[0530] The title compound (64.7 mg) was obtained as a white solid from methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (116.6 mg, 0.44 mmol) synthesized in Step 4 of Example 1, by a method similar to that in Step 5 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.19 (1H, br s), 7.91-7.87 (1H, m), 7.28 (1H, d, J = 8.7 Hz), 4.22 (2H, t, J = 5.7 Hz), 3.93 (3H, s), 3.65 (2H, t, J = 5.5 Hz), 3.32-3.25 (2H, m), 3.27 (3H, s), 3.01 (2H, t, J = 6.6 Hz), 2.42-2.32 (2H, m); LC-MS[M+1] = 324.2.

[0531] Step 2 (3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0532]

[0533] The title compound (249 mg) was obtained as white crystals from methyl 3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (53 mg, 0.16 mmol) in the same manner as in Step 6 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.42 (1H, s), 7.27 (1H, d, J = 8.2 Hz), 7.20 (1H, dd, J = 8.7, 1.4 Hz), 4.75 (2H, s), 4.19 (2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 5.5 Hz), 3.29-3.19 (2H, m), 3.26 (3H, s), 2.99 (2H, t, J = 6.6 Hz), 2.40-2.30 (2H, m); LC-MS[M+1] = 296.2.

[0534] Step 3: 3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0535]

[0536] The title compound (42.4 mg) was obtained as white crystals from (3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (50 mg, 0.17 mmol) in the same manner as in Step 7 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 10.02 (1H, s), 7.98 (1H, s), 7.75 (1H, dd, J = 8.7, 1.4 Hz), 7.37 (1H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.5 Hz), 3.66 (2H, t, J = 5.5 Hz), 3.30 (2H, t, J = 14.0 Hz), 3.27 (3H, s), 3.02 (2H, t, J = 6.6 Hz), 2.43-2.33 (2H, m); LC-MS[M+1] = 294.1.

[0537] Step 4: Methyl 2-(3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate

[0538]

[0539] The title compound (46.9 mg) was obtained as a white solid from 3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (39.2 mg, 0.13 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (20.8 mg, 0.93 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, s), 8.03 (1H, d, J = 8.7 Hz), 7.92 (1H, s), 7.59 (1H, d, J = 8.7 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 8.2 Hz), 4.47 (2H, t, J = 5.5 Hz), 4.26 (2H, t, J = 5.5 Hz), 3.96 (3H, s), 3.77 (2H, t, J = 5.5 Hz), 3.68 (2H, t, J = 5.5 Hz), 3.31 (3H, s), 3.29 (2H, t, J = 14.2 Hz), 3.04 (2H, q, J = 6.6 Hz), 2.44-2.34 (2H, m); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 498.2.

[0540] Step 5: 2-(3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0541]

[0542] The title compound (24.5 mg) was obtained as a white powder from methyl 2-(3,3-difluoro-9-(2-methoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (47.9 mg, 0.096 mmol) in the same manner as in Step 9 of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ: 8.15 (1H, s), 7.85-7.81 (2H, m), 7.65-7.62 (1H, m), 7.56-7.50 (2H, m), 4.46-4.44 (2H, m), 4.29-4.27 (2H, m), 3.63 (2H, t, J = 5.2 Hz), 3.57 (2H, t, J = 5.2 Hz), 3.23-3.19 (2H, m), 3.16 (3H, s), 3.08 (3H, s), 2.99-2.96 (2H, m), 2.38-2.26 (2H, m); 19 F-NMR (DMSO-d6) δ: -94.6 (2F, m); LC-MS[M+1] = 484.2.

[0543] Example 14 Synthesis of 2-(3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0544]

[0545] Step 1: Methyl 3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0546]

[0547] Using methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (122 mg, 0.46 mmol) synthesized in Step 4 of Example 1 and 1-bromo-2-(2-methoxyethoxy)ethane (247.4 mg, 1.35 mmol), the title compound (64.7 mg) was obtained as a white solid in the same manner as in Step 5 of Example 1. This product was used in the next step without purification. 1H-NMR (400 MHz, CDCl3) δ: 8.18 (1H, d, J = 1.4 Hz), 7.88 (1H, dd, J = 8.7, 1.8 Hz), 7.29 (1H, d, J = 8.7 Hz), 4.25 (2H, t, J = 5.5 Hz), 3.93 (3H, s), 3.75 (2H, t, J = 5.7 Hz), 3.49-3.46 (2H, m), 3.43-3.41 (2H, m), 3.31 (3H, s), 3.28 (2H, t, J = 14.0 Hz), 3.03 (2H, t, J = 6.6 Hz), 2.41-2.31 (2H, m); 19 F-NMR (CDCl3) δ: -97.8(2F, m); LC-MS[M+1] = 368.1.

[0548] Step 2 (3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0549]

[0550] 89.1 mg of the title compound was obtained as a colorless oil from methyl 3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (98.8 mg, 0.34 mmol) in the same manner as in Step 6 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 7.42 (1H, br s), 7.27 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 8.5, 1.6 Hz), 4.75 (2H, s), 4.22 (2H, t, J = 5.7 Hz), 3.72 (2H, t, J = 5.7 Hz), 3.47-3.42 (4H, m), 3.33 (3H, s), 3.23 (2H, t, J = 14.2 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.39-2.29 (2H, m), 1.72 (1H, s); 19F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 340.1.

[0551] Step 3: 3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0552]

[0553] The title compound (90.3 mg) was obtained as a pale yellow oil from (3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (90 mg, 0.24 mmol) in the same manner as in Step 7 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 10.02 (1H, s), 7.97 (1H, d, J = 1.4 Hz), 7.74 (1H, dd, J = 8.7, 1.4 Hz), 7.38 (1H, d, J = 8.7 Hz), 4.27 (2H, t, J = 5.5 Hz), 3.76 (2H, t, J = 5.5 Hz), 3.50-3.47 (2H, m), 3.44-3.41 (2H, m), 3.33-3.26 (2H, m), 3.31 (3H, s), 3.04 (2H, t, J = 6.6 Hz), 2.43-2.33 (2H, m); LC-MS[M+1] = 338.1.

[0554] Step 4: 2-(3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0555]

[0556] The title compound (82.3 mg) was obtained as white crystals from 3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (84.7 mg, 0.25 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (40.2 mg, 0.18 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 2.3 Hz), 8.03 (1H, dd, J = 8.7, 1.4 Hz), 7.92 (1H, d, J = 1.4 Hz), 7.59 (1H, dd, J = 8.2, 1.8 Hz), 7.50 (1H, d, J = 9.1 Hz), 7.42 (1H, d, J = 8.2 Hz), 4.47 (2H, t, J = 5.7 Hz), 4.29 (2H, t, J = 5.7 Hz), 3.96 (3H, s), 3.80-3.76 (4H, m), 3.51-3.44 (4H, m), 3.33 (3H, s), 3.30 (3H, s), 3.29 (2H, t, J = 14.0 Hz), 3.07 (2H, t, J = 6.6 Hz), 2.44-2.34 (2H, m); LC-MS[M+1] = 542.2.

[0557] Step 5: 2-(3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0558]

[0559] The title compound (14.9 mg) was obtained as a white powder from methyl 2-(3,3-difluoro-9-[2-(2-methoxyethoxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (82.3 mg, 0.15 mmol) in the same manner as in Step 9 of Example 1.1 H-NMR (400 MHz, DMSO-d6)δ: 7.79 (1H, s), 7.50 (1H, s), 7.46 (1H, dd, J = 8.2, 1.4 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 8.5, 1.6 Hz), 4.11 (2H, t, J = 5.3 Hz), 3.93 (2H, t, J = 5.0 Hz), 3.32-3.27 (4H, m), 3.07-3.05 (2H, m), 2.97-2.95 (2H, m), 2.78 (3H, s), 2.73 (2H, s), 2.73 (3H, t, J = 4.6 Hz), 2.66 (2H, t, J = 6.2 Hz), 2.02-1.92 (2H, m); 19 F-NMR (DMSO-d6) δ: -94.8(2F, m); LC-MS[M+1] = 528.2.

[0560] Example 15 Synthesis of 2-(3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0561]

[0562] Step 1: Methyl 3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0563]

[0564] Methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (250.3 mg, 0.94 mmol) was dissolved in THF (2.5 mL), and the solution was added to a suspension of sodium hydride (81.6 mg, 2.04 mmol) in THF (6.3 mL). After stirring the reaction mixture for 30 minutes, (2-bromoethoxy)benzene (600 mg, 2.98 mmol) was added and the mixture was stirred at room temperature overnight. Potassium iodide (780.3 mg, 4.7 mmol) and (2-bromoethoxy)benzene (380 mg, 1.8 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a yellow-brown oil. The residue was purified by silica gel column chromatography to give the title compound (140 mg) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ: 8.19 (1H, d, J = 1.4 Hz), 7.91 (1H, dd, J = 8.7, 1.4 Hz), 7.35 (1H, d, J = 8.7 Hz), 7.25-7.21 (2H, m), 6.93 (1H, t, J = 7.6 Hz), 6.77 (2H, d, J = 7.6 Hz), 4.47 (2H, t, J = 5.5 Hz), 4.23 (2H, t, J = 5.5 Hz), 3.93 (3H, s), 3.28 (2H, t, J = 13.7 Hz), 3.09 (2H, t, J = 6.6 Hz), 2.44-2.34 (2H, m); 19 F-NMR (CDCl3) δ: -97.8 (2F, m); LC-MS[M+1] = 386.2.

[0565] Step 2 (3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0566]

[0567] The title compound (128.2 mg) was obtained as a yellow viscous oil from methyl 3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (140 mg, 0.36 mmol) in the same manner as in Step 6 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 7.44 (1H, s), 7.33 (1H, d, J = 8.2 Hz), 7.26-7.22 (3H, m), 6.93 (1H, t, J = 7.6 Hz), 6.80-6.77 (2H, m), 4.77 (2H, s), 4.45 (2H, t, J = 5.7 Hz), 4.21 (2H, t, J = 5.7 Hz), 3.25 (2H, t, J = 14.0 Hz), 3.08 (2H, t, J = 6.6 Hz), 2.43-2.33 (2H, m); 19 F-NMR (CDCl3) δ: -97.6 (2F, m); LC-MS[M+1] = 358.2.

[0568] Step 3: 3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0569]

[0570] The title compound (130 mg) was obtained as a yellow viscous oil from (3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (128.2 mg, 0.36 mmol) in the same manner as in Step 7 of Example 1. This product was used in the next step without purification. 1H-NMR (400 MHz, CDCl3) δ: 10.02 (1H, s), 7.97 (1H, d, J = 1.4 Hz), 7.78-7.76 (1H, m), 7.44 (1H, d, J = 8.7 Hz), 7.26-7.21 (2H, m), 6.95-6.92 (1H, m), 6.78-6.75 (2H, m), 4.49 (2H, t, J = 5.5 Hz), 4.25 (2H, t, J = 5.5 Hz), 3.29 (2H, t, J = 13.7 Hz), 3.11 (2H, t, J = 6.6 Hz), 2.45-2.35 (2H, m); 19 F-NMR (CDCl3) δ: -97.8 (2F, m); LC-MS[M+1] = 356.1.

[0571] Step 4: 2-(3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0572]

[0573] The title compound (62.7 mg) was obtained as white crystals from 3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (62.7 mg, 0.17 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (30.4 mg, 0.14 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 0.9 Hz), 8.03 (1H, dd, J = 8.5, 1.6 Hz), 7.92 (1H, d, J = 0.9 Hz), 7.62 (1H, dd, J = 8.5, 1.6 Hz), 7.49 (2H, dd, J = 11.0, 8.2 Hz), 7.26-7.22 (2H, m), 6.94 (1H, t, J = 7.3 Hz), 6.80 (2H, d, J = 8.0 Hz), 4.50 (2H, t, J = 5.3 Hz), 4.46 (2H, t, J = 5.7 Hz), 4.27 (2H, t, J = 5.3 Hz), 3.96 (3H, s), 3.77 (2H, t, J = 5.5 Hz), 3.29 (3H, s), 3.28 (2H, t, J = 13.7 Hz), 3.12 (2H, t, J = 6.4 Hz), 2.46-2.36 (2H, m); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 560.2.

[0574] Step 5: 2-(3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0575]

[0576] The title compound (48 mg) was obtained as a white powder from methyl 2-(3,3-difluoro-9-(2-phenoxyethyl)-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (62.7 mg, 0.13 mmol) in the same manner as in Step 9 of Example 1. 1H-NMR (400 MHz, DMSO-d6)δ: 8.14 (1H, d, J = 1.4 Hz), 7.85 (1H, d, J = 1.4 Hz), 7.82 (1H, dd, J = 8.5, 1.6 Hz), 7.63 (2H, dd, J = 8.2, 2.3 Hz), 7.54 (1H, dd, J = 8.5, 1.6 Hz), 7.20-7.16 (2H, m), 6.84 (1H, t, J = 7.3 Hz), 6.79 (2H, d, J = 7.8 Hz), 4.52 (2H, t, J = 5.0 Hz), 4.44 (2H, t, J = 5.3 Hz), 4.21 (2H, t, J = 5.0 Hz), 3.61 (2H, t, J = 5.3 Hz), 3.24 (2H, t, J = 14.0 Hz), 3.08 (2H, d, J = 6.4 Hz), 3.06 (3H, s), 2.40-2.30 (2H, m); 19 F-NMR (DMSO-d6) δ: -94.9(2F, m); LC-MS[M+1] = 546.2.

[0577] Example 16 Synthesis of 2-[9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0578]

[0579] Step 1: Methyl 9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0580]

[0581] The title compound (108 mg) was obtained as white crystals from methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (250.3 mg, 0.94 mmol) and ((2-bromoethoxy)methyl)benzene (608.1 mg, 2.83 mmol) in the same manner as in Step 5 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.19 (1H, d, J = 1.8 Hz), 7.89-7.86 (1H, m), 7.28-7.22 (4H, m), 7.12-7.09 (2H, m), 4.38 (2H, s), 4.24 (2H, t, J = 5.5 Hz), 3.94 (3H, s), 3.74 (2H, t, J = 5.5 Hz), 3.28 (2H, t, J = 14.0 Hz), 2.99 (2H, t, J = 6.9 Hz), 2.36-2.26 (2H, m); 19 F-NMR (CDCl3) δ: -97.7(2F, m).

[0582] Step 2 (9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0583]

[0584] The title compound (86.1 mg) as a colorless oil was obtained from methyl 9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (108 mg, 0.27 mmol) in the same manner as in Step 6 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 7.44 (1H, d, J = 0.9 Hz), 7.31-7.22 (4H, m), 7.19 (1H, dd, J = 8.2, 1.4 Hz), 7.16-7.14 (2H, m), 4.77 (2H, s), 4.39 (2H, s), 4.24 (2H, t, J = 5.5 Hz), 3.74 (2H, t, J = 5.7 Hz), 3.26 (2H, t, J = 14.0 Hz), 2.99 (2H, t, J = 6.6 Hz), 2.36-2.26 (2H, m); 19 F-NMR (CDCl3) δ: -97.6 (2F, m); LC-MS[M+1] = 372.2.

[0585] Step 3: 9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0586]

[0587] The title compound (61.9 mg) was obtained as a pale yellow viscous oil from (9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (86.1 mg, 0.23 mmol) in the same manner as in Step 7 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3)δ: 10.03 (1H, s), 7.98 (1H, s), 7.73 (1H, dd, J = 8.7, 0.9 Hz), 7.34 (1H, d, J = 8.7 Hz), 7.25-7.23 (3H, m), 7.11-7.09 (2H, m), 4.40 (2H, s), 4.28 (2H, t, J = 5.3 Hz), 3.76 (2H, t, J = 5.5 Hz), 3.30 (2H, t, J = 14.0 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.38-2.28 (2H, m); 19 F-NMR (CDCl3)δ: -97.8 (2F, m); LC-MS[M+1] = 370.2.

[0588] Step 4: 2-[9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0589]

[0590] The title compound (61.1 mg) was obtained as pale yellow crystals from 9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (59.7 mg, 0.16 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (27.9 mg, 0.12 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 1.4 Hz), 8.03 (1H, dd, J = 8.5, 1.6 Hz), 7.94 (1H, d, J = 1.4 Hz), 7.58 (1H, dd, J = 8.5, 1.6 Hz), 7.50 (1H, d, J = 8.7 Hz), 7.40 (1H, d, J = 8.7 Hz), 7.30-7.24 (3H, m), 7.16-7.14 (2H, m), 4.47 (2H, t, J = 5.5 Hz), 4.42 (2H, s), 4.30 (2H, t, J = 5.5 Hz), 3.96 (3H, s), 3.79-3.76 (4H, m), 3.30 (2H, t, J = 14.0 Hz), 3.29 (3H, s), 3.03 (2H, t, J = 6.4 Hz), 2.39-2.29 (2H, m); 19 F-NMR (CDCl3) δ: -97.6(2F, m); LC-MS[M+1] = 574.2.

[0591] Step 5: 2-[9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0592]

[0593] The title compound (22.7 mg) was obtained as a pale yellow solid from methyl 2-[9-[2-(benzyloxy)ethyl]-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (42.2 mg, 0.13 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.16 (1H, s), 7.90-7.85 (2H, m), 7.62-7.54 (3H, m), 7.28-7.20 (3H, m), 7.14 (2H, d, J = 6.4 Hz), 4.47 (2H, t, J = 5.3 Hz), 4.42 (2H, s), 4.39 (2H, t, J = 5.0 Hz), 3.74 (2H, t, J = 5.0 Hz), 3.68 (2H, t, J = 5.3 Hz), 3.31-3.27 (2H, m), 3.12 (3H, s), 3.04 (2H, t, J = 6.2 Hz), 2.38-2.31 (2H, m); 19 F-NMR (DMSO-d6) δ: -94.9 (2F, m); LC-MS[M+1] = 560.2.

[0594] Example 17 Synthesis of 2-[3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy]ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0595]

[0596] Step 1: 2-[(4-(trifluoromethyl)benzyl)oxy]ethanol

[0597]

[0598] Ethylene glycol (1.6 mL, 14.18 mmol) and sodium hydroxide (283.9 mg, 7.09 mmol) were mixed, and 1-(chloromethyl)-4-(trifluoromethyl)benzene (1.3 g, 7.09 mmol) was slowly added thereto at room temperature, followed by stirring overnight at 55°C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (5% ethyl acetate-hexane) to give 2-[(4-(trifluoromethyl)benzyl)oxy]ethanol (1.0 g) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ: 7.66 (2H, d, J = 8.2 Hz),7.51 (2H, d, J = 7.8 Hz), 4.68 (2H, s), 3.84 (2H, t, J = 3.8 Hz), 3.68 (2H, t, J = 3.8 Hz), 1.96 (1H, br s); 19 F-NMR (CDCl3) δ: -63.3 (3F, s); LC-MS[M+1] = 221.2.

[0599] Step 2: 1-[(2-bromoethoxy)methyl]-4-trifluoromethylbenzene

[0600]

[0601] N-Bromosuccinimide (938.7 mg, 5.27 mmol) was suspended in dichloromethane (16 mL) and cooled to -78°C. To the mixture, a solution of triphenylphosphine (1.4 g, 5.27 mmol) in dichloromethane (10 mL) was slowly added dropwise, followed by a solution of 2-[(4-(trifluoromethyl)benzyl)oxy]ethanol (992.5 mg, 4.51 mmol) in dichloromethane (7 mL). The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. A 1:1 mixed solvent of methanol and toluene was added to the reaction mixture to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate-hexane) to obtain the title compound (571.0 mg) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 7.62 (2H, d, J = 7.8 Hz), 7.48 (2H, d, J = 8.2 Hz), 4.65 (2H, s), 3.82 (2H, t, J = 6.2 Hz), 3.52 (2H, t, J = 6.2 Hz); 19 F-NMR (CDCl3) δ: -63.1 (3F, s); LC-MS[M+1] = 284.2.

[0602] Step 3: Methyl 3,3-difluoro-9-[2-((4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0603]

[0604] The title compound (61 mg) was obtained as white crystals from 1-[(2-bromoethoxy)methyl]-4-trifluoromethylbenzene (511 mg, 1.81 mmol) and methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (159 mg, 0.6 mmol) synthesized in Step 4 of Example 1, in the same manner as in Step 5 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.20 (1H, d, J = 1.4 Hz), 7.87 (1H, dd, J = 8.7, 2.3 Hz), 7.48 (2H, d, J = 7.8 Hz), 7.26 (1H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.8 Hz), 4.43 (2H, s), 4.28 (2H, t, J = 5.3 Hz), 3.94 (3H, s), 3.78 (2H, t, J = 5.5 Hz), 3.30 (2H, t, J = 13.6 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.39-2.29 (2H, m); 19 F-NMR (CDCl3) δ: -63.1 (3F, s), -97.8 (2F, m); LC-MS[M+1] =468.2.

[0605] Step 4 (3,3-difluoro-9-[2-((4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0606]

[0607] The title compound (52.7 mg) as a colorless oil was obtained from methyl 3,3-difluoro-9-[2-((4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (61 mg, 0.13 mmol) in the same manner as in Step 6 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.47 (3H, t, J = 8.4 Hz), 7.24-7.17 (4H, m), 4.77 (2H, s),4.42 (2H, s), 4.26 (2H, t, J = 5.5 Hz), 3.76 (2H, t, J = 5.5 Hz), 3.26 (2H, t, J = 14.0 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.37-2.25 (2H, m); 19 F-NMR (CDCl3) δ: -63.1 (3F, s), -97.7 (2F, m); LC-MS[M+1] = 440.2.

[0608] Step 5: 3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0609]

[0610] The title compound (33.8 mg) was obtained as a pale yellow oil from (3,3-difluoro-9-[2-((4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (58.1 mg, 0.13 mmol) in the same manner as in Step 7 of Example 1. This product was used in the next step without purification. 1H-NMR (400 MHz, CDCl3)δ: 10.02 (1H, s), 7.98 (1H, s), 7.72 (1H, dd, J = 8.7, 1.4 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.34 (1H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.2 Hz), 4.43 (2H, s), 4.29 (2H, t, J = 5.3 Hz), 3.78 (2H, t, J = 5.3 Hz), 3.30 (2H, t, J = 14.0 Hz), 3.01 (2H, t, J = 6.6 Hz), 2.39-2.29 (2H, m); LC-MS[M+1] = 438.2.

[0611] Step 6: 2-[3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy]ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0612]

[0613] The title compound (31.5 mg) was obtained as pale yellow crystals from 3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy]ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (33.8 mg, 0.077 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (14.4 mg, 0.064 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 1.4 Hz), 8.03 (1H, dd, J = 8.5, 1.6 Hz), 7.96 (1H, d, J = 1.8 Hz), 7.60 (1H, dd, J = 8.5, 1.6 Hz), 7.51 (3H, dd, J = 8.2, 4.1 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.23 (2H, d, J = 7.8 Hz), 4.48-4.45 (2H, m), 4.46 (2H, s), 4.32 (2H, t, J = 5.3 Hz), 3.97 (3H, d, J = 4.6 Hz), 3.82-3.77 (4H, m), 3.30 (2H, t, J = 13.6 Hz), 3.30 (3H, s), 3.03 (2H, t, J = 6.6 Hz), 2.40-2.30 (2H, m); 19 F NMR (CDCl3) δ: -63.1 (3F, s), -97.8 (2F, m); LC-MS[M+1] = 642.2.

[0614] Step 7: 2-[3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0615]

[0616] The title compound (14.2 mg) was obtained as a white solid from methyl 2-[3,3-difluoro-9-[2-[(4-(trifluoromethyl)benzyl)oxy]ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (15.2 mg, 0.024 mmol) in the same manner as in Step 9 of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ: 8.16 (1H, s), 7.91 (1H, s), 7.87 (1H, d, J = 8.2 Hz), 7.64-7.55 (5H, m), 7.34 (2H, d, J = 7.8 Hz), 4.53 (2H, s), 4.47 (2H, t, J = 5.3 Hz), 4.42 (2H, t, J = 4.8 Hz), 3.78 (2H, t, J = 4.8 Hz), 3.68 (2H, t, J = 13.0 Hz), 3.31 (2H, t, J = 14.4 Hz), 3.12 (3H, s), 3.04 (2H, t, J = 5.9 Hz), 2.41-2.31 (2H, m); 19 F-NMR (DMSO-d6) δ: -60.6 (3F, s), -94.9 (2F, m); LC-MS[M+1] = 628.2.

[0617] Example 18 Synthesis of 2-(3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0618]

[0619] Step 1: Methyl 3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate

[0620]

[0621] The title compound (99.6 mg) was obtained as a pale yellow solid from 1-((2-bromoethoxy)methyl)-4-fluorobenzene (398.7 mg, 1.71 mmol) and methyl 3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (143.9 mg, 0.54 mmol) synthesized in Step 4 of Example 1, in the same manner as in Step 5 of Example 1. 1H-NMR (400 MHz, CDCl3) δ: 8.19 (1H, dd, J = 4.6, 1.4 Hz), 7.89-7.86 (1H, m), 7.31-7.24 (2H, m), 7.08-7.03 (1H, m), 6.95-6.90 (2H, m), 4.33 (2H, s), 4.25 (2H, t, J = 5.3 Hz), 3.94 (3H, s), 3.73 (2H, t, J = 5.3 Hz), 3.29 (2H, t, J = 14.0 Hz), 3.00-2.97 (2H, m), 2.41-2.27 (2H, m); LC-MS[M+1] = 418.2.

[0622] Step 2 (3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol

[0623]

[0624] The title compound (61.2 mg) as a colorless oil was obtained from methyl 3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (99.3 mg, 0.24 mmol) in the same manner as in Step 6 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.43-7.40 (3H, m), 7.24-7.15 (4H, m), 4.76 (2H, s), 4.32 (2H, s), 4.22 (2H, t, J = 5.5 Hz), 3.71 (2H, t, J = 5.5 Hz), 3.25 (2H, t, J = 14.2 Hz), 2.96 (2H, t, J = 6.6 Hz), 2.39-2.26 (2H, m); 19 F-NMR (CDCl3) δ: -97.6 (2F, m), -115.2(1F, m); LC-MS[M+1] = 390.2.

[0625] Step 3: 3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde

[0626]

[0627] The title compound (17 mg) was obtained as a colorless oil from (3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)methanol (62.1 mg, 0.16 mmol) in the same manner as in Step 7 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 10.03 (1H, s), 7.98 (1H, d, J = 1.4 Hz), 7.74-7.72 (1H, m), 7.34 (1H, d, J = 8.7 Hz), 7.08-7.03 (2H, m), 6.95-6.89 (2H, m), 4.34 (2H, s), 4.27 (2H, t, J = 5.5 Hz), 3.74 (2H, t, J = 5.5 Hz), 3.30 (2H, t, J = 14.0 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.39-2.29 (2H, m); 19 F-NMR (CDCl3) δ: -97.8(2F, m), -114.9(1F, m).

[0628] Step 4: 2-(3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0629]

[0630] The title compound (15.2 mg) was obtained as pale yellow crystals from 3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (17 mg, 0.044 mmol) and methyl 3-amino-4-[(2-methoxyethyl)amino]benzoate (9.6 mg, 0.04 mmol) synthesized in Step 2 of Example 1, in the same manner as in Step 8 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 1.4 Hz), 8.04 (1H, dd, J = 8.7, 1.4 Hz), 7.94 (1H, d, J = 1.4 Hz), 7.59 (1H, dd, J = 8.5, 1.6 Hz), 7.51 (1H, d, J = 8.7 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.11-7.07 (2H, m), 6.95 (2H, dq, J = 11.7, 3.0 Hz), 4.47 (2H, t, J = 5.7 Hz), 4.36 (2H, s), 4.30 (2H, t, J = 5.5 Hz), 3.96 (3H, s), 3.78 (4H, q, J = 5.8 Hz), 3.30 (3H, s), 3.30 (2H, t, J = 13.7 Hz), 3.02 (2H, t, J = 6.6 Hz), 2.39-2.30 (2H, m); 19 F-NMR (CDCl3) δ: -97.7(2F, m), 115.1(1F, m); LC-MS[M+1] = 592.2.

[0631] Step 5: 2-(3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0632]

[0633] The title compound (8.1 mg) was obtained as a white solid from methyl 2-(3,3-difluoro-9-[2-((4-fluorobenzyl)oxy)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (13.3 mg, 0.022 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.30 (1H, s), 8.20-8.12 (2H, m), 7.87-7.85 (1H, m), 7.81-7.75 (2H, m), 7.19-7.15 (2H, m), 7.03-6.99 (2H, m), 4.87-4.83 (2H, m), 4.52-4.50 (2H, m), 4.44 (2H, s), 3.89-3.87 (2H, m), 3.84-3.81 (2H, m), 3.37 (2H, t, J = 13.7 Hz), 3.23 (3H, s), 3.15-3.14 (2H, m), 2.43-2.36 (2H, m); 19 F-NMR (DMSO-d6) δ: -94.9 (2F, m), 115.1(1F, m); LC-MS[M+1] = 578.2.

[0634] Example 19 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-[2-(2-methoxyethoxy)ethyl]-1H-benzo[d]imidazole-5-carboxylic acid

[0635]

[0636] Step 1: Methyl 4-[[2-(2-methoxyethoxy)ethyl]amino]-3-nitrobenzoate

[0637]

[0638] The title compound (1.5 g) was obtained as yellow crystals from methyl 4-chloro-3-nitrobenzoate (1.05 g, 4.86 mmol) and 2-(2-methoxyethoxy)ethan-1-amine (0.93 g, 7.78 mmol) in the same manner as in Step 1 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 8.88 (1H, d, J = 2.3 Hz), 8.58 (1H, br s), 8.06-8.03 (1H, m), 6.89 (1H, d, J = 9.1 Hz), 3.90 (3H, s), 3.81 (2H, t, J = 5.5 Hz), 3.71-3.69 (2H, m), 3.60-3.55 (4H, m), 3.40 (3H, s); LC-MS[M+1] = 299.2.

[0639] Step 2: Methyl 3-amino-4-[[2-(2-methoxyethoxy)ethyl]amino]benzoate

[0640]

[0641] The title compound (869.5 mg) was obtained as pale purple crystals from methyl 4-[[2-(2-methoxyethoxy)ethyl]amino]-3-nitrobenzoate (1.05 g, 4.86 mmol) in the same manner as in Step 2 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.56 (1H, dd, J = 8.2, 1.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 6.59 (1H, d, J = 8.7 Hz), 3.85 (3H, s), 3.77 (2H, t, J = LC-MS[M+1] = 269.1.

[0642] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-[2-(2-methoxyethoxy)ethyl]-1H-benzo[d]imidazole-5-carboxylate methyl

[0643]

[0644] Using methyl 3-amino-4-[[2-(2-methoxyethoxy)ethyl]amino]benzoate (39.1 mg, 0.15 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (50.2 mg, 0.19 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (68 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.52 (1H, d, J = 1.4 Hz), 8.02 (1H, dd, J = 8.5, 1.6 Hz), 7.91 (1H, d, J = 1.4 Hz), 7.58 (1H, dd, J = 8.7, 1.4 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.40 (1H, d, J = 8.7 Hz), 4.49 (2H, t, J = 5.7 Hz), 4.14 (2H, q, J = 7.1 Hz), 3.96 (3H, s), 3.86 (2H, t, J = 5.7 Hz), 3.52-3.49 (2H, m), 3.43-3.41 (2H, m), 3.29 (2H, t, J = 13.7 Hz), 3.29 (3H, s), 3.00 (2H, t, J = 6.6 Hz), 2.45-2.35 (2H, m), 1.39 (3H, t, J = 7.3 Hz); LC-MS[M+1] = 512.2.

[0645] Step 4: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-[2-(2-methoxyethoxy)ethyl]-1H-benzo[d]imidazole-5-carboxylic acid

[0646]

[0647] The title compound (46 mg) was obtained as a white solid from methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-[2-(2-methoxyethoxy)ethyl]-1H-benzo[d]imidazole-5-carboxylate (68 mg, 0.13 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.20 (1H, d, J = 0.9 Hz), 7.93 (1H, s), 7.86 (1H, dd, J = 8.2, 1.4 Hz), 7.73 (1H, d, J = 8.7 Hz), 7.59 (2H, d, J = 0.9 Hz), 4.49 (2H, t, J = 5.3 Hz), 4.20 (2H, q, J = 7.2 Hz), 3.79 (2H, t, J = 5.5 Hz), 3.39 (2H, dd, J = 5.7, 3.4 Hz), 3.29-3.26 (4H, m), 3.10 (3H, s), 3.01 (2H, t, J = 6.4 Hz), 2.46-2.35 (2H, m), 1.28 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.9 (2F, m); LC-MS[M+1] = 498.2.

[0648] Example 20 Synthesis of 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-phenoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0649]

[0650] Step 1: Methyl 3-nitro-4-[(2-phenoxyethyl)amino]benzoate

[0651]

[0652] The title compound (1.44 g) was obtained as yellow crystals from methyl 4-chloro-3-nitrobenzoate (1.08 g, 5.02 mmol) and 2-phenoxyethan-1-amine (1.16 g, 8.43 mmol) in the same manner as in Step 1 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 8.90 (1H, d, J = 2.3 Hz), 8.68 (1H, br s), 8.09 (1H, dd, J = 8.9, 2.1 Hz), 7.32-7.28 (2H, m), 7.02-6.92 (4H, m), 4.27 (2H, t, J = 5.5 Hz), 3.91 (3H, s), 3.80 (2H, q, J = 5.5 Hz); LC-MS[M+1] = 317.2.

[0653] Step 2: Methyl 3-amino-4-[(2-phenoxyethyl)amino]benzoate

[0654]

[0655] The title compound (889.3 mg) was obtained as yellow crystals from methyl 3-nitro-4-[(2-phenoxyethyl)amino]benzoate (1.01 g, 4.3.22 mmol) in the same manner as in Step 2 of Example 1. 1 H-NMR (400 MHz, CDCl3) δ: 7.59 (1H, dd, J = 8.5, 2.1 Hz), 7.42 (1H, d, J = 2.3 Hz), 7.33-7.28 (2H, m), 7.00-6.92 (3H, m), 6.66 (1H, d, J = LC-MS[M+1] = 287.2.

[0656] Step 3: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-phenoxyethyl)-1H-benzo[d]imidazole-5-carboxylate methyl

[0657]

[0658] Using methyl 3-amino-4-[(2-phenoxyethyl)amino]benzoate (29.6 mg, 0.10 mmol) and 9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole-6-carbaldehyde (36.8 mg, 0.14 mmol) synthesized in Step 7 of Example 1, in the same manner as in Step 8 of Example 1, the title compound (50 mg) was obtained as white crystals. 1 H-NMR (400 MHz, CDCl3) δ: 8.53 (1H, d, J = 1.4 Hz), 8.06 (1H, dd, J = 8.7, 1.4 Hz), 7.91 (1H, d, J = 1.4 Hz), 7.60-7.57 (2H, m), 7.42 (1H, d, J = 8.2 Hz), 7.23-7.18 (2H, m), 6.92 (1H, t, J = 7.2 Hz), 6.76-6.73 (2H, m), 4.71 (2H, t, J = 5.7 Hz), 4.28 (2H, t, J = 5.7 Hz), 4.16 (2H, q, J = 7.1 Hz), 3.96 (3H, s), 3.28 (2H, t, J = 14.0 Hz), 3.01 (2H, t, J = 6.4 Hz), 2.46-2.36 (2H, m), 1.40 (3H, t, J = 7.1 Hz); 19 F-NMR (CDCl3) δ: -97.7 (2F, m); LC-MS[M+1] = 530.2.

[0659] Step 4: 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-phenoxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0660]

[0661] The title compound (28.7 mg) was obtained as a white solid from methyl 2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1-(2-phenoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (43 mg, 0.081 mmol) in the same manner as in Step 9 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.38 (1H, d, J = 1.4 Hz), 8.10 (1H, s), 8.07 (1H, dd, J = 8.7, 1.4 Hz), 7.99 (1H, d, J = 8.2 Hz), 7.81-7.76 (2H, m), 7.35 (2H, t, J = 7.0 Hz), 7.05-7.02 (1H, m), 6.95-6.92 (2H, m), 4.92 (2H, t, J = 5.0 Hz), 4.48 (2H, t, J = 5.0 Hz), 4.39 (2H, q, J = 7.2 Hz), 3.46-3.42 (2H, m), 3.20 (2H, t, J = 6.4 Hz), 2.63-2.53 (2H, m), 1.47 (3H, t, J = 7.1 Hz); 19 F-NMR (DMSO-d6) δ: -94.9(2F, m); LC-MS[M+1] = 516.2.

[0662] Example 21 Synthesis of 1-[2-(benzyloxy)ethyl]-2-(9-ethyl-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-1H-benzimidazole-5-carboxylic acid

[0663]

[0664] Step 1: Methyl 4-[[2-(benzyloxy)ethyl]amino]-3-nitrobenzoate

[0665]

[0666] The title compound (1.0 g) was obtained as yellow crystals from methyl 4-chloro-3-nitrobenzoate (1.01 g, 4.68 mmol) and 2-(benzyloxy)ethan-1-amine hydrochloride (1.42 g, 7.5 mmol) in the same manner as in Step 1 of Example 1. This product was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) δ: 8.89 (1H, d, J = 2.3 Hz), 8.60 (1H, s), 8.04 (1H, dd, J = 9.1, 2.3 Hz), 7.37 (4H, d, J = 4.1 Hz), 7.35-7.28 (1H, LC-MS[M+1] = 331.2.

[0667] Step 2: Methyl 3-amino-4-[[2-(benzyloxy)ethyl]amino]benzoate

[0668]

[0669] The title compound (210.9 mg) was obtained as purple crystals from methyl 4-[[2-(benzyloxy)ethyl]amino]-3-nitrobenzoate (310.5 mg, 0.94 mmol) in the same manner as in Step 3 of Example 4. 1 H-NMR (400 MHz, CDCl3) δ: 7.56 (1H, dd, J = 8.2, 1.8 Hz), 7.40 (1H, d, J = 1.8 Hz...

Claims

1. A compound represented by the following formula (I): [In the formula, R １ , R ２ , and R ３ are each independently a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group, C １－４ Alkoxy group or mono or di C １－４ represents an alkylamino group; ４ is a hydrogen atom, C optionally substituted with one or more substituents selected from the substituent group a １－４ Alkyl group, C １－６ Alkylsulfonyl group, halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ represents an alkyl-carbonyl group; １ａ , X １ｂ , and X ２ are each independently a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a; C １－４ Alkyl group or C １－４ represents an alkoxy group; １ is N.R. ５ , O, or S; ２ is CR ６ or N; ５ is a hydrogen atom or C which may be substituted with one or more substituents selected from the substituent group a １－４ R represents an alkyl group; ６ C may be substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the substituent group a. １－４ Alkyl group or C １－４ represents an alkoxy group; L represents a single bond, -CH ２ -, -CH=CH-, -CH ２ CH ２ --, --OCH ２ - or -CH ２ and Z represents a carboxy group, a hydroxy group, or a group biologically equivalent to a carboxy group, or a pharma- ceutically acceptable salt thereof. (Substituent group a): a halogen atom; a cyano group; a hydroxy group; a carboxy group; a nitro group; C １－４ C optionally substituted with an alkoxy group １－６ Alkoxy group; １－６ haloalkoxy group; １－６ Alkylsulfonyl group; １－６ Haloalkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; C ６－１４ Aryl-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a diC １－６ an alkylamino group, (iv) C １－６ an alkoxy group, and (v) C １－６ haloalkoxy group, １－６ a carbamoyl group optionally substituted with an alkyl group; １－６ Alkylamino group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ Aryl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ６－１４ An aryloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group, １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ an alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ６－１４ Arylsulfonyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group, １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ an alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy group; (i) a halogen atom, (ii) C １－６ (iii) an alkyl group; １－６ (iv) a haloalkyl group; １－６ an alkoxy group, (v) C １－６ (vi) a haloalkoxy group, １－６ (vii) an alkylsulfonyl group; １－６ (viii) a haloalkylsulfonyl group, １－６ (ix) an alkyl-carbonyl group; １－６ an alkoxy-carbonyl group, (x) C １－６ (xi) a haloalkyl-carbonyl group; １－６ (xii) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiii) a nitro group; ７－１８ Aralkyloxy-carbonyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８ Cycloalkyl group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ (xiv) a C alkyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; ３－８ Cycloalkyloxy group; (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group; and (i) a halogen atom, (ii) a hydroxy group, (iii) a carboxy group, (iv) C １－６ (v) an alkyl group; １－６ (vi) a haloalkyl group; １－６ an alkoxy group, (vii) C １－６ (viii) a haloalkoxy group, １－６ (ix) an alkylsulfonyl group; １－６ haloalkylsulfonyl group, (x) C １－６ (xi) an alkyl-carbonyl group; １－６ (xii) an alkoxy-carbonyl group; １－６ (xiii) a haloalkyl-carbonyl group, １－６ a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy-carbonyl group, and (xiv) a nitro group.

2. R １ , R ２ , and R ３ are each independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ Alkoxy group, C １－４ Fluoroalkoxy group, or mono- or di-C １－４ Alkoxy-C １－４ is an alkylamino group, R ４ is a hydrogen atom; １－４ (i) a fluoroalkyl group; or １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom; (b) C １－６ (c) an alkyl group; １－６ (d) a haloalkyl group; １－６ (e) an alkoxy group; and １－６ haloalkoxy group, ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ (d) a haloalkyl group; １－６ (e) an alkoxy group; and １－６ haloalkoxy group, ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, (a) a halogen atom, (b) C １－６ (c) an alkyl group; １－６ (d) a haloalkyl group; １－６ (e) an alkoxy group; １－６ haloalkoxy group, ６－１４ (viii) an aryl group, (viii) a hydroxy group, and (ix) a carboxy group; １－４ Alkyl group, C １－６ Alkyl sulfonyl group, or halogen atom or C １－６ C optionally substituted with an alkoxy group １－６ is an alkyl-carbonyl group, １ａ , X １ｂ , and X ２ are each independently a hydrogen atom, a halogen atom, or C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ Alkoxy group, or C １－４ is a fluoroalkoxy group; １ But, N.R. ５ , O, or S; ２ But, CR ６ or N; R ５ is a hydrogen atom; １－４ (i) a fluoroalkyl group; or １－４ an alkoxy group, (ii) C １－４ (iii) (a) a halogen atom; (b) C １－６ (c) an alkyl group; １－６ (d) a haloalkyl group; １－６ (e) an alkoxy group; １－６ haloalkoxy group, ６－１４ (iv) (a) an aryloxy group, (b) a halogen atom, １－６ (c) an alkyl group; １－６ (d) a haloalkyl group; １－６ (e) an alkoxy group; １－６ haloalkoxy group, ７－１８ (v) an aralkyloxy group; １－４ Alkoxy-C １－４ (vi) an alkoxy group, (vii) a cyclic ether group, and (vii) a 5- to 14-membered aromatic heterocyclic group, １－４ is an alkyl group, R ６ is a hydrogen atom, a halogen atom, C １－４ Alkyl group, C １－４ Fluoroalkyl group, C １－４ Alkoxy group, or C １－４ L is a single bond, -CH ２ -, -CH=CH-, -CH ２ CH ２ - or -OCH ２ The compound according to claim 1, wherein R is -R, R is -R, or a pharma- ceutically acceptable salt thereof.

3. Y １ But, N.R. ５ 3. The compound according to claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

4. Y １ But, N.R. ５ And Y ２ But, CR ６ 3. The compound according to claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

5. X １ａ and / or X １ｂ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is a fluorine atom.

6. X ２ , R ２ , and R ３ are all hydrogen atoms, or a pharma- ceutically acceptable salt thereof.

7. R １ The compound according to any one of claims 1 to 6, wherein is a hydrogen atom or a methyl group, or a pharma- ceutically acceptable salt thereof.

8. X １ａ and X １ｂ and R are both fluorine atoms, or a pharma- ceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein L is a single bond.

10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein Z is a carboxy group.

11. R ４ is a hydroxy group or C １－４ C which may be substituted with an alkoxy group １－４ The compound according to any one of claims 1 to 10, which is an alkyl group, or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, for the prevention and / or treatment of a disease whose symptoms can be alleviated by EP4 antagonism.

14. The pharmaceutical composition according to claim 13, wherein the disease whose symptoms can be alleviated by EP4 antagonism is cancer.

15. The pharmaceutical composition of claim 14, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

16. An EP4 antagonist comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof.

17. A medicine for preventing and / or treating cancer, comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof in combination with an immune checkpoint inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, familial adenomatous polyposis, gastric cancer, esophageal cancer, skin cancer, pancreatic cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, bladder cancer, head and neck cancer, uterine cancer, breast cancer, ovarian cancer, prostate cancer, brain tumor, malignant lymphoma, and leukemia.

19. The pharmaceutical composition according to claim 17 or 18, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or anti-PD-L1 antibody selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, atezolizumab, avelumab, and durvalumab.

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