Novel 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives and their pharmaceutical uses

Abstract

To provide a compound superior in ATX inhibitory action and useful for the prophylaxis or treatment of diseases involving ATX.SOLUTION: The invention provides a carboxylic acid compound represented by general formula (1) or a pharmacologically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to novel 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives or pharmacologically acceptable salts thereof having an autotaxin inhibitory action and being effective for the prevention or treatment of diseases caused by autotaxin in mammals including humans.

Background Art

[0002] Autotaxin (hereinafter sometimes referred to as ATX) was isolated from the culture supernatant of the human malignant melanoma cell line A2058 and identified as a cell migration promoting factor. ATX is also called secreted lysophospholipase D (hereinafter sometimes referred to as lysoPLD) and ENPP2 (Ectonucleotide Pyrophosphatase / Phosphodiesterase 2), is the main body of lysoPLD activity, and produces lysophosphatidic acid (hereinafter sometimes referred to as LPA), a lipid mediator having various physiological activities, by hydrolyzing lysophosphatidylcholine (LPC).

[0003] LPA produced by ATX binds to G protein-coupled receptors (GPCRs), transmits signals into cells, and exhibits various physiological effects. Six subtypes of LPA receptors, from LPA1 to LPA6, are known. LPA receptor subtypes are distributed throughout the body, but their localization tissues vary depending on the subtype, and various receptor subtypes are involved in their respective biological functions depending on the tissue. LPA receptors are classified into two subfamilies. LPA1 to LPA3 are classified into the endothelial differentiation gene (Edg) family. LPA4 to LPA6 are non-Edg family LPA receptors and are receptors similar to the purinergic receptor family (Non-Patent Documents 1 and 2). Through these LPA receptors, LPA is involved in a wide variety of life phenomena physiologically (both in maintaining homeostasis and in pathological conditions).

[0004] On the other hand, as for the relationship with diseases, it has been clarified that intracellular signaling pathways via ATX and LPA receptors are involved in various cancers and various inflammatory diseases. Specifically, various cancers such as cancer, tumor, neoplasm, malignant melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV-positive Hodgkin lymphoma, glioma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostate intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor, renal cell carcinoma, etc., various fibrotic diseases such as pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, diabetic nephropathy or atherosclerosis, various inflammatory diseases such as asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, obesity related to type II diabetes, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, itching, etc., eye diseases such as glaucoma, urological diseases such as benign prostatic hyperplasia, etc. are associated (Non-Patent Documents 2 to 13).

[0005] Furthermore, it has been clarified that intracellular signaling pathways via ATX and LPA receptors are involved in various fibrotic diseases.

[0006] Regarding the involvement with the disease, regarding pulmonary fibrosis, it has been shown that the LPA concentration increases in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and that the concentration of ATX increases in the lung tissue of a bleomycin-induced pulmonary fibrosis model. Furthermore, it has been shown that in LPA1-deficient mice, the progression and death of bleomycin-induced pulmonary fibrosis are significantly suppressed (Non-Patent Documents 14 and 15).

[0007] Regarding liver fibrosis, it has been shown that LPA promotes the contraction and proliferation of hepatic stellate cells, which play a central role in liver fibrosis, and suppresses apoptosis, and that in patients with chronic hepatitis C, the serum autotaxin activity and plasma LPA amount increase with the progression of liver fibrosis (Non-Patent Documents 16 to 18).

[0008] Regarding renal fibrosis, in a unilateral ureteral obstruction model, the production of LPA and the expression of LPA1 are enhanced, LPA1-deficient mice show resistance to fibrosis, and it has been shown that an LPA receptor antagonist suppresses the progression of fibrosis (Non-Patent Document 19).

[0009] Regarding scleroderma, the expression of ATX is enhanced in the skin of patients with scleroderma. Furthermore, in a bleomycin-induced scleroderma model, the ATX expression in the skin is enhanced, and it has been shown that an ATX inhibitor suppresses the production of IL-6 and the infiltration of CD3-positive cells in the skin, and suppresses skin sclerosis and hydroxyproline production (Non-Patent Document 20).

[0010] Regarding the urinary excretion disorder in benign prostatic hyperplasia, which is one of urological diseases, it has been shown that acting on the isolated rat urethra with LPA causes urethral contraction. Furthermore, it has been shown that the intraurethral pressure can be decreased by administering an ATX inhibitor to rats (Non-Patent Document 21).

[0011] Regarding glaucoma, the concentrations of ATX and LPA are increased in the aqueous humor of patients with normal-tension glaucoma, primary open-angle glaucoma, secondary open-angle glaucoma, and exfoliation glaucoma, respectively, and it has been shown that the LPA concentration, ATX concentration, and LysoPLD activity are each positively correlated with intraocular pressure. Furthermore, it has been shown that an ATX inhibitor reduces intraocular pressure in a rabbit intraocular pressure test (Dutch belted rabbits) (Non-Patent Documents 22 and 23).

[0012] Regarding neuropathic pain, it has been shown that intrathecal administration of LPA into mice induces hyperalgesic response and allodynia (Non-Patent Document 24). Furthermore, in a rat chronic constriction injury (CCI) model, an ATX inhibitor has shown analgesic and anti-allodynic effects (Non-Patent Document 25).

[0013] Regarding COPD, in a COPD model of cigarette smoke-exposed mice, an ATX inhibitor suppressed the gene expression of CCL2, SSA3, TIMP1, SLC26A4, LCN2, and MMP12 in the lungs (Patent Documents 6 and 7).

[0014] Regarding inflammatory diseases such as NASH and NAFLD, it has been shown that the serum ATX concentration is increased in patients with liver cirrhosis, and furthermore, the serum ATX concentration is positively correlated with the Child-Pugh stage and MELD score (Non-Patent Document 26). Also, in a mouse STAM-NASH model combining streptozotocin (STZ) administration with a high-fat diet load, an ATX inhibitor showed improvement in the NAS score due to its anti-inflammatory effect and the effect of suppressing ballooning degeneration of hepatocytes. Furthermore, in a mouse NASH model using a choline-deficient high-fat diet (CDAHFD), it has been shown that an ATX inhibitor suppresses liver fibrosis (Non-Patent Document 27).

[0015] Regarding rheumatoid arthritis, it has been shown that the concentration of ATX is increased in fibroblast-like synoviocytes (SFC) of rheumatoid arthritis patients (Non-Patent Document 28). Furthermore, in a collagen-induced arthritis model, the ATX concentration in the synovium is increased (Non-Patent Document 5), and it has been shown that an ATX inhibitor improves the joint pathology score (Non-Patent Document 29).

[0016] Regarding osteoarthritis, it has been shown that the ATX concentration is increased in the synovial fluid of osteoarthritis patients. Furthermore, it has been shown that there is a positive correlation between the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and the ATX concentration in the synovial fluid (Non-Patent Document 30). Furthermore, it has been shown that an ATX inhibitor suppresses pain in a monoiodoacetate-induced osteoarthritis model (Non-Patent Document 31).

[0017] As ATX inhibitors, lipid analogs (Non-Patent Document 32), tetrahydrocarboline derivatives (Patent Document 1), 1H-indole compounds (Patent Document 2), piperidine or piperazine derivatives (Patent Document 3), pyridazine derivatives (Patent Document 4), 2-amino-pyridine and 2-amino-pyrimidine derivatives (Patent Document 5) are known. These have structures different from those of the 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives which are the compounds of the present invention.

Prior Art Documents

Patent Documents

[0018]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

[0019] [Non-Patent Document 1] Choi et al., Annu Rev Pharmacol Toxicol. 2010, 50:157-186 [Non-Patent Document 2] Houben et al., Cancer Metastasis Rev. 2011, 30(3-4):557-565 [Non-Patent Document 3] Benesch et al., FEBS Lett. 2014;588:2712-2727 [Non-Patent Document 4] Inoue et al., Mol Pain. 2008;4:6 [Non-Patent Document 5] Nikitopoulou et al., J Exp Med. 2012;209(5):925-933 [Non-Patent Document 6] Siess et al., Proc Natl Acad Sci USA. 1999;96(12):6931-6936 [Non-Patent Document 7] Zhou et al., Cell Metab. 2011;13(5):592-600 [Non-Patent Document 8] Im et al., Clinical Lipidology 2015;10(2):177-190 [Non-Patent Document 9] Valdes-Rives et al., Mediators Inflamm. 2017;2017:9173090 [Non-Patent Document 10] D´Souza et al., Nutrients. 2018;10(4):E399 [Non-Patent Document 11] Kremer et al., Hepatology 2012;56(4):1391-1400 [Non-Patent Document 12] Hegade et al., Frontline Gastroenterol. 2016;7(3):158-166 [Non-Patent Document 13] Chu et al., Int J Clin Exp Med. 2015;8(10):17117-17122 [Non-Patent Document 14] Tager et al., Nat Med.2008;14(1):45-54 [Non-Patent Document 15] Oikonomou et al., Am J Respir Cell Mol Biol.2012;47(5):566-574 [Non-Patent Document 16] Ikeda et al., Biochem Biophys Res Commun.1998;248(2):436-440 [Non-Patent Document 17] Yanase et al., Biochem Biophys Res Commun.2000;277(1):72-78 [Non-Patent Document 18] Ikeda et al., Am J Physiol Gastrointest Liver Physiol.2003;285(5):G880-G886 [Non-Patent Document 19] Pradere et al., J Am Soc Nephrol. 2007;18(12):3110-3118 [Non-Patent Document 20] Castelino et al., Arthritis Rheumatol. 2016;68(12):2964-2974 [Non-Patent Document 21] Saga et al., PLoS One 2014;9(4):e93230 [Non-Patent Document 22] Honjo et al., Invest Ophthalmol Vis Sci. 2018;59(2):693-701 [Non-Patent Document 23] Iyer et al., PLoS One. 2012;7(8):e42627

Non-Patent Document 24

Non-Patent Document 25

Non-Patent Document 26

Non-Patent Document 27

Non-Patent Document 28

Non-Patent Document 29

Non-Patent Document 30

Non-Patent Document 31

Non-Patent Document 32

Summary of the Invention

Problems to be Solved by the Invention

[0020] An object of the present invention is to provide a compound having excellent ATX inhibitory activity and being useful for the prevention or treatment of diseases involving ATX.

Means for Solving the Problems

[0021] As a result of intensive studies to solve the above problems, the present inventors have found a compound that inhibits ATX and have found that it can provide a prophylactic or therapeutic agent for diseases involving ATX, thus completing the present invention.

[0022] That is, the gist of the present invention relates to the following [1] to

[24] , but is not limited thereto. [1] A carboxylic acid compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof (which may be abbreviated as "compound (1)" in this specification).

[0023] [Chemical formula]

[0024] [In the formula, R 1 is

[0025] [Chemical formula]

[0026] [In the formula, X 1a is -C(R 1a )2- (wherein R 1a may be the same or different and each represents a hydrogen atom, a halogen atom, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C6 alkyl, or R 1a binds to form 1,1-C3-C6 cycloalkylene) or -NR 1b - (wherein R 1b represents a hydrogen atom or C1-C2 perfluoroalkyl), and X 1b and X 1c are the same or different and each represents -O- or -CH2- (provided that X 1b and X 1c do not simultaneously represent -O-), R 1crepresents a hydrogen atom, a halogen atom, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, C1-C6 alkyl or C1-C2 perfluoroalkylthio, R 1d represents a hydrogen atom, a halogen atom or C1-C6 alkyl, R 1e represents a hydrogen atom, C1-C2 perfluoroalkyl or C1-C2 perfluoroalkoxy, X represents -N= or -CH=, Ring A is

[0027]

Chemical formula

[0028] [In the formula, X 2a represents -N= or -CR 2a =(wherein R 2a represents a hydrogen atom, a halogen atom, C1-C6 alkyl or C1-C6 alkoxy), R 2b represents a hydrogen atom, a halogen atom, C1-C6 alkyl or C1-C6 alkoxy, R 2c represents a hydrogen atom or C1-C6 alkyl, X 2b represents -O-, -NR 2d -(wherein R 2d represents a hydrogen atom or C1-C2 perfluoroalkyl) or -CHR 2e -(wherein R 2e represents a hydrogen atom or C1-C6 alkyl), X 2c represents -(CH2) n’ -(wherein n' represents 0 or 1) or -O-], L represents -(CHR 3a ) n -(wherein n represents 0, 1, 2 or 3, and R 3a may be the same or different and each represents a hydrogen atom or C1-C6 alkyl), -(CH2) m -O-(CH2) m’-(wherein m and m' are the same or different and each represents 0, 1 or 2), C2-C3 alkenylene,

[0029]

Chemical formula

[0030] (wherein R 3b and R 3c may be the same or different and each represents a hydrogen atom or C1-C6 alkyl, and R 3d represents a hydrogen atom, C1-C6 alkoxy, C1-C6 alkyl or C1-C2 perfluoroalkyl, and R 3e represents a hydrogen atom, C1-C6 alkoxy, C1-C6 alkyl or C1-C2 perfluoroalkyl).}.

[0031] [2]R 1 is

[0032]

Chemical formula

[0033] (wherein X 1aa is -C(R 1aa )2- (wherein R 1aa are the same or different and each represents a hydrogen atom, C1-C2 perfluoroalkyl or C1-C6 alkyl, or R 1aa are bonded to form 1,1-C3-C6 cycloalkylene) or -NR 1ba - (wherein R 1ba represents a hydrogen atom or C1-C2 perfluoroalkyl), and R 1ca represents C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C2 perfluoroalkylthio, and R 1da represents a halogen atom or C1-C6 alkyl), the carboxylic acid compound or a pharmacologically acceptable salt thereof according to [1] above.

[0034] [3]Ring A is

[0035] [Chemical formula]

[0036] (wherein, R 2ab represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2bb represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2cb represents a hydrogen atom or C1-C6 alkyl) The carboxylic acid compound or a pharmacologically acceptable salt thereof according to any one of the above [1] or [2].

[0037] [4] Ring A is

[0038] [Chemical formula]

[0039] (wherein, R 2ac represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2bc represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2cc represents a hydrogen atom or C1-C6 alkyl) The carboxylic acid compound or a pharmacologically acceptable salt thereof according to any one of the above [1] to [3].

[0040] [5] Ring A is

[0041] [Chemical formula]

[0042] (wherein, R 2ad represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2bd represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2cdThe carboxylic acid compound or a pharmacologically acceptable salt thereof according to any one of [1] to [4] above, wherein (represents a hydrogen atom or C1-C6 alkyl).

[0043] [6] L is -(CH2) n -(wherein n represents 1 or 2) or

[0044] [Chemical formula]

[0045] (wherein R 3ab and R 3bb may be the same or different and each represents a hydrogen atom or C1-C6 alkyl), the carboxylic acid compound or a pharmacologically acceptable salt thereof according to any one of [1] to [5] above.

[0046] [7] The carboxylic acid compound or a pharmacologically acceptable salt thereof according to any one of [1] to [6] above, wherein X is -N=.

[0047] [8] The carboxylic acid compound or a pharmacologically acceptable salt thereof according to [1] above, wherein the compound represented by the general formula (1) is any of the following. trans-2-[2-Methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1R,2R)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-Methoxy-5’-{[4-(trifluoromethoxy)benzyl]oxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1R,2R)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1S,2S)-2-[2-Ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-Fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Methyl-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-Chloro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S,6R)-6-Methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, or (1S,2S)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid.

[0048] [9]A pharmaceutical composition comprising the carboxylic acid compound according to any one of [1] to [8] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0049]

[10] The pharmaceutical composition according to [9] above, which is used as an autotaxin inhibitor.

[0050]

[11] The pharmaceutical composition according to [9] above, which is used for the treatment or prevention of a disease involving autotaxin.

[0051]

[12] The pharmaceutical composition according to

[11] above, wherein the disease involving autotaxin is cancer or tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity associated with type II diabetes or acute coronary syndrome.

[0052]

[13] The pharmaceutical composition according to

[12] above, wherein the cancer or tumor is malignant melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostate intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor or renal cell carcinoma.

[0053]

[14] The pharmaceutical composition according to

[12] above, wherein the fibrosis disease is pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, diabetic nephropathy or atherosclerosis.

[0054]

[15] The pharmaceutical composition according to

[14] , wherein the fibrotic disease is pulmonary fibrosis, scleroderma, liver fibrosis or renal fibrosis.

[0055]

[16] The pharmaceutical composition according to

[12] , wherein the inflammatory disease is asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain or pruritus.

[0056]

[17] The pharmaceutical composition according to

[16] , wherein the inflammatory disease is asthma or COPD.

[0057]

[18] The pharmaceutical composition according to

[16] , wherein the inflammatory disease is rheumatoid arthritis or osteoarthritis.

[0058]

[19] The pharmaceutical composition according to

[16] , wherein the inflammatory disease is NASH or NAFLD.

[0059]

[20] The pharmaceutical composition according to

[16] , wherein the inflammatory disease is inflammatory bowel disease, Crohn's disease or ulcerative colitis.

[0060]

[21] The pharmaceutical composition according to

[16] , wherein the inflammatory disease is neuropathic pain or pruritus.

[0061]

[22] The pharmaceutical composition according to

[12] , wherein the acute coronary syndrome is angina pectoris or myocardial infarction.

[0062]

[23] The pharmaceutical composition according to

[12] , wherein the eye disease is glaucoma.

[0063]

[24] The pharmaceutical composition according to

[12] , wherein the urinary disease is benign prostatic hyperplasia.

[25] A method for treating or preventing a disease in a subject, characterized by administering to the subject an effective amount of the carboxylic acid compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein autotaxin is involved in the disease in the subject.

[26] The method according to

[25] above, wherein the disease involving autotaxin is cancer or tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity related to type II diabetes or acute coronary syndrome.

[27] Use of the carboxylic acid compound according to any one of [1] to [8] above or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease involving autotaxin.

[28] The use according to

[27] above, wherein the disease involving autotaxin is cancer or tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity related to type II diabetes or acute coronary syndrome. [Advantages of the Invention]

[0064] The present invention can provide a compound having excellent ATX inhibitory action and being effective as a prophylactic or therapeutic agent for diseases involving ATX, such as cancer, tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity related to type II diabetes or acute coronary syndrome. [Brief Description of the Drawings]

[0065]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0066] Unless otherwise specified, the definitions of each group in this specification can be freely combined.

[0067] The definitions of each symbol in this specification are as follows.

[0068] R 1a 、R 1c 、R 1d 、R 2a 、R 2b 、R 2c 、R 2e 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 1aa 、R 1da 、R 2ab 、R 2bb 、R 2cb 、R 2ac 、R 2bc 、R 2cc 、R 2ad 、R 2bd 、R 2cd 、R 3bb and R 3bc The C1-C6 alkyl in R

[0069] R 1a 、R 1c 、R 1d 、R 2a 、R 2b and R 1daThe halogen atom in the above formula (I) refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, with a fluorine atom and a chlorine atom being particularly preferred.

[0070] R 1a , R 1b , R 1c , R 1e , R 2d , R 3d , R 3e , R 1aa , R 1ba and R 1ca In the above formula, the C1-C2 perfluoroalkyl is a methyl or ethyl group substituted with 1 to 5 fluorines. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl. In particular, trifluoromethyl and 2,2,2-trifluoroethyl are preferred.

[0071] R 1a , R 1c , R 1e and R 1ca The C1-C2 perfluoroalkoxy in the above means a monovalent group in which the perfluoroalkyl is bonded to oxygen, and includes perfluoroalkyl-O- having 1 to 2 carbon atoms (C1-C2). Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, etc. In particular, trifluoromethoxy or 2,2,2-trifluoroethoxy is preferred.

[0072] R 1a and R 1aa In the above formula, 1,1-C3 to C6 cycloalkylene refers to a 1,1-cycloalkylene having 3 to 6 carbon atoms, such as 1,1-cyclopropylene, 1,1-cyclobutylene, 1,1-cyclopentylene, or 1,1-cyclohexylene.

[0073] R 1c and R 1caThe C1-C2 perfluoroalkylthio in [description] refers to a monovalent group in which the above-mentioned perfluoroalkyl is bonded to sulfur, and examples thereof include perfluoroalkyl-S- having 1 to 2 carbon atoms (C1-C2). Specifically, fluoromethylthio, difluoromethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio, etc. are shown. Among them, trifluoromethylthio or 2,2,2-trifluoroethylthio is preferred.

[0074] R 2a 、R 2b 、R 3d 、R 3e 、R 2ab 、R 2bb 、R 2ac 、R 2bc 、R 2ad and R 2bd The C1-C6 alkoxy in [description] refers to a monovalent group in which the C1-C6 alkyl shown in R 1a is bonded to oxygen, and examples thereof include linear or branched alkyl-O- having 1 to 6 carbon atoms (C1-C6). Among them, alkyl-O- having 1 to 4 carbon atoms (C1-C4) is preferred, and particularly alkyl-O- having 1 to 2 carbon atoms (C1-C2) is preferred. Specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, etc. are shown. Among them, methoxy or ethoxy is preferred.

[0075] The C2-C3 alkenylene in L refers to a divalent linear hydrocarbon group having 2 to 3 carbon atoms (C2-C3) and having at least 1 double bond. Specifically, vinylene or propenylene is shown.

[0076] Diseases involving autotaxin include, for example, cancer or tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity related to type II diabetes or acute coronary syndrome. Examples of cancer or tumor include melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostate intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor, renal cell carcinoma, etc. Examples of fibrosis disease include pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, diabetic nephropathy, atherosclerosis, etc. Examples of inflammatory disease include asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, itching, etc. Examples of eye disease include glaucoma, etc. Examples of urinary disease include benign prostatic hyperplasia, etc., but are not limited thereto. Preferably, the diseases involving autotaxin are selected from the group consisting of fibrosis diseases such as pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, etc., inflammatory diseases such as asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, neuropathic pain or itching, etc., and eye diseases such as glaucoma, etc. More preferably, the diseases involving autotaxin are selected from the group consisting of fibrosis diseases such as pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, etc.

[0077] R shown in general formula (1) 1 is preferably any group represented by the following general formula.

[0078]

Chemical formula

[0079] (In the formula, R A is preferably a hydrogen atom, C1-C2 perfluoroalkyl or C1-C6 alkyl, more preferably C1-C2 perfluoroalkyl or C1-C6 alkyl, R Bis preferably C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C2 perfluoroalkylthio, more preferably C1-C2 perfluoroalkyl or C1-C2 perfluoroalkoxy, R C is preferably a halogen atom or C1-C6 alkyl, more preferably C1-C6 alkyl.)

[0080] In another embodiment of the present invention, R shown in general formula (1) 1 is preferably

[0081]

Chemical formula

[0082] (wherein X 1aa is -C(R 1aa )2- (wherein R 1aa are the same or different and each represents a hydrogen atom, C1-C2 perfluoroalkyl or C1-C6 alkyl, or R 1aa are bonded to form 1,1-C3-C6 cycloalkylene) or -NR 1ba - (wherein R 1ba represents a hydrogen atom or C1-C2 perfluoroalkyl), and R 1ca represents C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C2 perfluoroalkylthio, and R 1da represents a halogen atom or C1-C6 alkyl).

[0083] The following substituents containing ring A in general formula (1)

[0084]

Chemical formula

[0085] is preferably any group represented by the following general formula:

[0086] [Chemical formula]

[0087] (wherein, R D is preferably a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, more preferably a hydrogen atom or C1-C6 alkoxy, R E is preferably a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, more preferably a hydrogen atom or C1-C6 alkoxy)

[0088] More preferably, it is any group represented by the following general formula.

[0089] [Chemical formula]

[0090] (wherein, R D and R E are the same as those described above)

[0091] In another embodiment of the present invention, the ring A shown in the general formula (1) is preferably

[0092] [Chemical formula]

[0093] (wherein, R 2ab represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, R 2bb represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, R 2cb represents a hydrogen atom or C1-C6 alkyl), and more preferably

[0094] [Chemical formula]

[0095] (wherein, R 2ac represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2bc represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2cc represents a hydrogen atom or C1-C6 alkyl), and more preferably,

[0096]

Chemical formula

[0097] (wherein, R 2ad represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2bd represents a hydrogen atom, C1-C6 alkoxy or C1-C6 alkyl, and R 2cd represents a hydrogen atom or C1-C6 alkyl).

[0098] In another embodiment of the present invention, X represented in general formula (1) is preferably -N=.

[0099] L represented in general formula (1) is preferably -(CH2) n -(wherein, n represents 1 or 2) or

[0100]

Chemical formula

[0101] (wherein, R 3ab and R 3bb may be the same or different and each represents a hydrogen atom or C1-C6 alkyl) and more preferably,

[0102]

Chemical formula

[0103] (wherein, R 3ab and R 3bbis the same as the above).

[0104] Preferable examples of the compound (1) include the following compounds. [Compound 1-A] R 1 is

[0105] [Chemical formula]

[0106] [In the formula, X 1a is -C(R 1a )2- (wherein R 1a may be the same or different and each is a hydrogen atom, a halogen atom (e.g., fluorine atom), C1-C2 perfluoroalkyl (e.g., trifluoromethyl) or C1-C6 alkyl (e.g., methyl), or R 1a are bonded to form 1,1-C3-C6 cycloalkylene (e.g., 1,1-cyclopropylene, 1,1-cyclobutylene)) or -NR 1b - (wherein R 1b is C1-C2 perfluoroalkyl (e.g., trifluoroethyl)), and X 1b and X 1c are the same or different and each is -O- or -CH2- (provided that X 1b and X 1c do not simultaneously represent -O-), R 1c is a hydrogen atom, a halogen atom (e.g., fluorine atom, chlorine atom), C1-C2 perfluoroalkyl (e.g., trifluoromethyl), C1-C2 perfluoroalkoxy (e.g., trifluoromethoxy) or C1-C2 perfluoroalkylthio (e.g., trifluoromethylthio), R 1d is a hydrogen atom, a halogen atom (e.g., fluorine atom, chlorine atom) or C1-C6 alkyl (e.g., methyl), R 1e is C1-C2 perfluoroalkoxy (e.g., trifluoromethoxy)]; X is -N= or -CH=; Ring A is

[0107]

Chemical formula

[0108] [wherein, X 2a is -CR 2a =(wherein, R 2a is a hydrogen atom or C1-C6 alkoxy (e.g., methoxy)), R 2b is a hydrogen atom or C1-C6 alkoxy (e.g., methoxy, ethoxy)), R 2c is a hydrogen atom or C1-C6 alkyl (e.g., methyl)), X 2b is -O-, -NR 2d -(wherein, R 2d is C1-C2 perfluoroalkyl (e.g., trifluoroethyl)) or -CHR 2e -(wherein, R 2e is a hydrogen atom)), X 2c is -(CH2) n’ -(wherein, n’ is 0 or 1) or -O-], L is -(CHR 3a ) n -(wherein, n is 0, 1, 2 or 3, and R 3a may be the same or different and are each a hydrogen atom or C1-C6 alkyl (e.g., methyl)), -(CH2) m -O-(CH2) m’ -(wherein, m and m’ are each 1), C2-C3 alkenylene (e.g., vinylene, propenylene)),

[0109]

Chemical formula

[0110] (wherein, R 3b and R 3cmay be the same or different and each is a hydrogen atom or C1-C6 alkyl (e.g., methyl), R 3d is a hydrogen atom, C1-C6 alkoxy (e.g., methoxy), C1-C6 alkyl (e.g., methyl) or C1-C2 perfluoroalkyl (e.g., trifluoromethyl), R 3e is a hydrogen atom or C1-C6 alkoxy (e.g., methoxy)); Compound (1).

[0111] Specific examples of Compound (1) include, for example, the compounds of Examples 1 to 101 described later, preferably, trans-2-[2-Methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, trans-2-(5-Methoxy-5’-{[4-(trifluoromethoxy)benzyl]oxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, trans-2-[3-Methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, trans-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, trans-2-(5-Methoxy-5’-{[4-(trifluoromethyl)phenoxy]methyl}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, trans-2-(5-Methoxy-5’-{2-[4-(trifluoromethoxy)phenyl]ethyl}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, trans-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, trans-2-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, trans-2-[4-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, trans-2-(5’-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, trans-2-[3-Methoxy-6-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, trans-2-[2-Ethoxy-5-(6-{[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 1-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)-2,3-dihydro-1H-indole-5-carboxylic acid, 1-(5-{[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]methoxy}pyridin-3-yl)-2,3-dihydro-1H-indole-5-carboxylic acid, 4-[4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]benzoic acid, 3-[4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]benzoic acid, 2-Methoxy-4-[4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]benzoic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-methyl-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-chloro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S,6R)-6-methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[1-(2,2,2-trifluoroethyl)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)piperazin-2-yl]propanoic acid, [1-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)piperidin-3-yl]acetic acid, 4-[1-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)pyrrolidin-2-yl]butanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, or, (1S,2S)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid wherein, more preferably, trans-2-[2-Methoxy-5-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[4-(Trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-[2-Methoxy-5-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1R,2R)-2-[2-Methoxy-5-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-Methoxy-5’-{[4-(Trifluoromethoxy)benzyl]oxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[4-(Trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1R,2R)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1S,2S)-2-[2-Ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-Fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Methyl-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-Chloro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S,6R)-6-Methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, or (1S,2S)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid and more preferably trans-2-[2-Methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1R,2R)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-Methoxy-5’-{[4-(trifluoromethoxy)benzyl]oxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[4-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[4-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5’-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5’-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1R,2R)-2-[3-methoxy-6-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, or (1S,2S)-2-[2-ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid.

[0112] Prevention means the act of administering the compound of the present invention or a pharmaceutical composition containing the same to an individual who has not developed a disease, disorder, or symptom. Treatment means the act of administering the compound of the present invention or a pharmaceutical composition containing the same to an individual who has already developed a disease, disorder, or symptom. Therefore, the act of administering to an individual who has already developed a disease, disorder, or symptom for the purpose of preventing exacerbation of symptoms, preventing seizures, or preventing recurrence is a form of treatment.

[0113] When the compound of the present invention is used as a medicine, it can be administered orally or parenterally in the form of a pharmaceutical composition or preparation (oral preparation, injection, etc.) obtained by mixing the compound of the present invention with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, odor-correcting agent, emulsifier, diluent, solubilizing agent, etc.). The pharmaceutical composition can be formulated according to a conventional method.

[0114] Examples of preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, or syrups, etc. Preparations suitable for parenteral administration include injections, drip infusions, or suppositories, etc. For preparations suitable for oral administration, excipients, disintegrants, binders, lubricants, coating agents, or bases, etc. can be used as additives. In addition, when the compound of the present invention is administered to a patient to be treated, the compound of the present invention may be used in combination with other agents appropriate for the treatment of the target disease.

[0115] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method, or local administration (transdermal administration, ophthalmic administration, pulmonary / bronchial administration, nasal administration, or rectal administration, etc.).

[0116] The compounds of the present invention can, in some cases, be used in combination with other pharmaceuticals or the like. The administration timing of the compound of the present invention, its pharmacologically acceptable salt, or their solvates and the concomitant agent is not limited, and these may be administered simultaneously to the administration subject or at different times. Further, the compound of the present invention and the concomitant agent may be administered as two types of preparations each containing the respective active ingredient, or may be administered as a single preparation containing both active ingredients.

[0117] The dosage of the compound of the present invention is determined in consideration of these or other factors according to age, body weight, general health condition, sex, administration time, administration method, excretion rate, and the degree of the disease state being treated in the patient at that time. The daily dosage of the compound of the present invention varies depending on the patient's condition, body weight, type of compound, administration route, etc. For example, parenterally, it is administered subcutaneously, intravenously, intramuscularly, transdermally, ophthalmically, via the lung / bronchus, nasally, or rectally at about 0.0001 to 500 mg / person / day, and orally at about 0.001 to 5000 mg / person / day.

[0118] The compound (1) of the present invention can be produced, for example, according to the following production methods 1 to 29.

[0119] Production method 1 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0120]

Chemical formula

[0121] (In the formula, R 4 is alkyl, X A and X B are halogen atoms, Q 1 is a borate ester, and the other symbols are as defined above.) [Step 1a] Compound (A2) can be produced by reacting compound (A1) with bis(pinacolato)diboron in a solvent in the presence of a transition metal complex and a base. As the solvent, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc. can be appropriately used.

[0122] As the transition metal complex, for example, zero-valent palladium complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and other divalent palladium complexes are used.

[0123] In addition, an appropriate ligand may be added to the transition metal complex. Examples of the appropriate ligand include tri-tert-butylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri(ortho-tolyl)phosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, di(1-adamantyl)-n-butylphosphine, (2-biphenyl)di-tert-butylphosphine, (S)-1-[(1R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and the like.

[0124] Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and the like. The amount of the transition metal complex used can be 0.01 to 0.5 equivalent, preferably 0.03 to 0.1 equivalent, based on the compound (A1). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, based on the compound (A1). In particular, it can be preferably produced by a method using the reaction conditions as described in J. Org. Chem., 1995, 60, 7508 - 7510.

[0125] [Step 1b] Compound (A4) can be produced by reacting compound (A2) and compound (A3) in a solvent in the presence of a transition metal complex and a base. As the solvent, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, 2-propanol, tert-butyl alcohol, water or a mixed solvent can be appropriately used. As the transition metal complex, for example, zerovalent palladium complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and other divalent palladium complexes are used.

[0126] In addition, an appropriate ligand may be added to the transition metal complex. Examples of the appropriate ligand include tri-tert-butylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri(ortho-tolyl)phosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, di(1-adamantyl)-n-butylphosphine, (2-biphenyl)di-tert-butylphosphine, (S)-1-[(1R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and the like.

[0127] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, dipotassium hydrogen phosphate, and the like. The amount of the transition metal complex used can be 0.01 to 0.5 equivalent, preferably 0.03 to 0.1 equivalent, relative to the compound (A3). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to the compound (A3). In particular, it can be preferably produced by a method using reaction conditions as described in Acc. Chem. Res., 2008, 41, 1461 - 1473. Further, it can be preferably produced by a method using a palladium catalyst precursor containing an appropriate ligand as described in J. Am. Chem. Soc., 2010, 132, 14073 - 14075.

[0128] [Process 1c] Compound (A5) can be produced by hydrolyzing compound (A4) by a commonly used method. It can be produced by hydrolysis in a suitable mixed aqueous solution in the presence of a base. As the solvent, for example, methanol, ethanol, tetrahydrofuran, etc. can be preferably used by making them into a mixed aqueous solution. As the base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide can be preferably used.

[0129] Production method 2 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0130] [Chemical formula]

[0131] (In the formula, R 4 is alkyl, X A and X B are halogen atoms, Q 1 is a borate ester, and the other symbols are as described above.) [Process 2a] Compound (B1) can be produced by reacting compound (A3) with bis(pinacolato)diboron using the same method as in [Process 1a].

[0132] [Process 2b] Compound (A4) can be produced by reacting compound (B1) with compound (A1) using the same method as in [Process 1b].

[0133] Production method 3 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0134] [Chemical formula]

[0135] (In the formula, R 4 is alkyl, X Bis a halogen atom, and Q 1 is a borate ester, and the other symbols are as described above.) [Step 3a] Compound (C2) can be produced by reacting compound (C1) and compound (B1) using the same method as in [Step 1b].

[0136] [Step 3b] Compound (C4) can be produced by reacting compound (C2) and compound (C3) in a solvent in the presence of a Mitsunobu reagent and a phosphine reagent. Examples of the Mitsunobu reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, di-p-nitrobenzyl azodicarboxylate, 1,1'-azobis(N,N'-diisopropylformamide), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione, N,N,N',N'-tetramethylazodicarboxamide, di-p-chlorobenzyl azodicarboxylate, di-2-methoxyethyl azodicarboxylate, and the like. Examples of the phosphine reagent include triphenylphosphine, tri-n-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, diphenyl-2-pyridylphosphine, and the like. Further, this reaction proceeds preferably even in the absence of a phosphine reagent when using a Kuroda reagent such as cyanomethylene tributylphosphorane or cyanomethylene trimethylphosphorane. Examples of the solvent include toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and the like. This reaction preferably proceeds at -40°C to 100°C, more preferably at 0°C to 70°C.

[0137] [Step 3c] Compound (C5) can be produced by hydrolyzing compound (C4) using the same method as in [Step 1c].

[0138] Production method 4 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0139] [Chemical formula]

[0140] (In the formula, R 4 and R 5 are alkyl, X A and X B are halogen atoms, Q 1 is a borate ester, and the other symbols are as defined above.) [Step 4a] Compound (D2) can be produced by reacting compound (D1) and compound (B1) using the same method as in [Step 1b].

[0141] [Step 4b] Compound (D3) can be produced by reacting compound (D2) in a solvent in the presence of a transition metal complex and a base under a carbon monoxide atmosphere. Examples of the solvent include alcohol solvents such as methanol, ethanol, 2-propanol, and tert-butyl alcohol, and mixed solvents with toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the transition metal complex include zero-valent palladium complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), and bis(tricyclohexylphosphine)palladium(0), and divalent palladium complexes such as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0142] In addition, an appropriate ligand may be added to the transition metal complex. Examples of the appropriate ligand include tri-tert-butylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri(ortho-tolyl)phosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, di(1-adamantyl)-n-butylphosphine, (2-biphenyl)di-tert-butylphosphine, (S)-1-[(1R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and the like. Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, and the like. The amount of the transition metal complex used can be 0.01 to 0.3 equivalent, preferably 0.03 to 0.1 equivalent, relative to the compound (D2). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to the compound (D2). In particular, it can be preferably produced by a method using reaction conditions as described in Organometallics, 2008, 27, 5402-5422.

[0143] [Step 4c] Compound (D4) can be produced by treating compound (D3) with a reducing agent in a solvent. Examples of the solvent include toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, etc., and a mixed solvent with an alcohol solvent such as methanol, ethanol, 2-propanol may also be used. As the reducing agent, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc. are used. This reaction preferably proceeds at -78°C to 100°C, more preferably at -10°C to room temperature.

[0144] [Step 4d] Compound (D6) can be produced by reacting compound (D4) and compound (D5) in a solvent in the presence or absence of a base and a phase transfer catalyst. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, butyllithium, etc. Examples of the phase transfer catalyst include quaternary ammonium halide salts or crown ethers. This reaction preferably proceeds at 0°C to 200°C, more preferably at room temperature to 100°C.

[0145] [Step 4e] Compound (D7) can be produced by hydrolyzing compound (D6) using the same method as in [Step 1c].

[0146] Production Method 5 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0147] [Chemical formula]

[0148] (In the formula, R 4 is alkyl, X B is a halogen atom, Q 1 is a borate ester, and the other symbols are as described above.)

[0149] [Step 5a] Compound (E2) can be produced by reacting compound (E1) with compound (B1) using the same method as in [Step 1b].

[0150] [Step 5b] Compound (E3) can be produced by subjecting compound (E2) to a catalytic hydrogenation reaction in a solvent in the presence of a transition metal catalyst under a hydrogen atmosphere. The solvent may be any one that does not interfere with this reaction, and examples thereof include methanol, ethanol, ethyl acetate, and tetrahydrofuran. As the transition metal catalyst, palladium on carbon (Pd / C), palladium hydroxide on carbon (Pd(OH)2 / C), etc. are used. This reaction preferably proceeds at 0°C to 100°C, preferably at room temperature.

[0151] [Step 5c] Compound (E4) can be produced by hydrolyzing compound (E3) using the same method as in [Step 1c].

[0152] Production method 6 (when A is aryl or heteroaryl such as phenyl or pyridyl)

[0153] [Chemical formula]

[0154] (In the formula, R 4 is alkyl, X A and X B are halogen atoms, Q 1is a borate ester, and other symbols are as described above.) [Step 6a] Compound (F2) can be produced by reacting compound (F1) with bis(pinacolato)diborane using the same method as in [Step 1a].

[0155] [Step 6b] Compound (F3) can be produced by reacting compound (F2) with compound (A3) using the same method as in [Step 1b].

[0156] [Step 6c] Compound (E3) can be produced by reacting compound (F3) using the same method as in [Step 5b].

[0157] Production method 7 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl or indolinyl)

[0158] [Chemical formula]

[0159] (In the formula, R 4 is alkyl, X B is a halogen atom, and other symbols are as described above.) [Step 7a] Compound (G2) can be produced by reacting compound (G1) and (A1) in a suitable solvent in the presence of a transition metal complex and a base. As the solvent, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc. can be appropriately used. As the transition metal complex, for example, palladium(0) tetrakis(triphenylphosphine), palladium(0) tris(dibenzylideneacetone)dipalladium, palladium(0) bis(dibenzylideneacetone), palladium(0) bis(tri-tert-butylphosphine), palladium(0) bis(tricyclohexylphosphine) and other zero-valent palladium complexes, palladium(II) acetate, palladium(II) bis(triphenylphosphine) dichloride, palladium(II) bis(tri-O-tolylphosphine) dichloride, palladium(II) bis(tricyclohexylphosphine) dichloride, palladium(II) bis(benzonitrile) dichloride, palladium(II) bis(acetonitrile) dichloride, palladium(II) [1,1'-bis(diphenylphosphino)ferrocene] dichloride, palladium(II) bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloride and other divalent palladium complexes are used.In addition, an appropriate ligand may be added to the transition metal complex. Examples of appropriate ligands include tri-tert-butylphosphine, tri-cyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri(ortho-tolyl)phosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, di(1-adamantyl)-n-butylphosphine, (2-biphenyl)di-tert-butylphosphine, (S)-1-[(1R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and the like.

[0160] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, tripotassium phosphate, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, and the like. The amount of the transition metal complex used can be 0.01 to 0.5 equivalent, preferably 0.03 to 0.1 equivalent, relative to the compound (A1). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to the compound (A1). In particular, it can be preferably produced under the reaction conditions as described in Angew. Chem. Int. Ed., 2008, 47, 6338 - 6361. Further, it can be preferably produced by the method using a palladium catalyst precursor containing a suitable ligand as described in Chemical Science, 2013, 4, 916 - 920.

[0161] [Step 7b] The compound (G3) can be produced by hydrolyzing the compound (G2) using the same method as in [Step 1c].

[0162] Production Method 8 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl or indolinyl)

[0163] [Chemical formula]

[0164] (In the formula, X B is a halogen atom, and the other symbols are as described above.) [Step 8a] The compound (H2) can be produced by reacting the compound (H1) and the compound (A1) using the same method as in [Step 7a].

[0165] [Process 8b] Compound (G3) can be produced by hydrolyzing compound (H2) in a suitable mixed aqueous solution in the presence of a base. As the solvent, for example, 1,4-dioxane, ethylene glycol, etc. can be used as a mixed aqueous solution, and it can be preferably used. As the base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide can be preferably used. This reaction preferably proceeds at 0 °C to 200 °C, preferably at room temperature to 120 °C.

[0166] Production method 9 (when A is a heterocyclic group such as piperidinyl, piperazinyl, morpholinyl, etc.)

[0167] [Chemical formula]

[0168] (In the formula, R 4 is alkyl, X B is a halogen atom, and other symbols are as defined above.) [Process 9a] Compound (I2) can be produced by reacting compound (I1) with compound (A1) using the same method as in [Process 7a].

[0169] [Process 9b] Compound (I3) can be produced by reacting compound (I2) in a suitable solvent in the presence of 2 equivalents of a base. As the solvent, alcohol solvents such as methanol and ethanol can be used. As the base, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. can be used. This reaction preferably proceeds at 0 °C to 100 °C, preferably at 0 °C to room temperature.

[0170] [Process 9c] Compound (I4) can be produced by hydrolyzing compound (I3) using the same method as in [Process 1c].

[0171] Production Method 10 (when A is a heterocyclic group such as piperidinyl, piperazinyl, morpholinyl, etc.)

[0172]

Chemical Formula

[0173] (In the formula, R 4 is alkyl, X B is a halogen atom, PG 1 is a protecting group for the hydroxyl group, and the other symbols are as described above.) [Step 10a] Compound (J2) can be produced by reacting compound (J1) with compound (I1) using the same method as in [Step 7a].

[0174] [Step 10b] Compound (J3) can be produced by reacting compound (J2) using the same method as in [Step 9b].

[0175] [Step 10c] Compound (J4) can be produced by removing the PG 1 of compound (J3) using a conventional method.

[0176] [Step 10d] Compound (J5) can be produced by reacting compound (J4) with compound (C3) using the same method as in [Step 3b].

[0177] [Step 10e] Compound (J6) can be produced by hydrolyzing compound (J5) using the same method as in [Step 1c].

[0178] Production Method 11 (when A is a heterocyclic group such as piperidinyl, piperazinyl, morpholinyl, etc.)

[0179]

Chemical Formula

[0180] (In the formula, R 4 is alkyl, R 5 is alkyl or aryl, and other symbols are as described above.) [Step 11a] Compound (K3) can be produced by reacting compound (K1) and compound (K2) in a solvent in the presence of a base. Examples of the solvent include toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. This reaction preferably proceeds at -40°C to 100°C, more preferably at 0°C to room temperature.

[0181] [Step 11b] Compound (K4) can be produced by reacting compound (K3) and compound (J4) in a solvent in the presence or absence of a base and in the presence or absence of a phase transfer catalyst. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and butyllithium. Examples of the phase transfer catalyst include quaternary ammonium halide salts or crown ethers. This reaction preferably proceeds at -40°C to 120°C, more preferably at 0°C to room temperature.

[0182] [Step 11c] Compound (K5) can be produced by hydrolyzing compound (K4) using the same method as in [Step 1c].

[0183] Production method 12 (when A is a heterocyclic group such as piperidinyl, piperazinyl, morpholinyl, etc.)

[0184] [Chemical formula]

[0185] (In the formula, R 4 is alkyl, X B is a halogen atom, and the other symbols are as defined above.) [Step 12a] Compound (L2) can be produced by reacting compound (L1) with compound (A1) using the same method as in [Step 7a].

[0186] [Step 12b] Compound (L3) can be produced by reacting compound (L2) in a suitable solvent in the presence of a base and then heating in the presence of an acid. As the solvent, alcohol solvents such as methanol and ethanol can be appropriately used. As the base, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. can be appropriately used. As the acid, acetic acid, hydrochloric acid, sulfuric acid, etc. can be appropriately used. This reaction preferably proceeds by raising the temperature from 0 °C to room temperature in the presence of a base and then from room temperature to 100 °C in the presence of an acid.

[0187] Production method 13 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl or indolinyl, etc.)

[0188] [Chemical formula]

[0189] (In the formula, R 4 is alkyl, XB is a halogen atom, and the other symbols are as described above.) [Step 13a] Compound (M1) can be produced by reacting compound (G1) and compound (F1) using the same method as in [Step 7a].

[0190] [Step 13b] Compound (M2) can be produced by reacting compound (M1) using the same method as in [Step 5b].

[0191] [Step 13c] Compound (M3) can be produced by hydrolyzing compound (M2) using the same method as in [Step 1c].

[0192] Production Method 14 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl or indolinyl)

[0193]

Chemical formula

[0194] (In the formula, R 4 is alkyl, X B is a halogen atom, and the other symbols are as described above.)

[0195] [Step 14a] Compound (N2) can be produced by reacting compound (N1) and compound (A1) using the same method as in [Step 7a].

[0196] [Step 14b] Compound (N3) can be produced by reacting compound (N2) using the same method as in [Step 5b].

[0197] [Step 14c] Compound (N4) can be produced by hydrolyzing compound (N3) using the same method as in [Step 1c].

[0198] Production method 15 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl, or indolinyl)

[0199]

Chemical formula

[0200] (In the formula, R 4 is alkyl, X A and X B are halogen atoms, PG 1 is a protecting group for the hydroxyl group, and the other symbols are as described above.) [Step 15a] Compound (O2) can be produced by reacting compound (O1) and compound (A1) using the same method as in [Step 7a].

[0201] [Step 15b] Compound (O3) can be produced by removing the PG 1 of compound (O2) using a conventional method.

[0202] [Step 15c] Compound (O5) can be produced by reacting compound (O3) and compound (O4) in a solvent, in the presence or absence of a base and in the presence or absence of a phase transfer catalyst. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and butyllithium. Examples of the phase transfer catalyst include quaternary ammonium halide salts and crown ethers. This reaction preferably proceeds at -40°C to 120°C, more preferably at 0°C to room temperature.

[0203] [Step 15d] Compound (O6) can be produced by hydrolyzing compound (O5) using the same method as in [Step 1c].

[0204] Production Method 16 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl, or indolinyl)

[0205] [Chemical Formula]

[0206] (In the formula, R 4 and R 5 are alkyl, X A and X B are halogen atoms, and the other symbols are as defined above.) [Step 16a] Compound (P2) can be produced by reacting compound (P1) and compound (A1) using the same method as in [Step 7a].

[0207] [Step 16b] Compound (P3) can be produced by reducing compound (P2) using the same method as in [Step 4c].

[0208] [Step 16c] Compound (O5) can be produced by reacting compound (P3) and compound (O4) using the same method as in [Step 15c].

[0209] Production Method 17 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl or indolinyl)

[0210] [Chemical Formula]

[0211] (In the formula, R 4 and R 5 are alkyl, X B is a halogen atom, PG 1 is a protecting group for the hydroxyl group, and the other symbols are as defined above.) [Step 17a] Compound (Q2) can be produced by reacting compound (Q1) and compound (A1) using the same method as in [Step 7a].

[0212] [Step 17b] Compound (Q3) can be produced by removing the PG 1 of compound (Q2) using a conventional method. [Step 17c] Compound (Q4) can be produced by the usual method of oxidizing the primary alcohol of compound (Q3) to an aldehyde. In particular, oxidation reaction conditions using dimethyl sulfoxide as described in Tetrahedron, 1978, 34, 1651 - 1660, oxidation reaction conditions using 2,2,6,6 - tetramethyl - 1 - piperidinyloxy free radical as described in Org. Synth., 1990, 69, 212 - 217, oxidation reaction conditions using Dess - Martin periodinane as described in J. Org. Chem., 1983, 48, 4155 - 4156, etc., can be preferably used for production.

[0213] [Step 17d] Compound (Q6) can be produced by reacting compound (Q4) with Wittig - Horner reagent (Q5) in a solvent in the presence of a base. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2 - dimethoxyethane, 1,4 - dioxane, diethyl ether, N,N - dimethylformamide, dimethyl sulfoxide, N - methylpyrrolidone, etc. Examples of the base include sodium hydride, lithium tert - butoxide, sodium tert - butoxide, potassium tert - butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc. This reaction preferably proceeds at - 20°C to 100°C, particularly at 0°C to 60°C.

[0214] [Step 17e] Compound (Q7) can be produced by hydrolyzing compound (Q6) using the same method as in [Step 1c].

[0215] Production Method 18 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0216]

Chemical Structure

[0217] (In the formula, R 4 and R 5 are alkyl, X A and X B are halogen atoms, and other symbols are as defined above.) [Step 18a] Compound (R2) can be produced by reacting compound (R1) with Wittig-Horner reagent (Q5) using a method similar to [Step 17d].

[0218] [Step 18b] Compound (R4) can be produced by the Corey-Chaykovsky reaction of compound (R2) and compound (R3). In particular, it can be preferably produced by a method using reaction conditions as described in J.Am.Chem.Soc., 1965, 87, 1353-1364.

[0219] Production method 19 (when A is aryl or heteroaryl such as phenyl or pyridyl)

[0220] [Chemical formula]

[0221] (In the formula, R 4 and R 5 are alkyl, X A and X B are halogen atoms, and other symbols are as defined above.) [Step 19a] Compound (S3) can be produced by reacting compound (S1) and compound (S2) in a solvent in the presence of a base. As the solvent, an ether solvent such as tetrahydrofuran can be used. As the base, an alkyl metal such as butyllithium or isopropylmagnesium chloride can be used. This reaction preferably proceeds at -78°C to 100°C, more preferably at 0°C to room temperature.

[0222] [Step 19b] Compound (S4) can be produced by treating compound (S3) with a reducing agent in a solvent. As the solvent, a mixed solvent of an ether solvent such as tetrahydrofuran and an alcohol solvent such as methanol, ethanol, 2-propanol, etc. can be used. As the reducing agent, sodium borohydride etc. are used. This reaction preferably proceeds at -78°C to 100°C, preferably -10°C to room temperature. Also, an optically active substance can be preferably produced by using the Noyori asymmetric hydrogen transfer reaction as described in J.Am.Chem.Soc., 1996, 118, 2521-2522.

[0223] [Step 19c] Compound (S5) can be produced by reacting compound (S4) in a solvent in the presence or absence of a base and in the presence or absence of a phase transfer catalyst. Examples of the solvent include toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. Examples of the phase transfer catalyst include quaternary ammonium halide salts or crown ethers, etc. This reaction preferably proceeds at -40°C to 120°C, preferably 0°C to room temperature.

[0224] [Step 19d] Compound (R4) can be produced by reacting compound (S5) with Wittig-Horner reagent (Q5) in a solvent in the presence of a base. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and the like. Examples of the base include sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and the like. This reaction preferably proceeds at 0°C to 120°C, more preferably at room temperature to 60°C.

[0225] Production method 20 (when A is an aryl or heteroaryl such as phenyl or pyridyl)

[0226] [Chemical formula]

[0227] (In the formula, R 4 and R 5 are alkyl, X A and X B are halogen atoms, and other symbols are as defined above.) [Step 20a] Compound (T2) can be produced by the Corey-Chaykovsky reaction of compound (T1) and compound (R3). It can be preferably produced by a method using reaction conditions as described in J. Am. Chem. Soc., 1965, 87, 1353-1364.

[0228] [Step 20b] Compound (T3) can be produced by reacting compound (T2) with Wittig-Horner reagent (Q5) using the same method as in [Step 19d].

[0229] Manufacturing method 21 (when A is a heterocyclic group such as morpholinyl)

[0230]

Chemical formula

[0231] (In the formula, R 4 is alkyl, R 5 is alkyl or aryl, PG 2 is a protecting group for the amino group, and the other symbols are as described above.) [Step 21a] Compound (T2) can be produced by reacting compound (T1) and compound (K2) using the same method as in [Step 11a].

[0232] [Step 21b] Compound (T4) can be produced by reacting compound (T2) and compound (T3) in a solvent in the presence of a base. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide. In some cases, sodium iodide, potassium iodide, cesium iodide, etc. may be added to accelerate the reaction. This reaction preferably proceeds at 0°C to 120°C, more preferably at room temperature to 100°C.

[0233] [Step 21c] Compound (T5) can be produced by removing the PG 2 of compound (T4) using a conventional method.

[0234] Manufacturing method 22 (when A is a heterocyclic group such as morpholinyl)

[0235] [Chemical formula]

[0236] (In the formula, R 4 and R 5 are alkyl, PG 1 is a protecting group for a hydroxyl group, PG 2 is a protecting group for an amino group, and other symbols are as described above.) [Step 22a] Compound (U2) can be produced by reacting compound (U1) using a method similar to that in step [4c].

[0237] [Step 22b] Compound (U3) can be produced by protecting the hydroxyl group of compound (U2) with PG 1 using a conventional method.

[0238] [Step 22c] Compound (U4) can be produced by subjecting compound (U3) to the Simmons-Smith reaction. In particular, it can be preferably produced by a method using reaction conditions as described in Tetrahedron Lett., 1966, 28, 3353 - 3354.

[0239] [Step 22d] Compound (U5) can be produced by removing PG 1 of compound (U4) using a conventional method.

[0240] [Step 22e] Compound (U6) can be produced by a conventional method of oxidizing the primary alcohol of compound (U5) to a carboxylic acid. In particular, it can be preferably produced under oxidation reaction conditions using 2,2,6,6-tetramethyl-1-piperidinyloxy free radical as described in Org. Synth., 2005, 81, 195 - 203, or under oxidation reaction conditions using ruthenium(IV) oxide as described in Tetrahedron, 1972, 28, 4259 - 4266.

[0241] [Step 22f] Compound (U7) can be produced by a conventional method of converting a carboxylic acid to an ester, such as a method of reacting compound (U6) with an alcohol in the presence of a condensing agent or a method of reacting with an alkylating agent in the presence of a base.

[0242] [Step 22g] Compound (U8) 2 can be produced by removing the PG using a conventional method.

[0243] Production Method 23 (when A is a heterocyclic group such as morpholinyl)

[0244]

Chemical Formula

[0245] (In the formula, Z 1 is -N= or -CH=, R 4 is alkyl, X A is a halogen atom, PG 2 is a protecting group for an amino group, and other symbols are as defined above.) [Step 23a] Compound (V2) can be produced by reacting compound (V1) with a vinyl boronic acid ester using a method similar to [Step 1b].

[0246] [Step 23b] Compound (V3) can be produced by reacting compound (V2) with a halogenating reagent in a solvent and then treating with a base. The solvent can be preferably used by making a mixed aqueous solution of tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, tert-butyl alcohol, etc. Examples of the halogenating reagent include N-iodosuccinimide, N-bromosuccinimide, etc. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, tripotassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. This reaction preferably proceeds at -20°C to 100°C, preferably 0°C to 60°C.

[0247] [Step 23c] Compound (V5) can be produced by reacting compound (V3) and compound (V4) in a solvent in the presence or absence of a base. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc. This reaction preferably proceeds at 0°C to 180°C, preferably room temperature to 100°C.

[0248] [Step 23d] Compound (V6) can be produced by reacting compound (V5) in a solvent in the presence of a Mitsunobu reagent and a phosphine reagent. Examples of the Mitsunobu reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, di-p-nitrobenzyl azodicarboxylate, 1,1'-azobis(N,N'-diisopropylformamide), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione, N,N,N',N'-tetramethylazodicarboxamide, di-p-chlorobenzyl azodicarboxylate, di-2-methoxyethyl azodicarboxylate, and the like. Examples of the phosphine reagent include triphenylphosphine, tri-n-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, diphenyl-2-pyridylphosphine, and the like. Further, this reaction proceeds preferably even in the absence of a phosphine reagent when using a Kakitani reagent such as cyanomethylene tributylphosphorane or cyanomethylene trimethylphosphorane. Examples of the solvent include toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and the like. This reaction preferably proceeds at -40°C to 100°C, more preferably at 0°C to 70°C.

[0249] [Step 23e] Compound (V7) can be produced by removing the PG of compound (V6) using a conventional method. 2

[0250] Production Method 24 (when A is a heterocyclic group such as morpholinyl)

[0251] [Chemical formula]

[0252] (In the formula, R 4 and R 5 are alkyl, PG 2 is a protecting group for an amino group, and other symbols are as defined above.) [Step 24a] Compound (W2) can be produced by reacting compound (W1) using the same method as in [Step 17c].

[0253] [Step 24b] Compound (W3) can be produced by reacting compound (W2) with a Wittig-Horner reagent (Q5) using the same method as in [Step 17d].

[0254] [Step 24c] Compound (W4) can be produced by removing the PG 2 of compound (W3) using a conventional method.

[0255] Production Method 25

[0256] [Chemical formula]

[0257] (In the formula, X A and X B are halogen atoms, ring B is

[0258] [Chemical formula]

[0259] and other symbols are as defined above.) [Step 25a] Compound (X3) can be produced by reacting compound (X1) and compound (X2) in a solvent, in the presence or absence of a base and in the presence or absence of a phase transfer catalyst. Examples of the solvent include toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and butyllithium. This reaction preferably proceeds particularly when using sodium hydride or butyllithium. Examples of the phase transfer catalyst include quaternary ammonium halide salts or crown ethers. This reaction preferably proceeds at 0°C to 120°C, preferably at room temperature to 60°C.

[0260] Production Method 26

[0261]

Chemical formula

[0262] (In the formula, X B is a halogen atom, and ring B is

[0263]

Chemical formula

[0264] as defined above, and the other symbols are as defined above.) [Step 26a] Compound (Y1) can be produced by reacting compound (X1) and compound (C1) using the same method as in [Step 3b].

[0265] Production Method 27

[0266] [Chemical formula]

[0267] (In the formula, X A and X B are halogen atoms, and other symbols are as defined above.) [Step 27a] Compound (E1) can be produced by reacting compound (Z1) and compound (D1) in a solvent in the presence or absence of a catalytic amount of copper iodide and in the presence of a transition metal complex and a base. Examples of the solvent that can be used include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc. Examples of the transition metal complex that can be used include zero-valent palladium complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0); divalent palladium complexes such as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0268] In addition, an appropriate ligand may be added to the transition metal complex. Examples of the appropriate ligand include tri-tert-butylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri(ortho-tolyl)phosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, di(1-adamantyl)-n-butylphosphine, (2-biphenyl)di-tert-butylphosphine, (S)-1-[(1R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and the like. Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, diisopropylethylamine, diisopropylamine, and the like. The amount of the transition metal complex used can be 0.01 to 0.5 equivalents, preferably 0.03 to 0.1 equivalents, based on the compound (Z1). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, based on the compound (Z1). In particular, it can be preferably produced by a method using reaction conditions as described in J. Organomet. Chem., 2002, 653, 46-49.

[0269] Production Method 28

[0270]

Chem.

[0271] (wherein X A and X B are halogen atoms, and the other symbols are as defined above.) [Step 28a] Compound (F1) can be produced by reacting compound (AA1) and compound (AA2) in a solvent in the presence of a base. As the solvent, an ether solvent such as tetrahydrofuran or an amide solvent such as N,N-dimethylformamide can be appropriately used. Examples of the base include sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and butyllithium. This reaction preferably proceeds at -78°C to 60°C, more preferably at -10°C to room temperature.

[0272] Production Method 29

[0273] [Chemical Formula]

[0274] (wherein X B is a halogen atom, and the other symbols are as defined above.) [Step 29a] Compound (AB3) can be produced by reacting compound (AB1) and compound (AB2) using the same method as in [Step 3b].

[0275] The compound of the present invention thus obtained can be isolated and purified by separation means known per se, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, chromatography, etc. When the compound of the present invention is obtained as a free form, it can be converted into the desired salt by a method known per se or a method analogous thereto. Conversely, when obtained as a salt, it can be converted into the free form or another desired salt by a method known per se or a method analogous thereto.

[0276] Since the compounds of the present invention have a basic group and an acidic group in the molecule, examples of the pharmacologically acceptable salts thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, salts with acidic amino acids, and the like.

[0277] Preferable examples of the metal salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; aluminum salts, and the like. Preferable examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Preferable examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferable examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferable examples of the salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Preferable examples of the salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0278] In addition to the above-mentioned compound (1) and its pharmacologically acceptable salts, the compounds of the present invention also include their hydrates and solvates.

[0279] When the compound of the present invention has isomers such as optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any one of the isomers or a mixture is included in the compound of the present invention. For example, when an optical isomer exists in the compound of the present invention, the optical isomer separated from the racemate is also included in the compound of the present invention. These isomers can be obtained as single products by synthetic methods and separation methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization).

[0280] Furthermore, the enantiomeric excess (%ee) can be determined using chiral HPLC with respect to a standard substance. The enantiomeric excess can be calculated as follows: [(R mole - S mole) / (R mole + S mole)] × 100% In the formula, R mole and S mole are the R and S molar fractions in the mixture such that R mole + S mole = 1. Alternatively, the enantiomeric excess can also be calculated from the specific rotation of the desired enantiomer and the prepared mixture as follows: ee = ([α - Obs] / [α - max]) × 100%

[0281] The compound of the present invention may be a crystal, and whether the crystal form is single or a mixture of crystal forms is included in the compound of the present invention. The crystal can be produced by applying a crystallization method known per se and crystallizing. Further, the compound of the present invention may be a pharmaceutically acceptable co - crystal or co - crystal salt. Here, the co - crystal or co - crystal salt means a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, stability). The co - crystal or co - crystal salt can be produced according to a co - crystallization method known per se.

[0282] Isotopes (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 35 S), etc. - labeled compounds are also included in the compound of the present invention.

Examples

[0283] Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but the present invention is not limited thereto in any way. In the following examples, the following abbreviations are used. Me: Methyl Et: Ethyl iPr: Isopropyl tBu: tert-Butyl Ph: Phenyl Bn: Benzyl Boc: tert-Butoxycarbonyl TBDPS: tert-Butyldiphenylsilyl Ms: Methanesulfonyl Tf: Trifluoromethanesulfonyl Ts: 4-Toluenesulfonyl HPLC: High Performance Liquid Chromatography

[0284] Example 1 (1S,2S)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1R,2R)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid

[0285] [Chemical Formula]

[0286] [Step a] To a solution of Compound 1 (200 mg, 679 μmol) obtained in Step a of Reference Example 44 and Compound 2 (508 mg, 1.36 mmol) obtained in Step c of Reference Example 1 in 1,4-dioxane (10 mL), a solution of potassium carbonate (188 mg, 1.36 mmol) in water (1.0 mL), tris(dibenzylideneacetone)dipalladium(0) (62 mg, 68 μmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (129 mg, 271 μmol) were added, and the mixture was stirred overnight under heating under reflux in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography and silica gel chromatography to obtain Compound 3 (207 mg, 60.2%). MS(ESI) m / z: 507 (M+1) + 。

[0287] [Step b] Compound 3 (170 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, tert-butyl methyl ether:methanol:diethylamine = 95:5:0.1, 20 mL / min) to obtain Compound 3a (82.4 mg, 99.9% ee, peak with retention time of 17 minutes) and Compound 3b (81.1 mg, 99.3% ee, peak with retention time of 23 minutes).

[0288] [Step c] To a solution of Compound 3a (82.4 mg, 160 μmol) in dichloromethane (2.0 mL), trifluoroacetic acid (249 μL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 4a (54.3 mg, 74.1%). This enantiomer is designated as Example 1-1. MS(ESI) m / z: 451 (M+1) + 。

[0289] [Step d] To a solution of compound 3b (81.1 mg, 160 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (245 μL), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was further added trifluoroacetic acid (122 μL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4b (56.1 mg, 77.8%). This enantiomer was used as Example 1-2. MS (ESI) m / z: 451 (M+1) + .

[0290] Example 2 trans-2-[2-Methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid

[0291] [Chemical formula]

[0292] [Step a] To a solution of compound 1 (2.37 g, 6.33 mmol) and compound 2 (1.00 g, 5.75 mmol) obtained in Step c of Reference Example 1 in 1,4-dioxane (20 mL) were added a solution of tripotassium phosphate (3.66 g, 17.2 mmol) in water (2 mL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (204 mg, 287 μmol), and the mixture was stirred overnight under heating at 80 °C in a nitrogen atmosphere. 1M-Hydrochloric acid was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (894 mg, 45.6%). MS (APCI) m / z: 342 (M+1) + .

[0293] [Step b] To a solution of compound 3 (60.0 mg, 176 μmol) and compound 4 (64.0 μL, 439 μmol) in tetrahydrofuran (1.0 mL) were added triphenylphosphine (115 mg, 439 μmol) and bis(2-methoxyethyl) azodicarboxylate (103 mg, 439 μmol), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 5 (46.2 mg, 51.0%). MS (ESI) m / z: 516 (M+1) + .

[0294] [Step c] To a solution of compound 5 (44.0 mg, 85.4 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (653 μL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM ,RxnCX) and then by silica gel chromatography to obtain compound 6 (23.9 mg, 61.0%). MS (APCI) m / z: 460 (M+1) + .

[0295] Example 3 trans-2-[2-Methoxy-5-(6-{[4-(trifluoromethyl)phenoxy]methyl}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid

[0296] [Chemical formula]

[0297] [Step a] To a toluene (13 mL) solution of Compound 1 (1.26 g, 3.36 mmol) and Compound 2 (500 mg, 3.36 mmol) obtained in Step c of Reference Example 1, a water (3.4 mL) solution of potassium fluoride (487 mg, 8.39 mmol), palladium(II) acetate (37.7 mg, 168 μmol), and 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (119 mg, 168 μmol) were added, and the mixture was stirred for 19 hours under heating at 70 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was filtered through celite and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 3 (398 mg, 32.9%). MS(ESI) m / z: 361, 363 (M+1) + 。

[0298] [Step b] To a mixed solution of Compound 3 (370 mg, 1.03 mmol) in N,N-dimethylformamide (4.0 mL) and ethanol (1.0 mL), sodium acetate (168 mg, 2.05 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (83.7 mg, 103 μmol) were added, and the mixture was stirred for 4 hours under heating at 90 °C in a carbon monoxide atmosphere. To the reaction solution, ethanol (1.0 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (83.7 mg, 103 μmol) were further added, and the mixture was stirred overnight under heating at 90 °C in a carbon monoxide atmosphere. After allowing the reaction solution to cool to room temperature, water (30 mL) and ethyl acetate (30 mL) were added, and the mixture was filtered through celite. The filtrate was phase-separated, and the organic layer was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography to obtain Compound 4 (98.3 mg, 24.1%). MS(ESI) m / z: 399 (M+1) + 。

[0299] [Step c] To a mixed suspension of compound 4 (95.0 mg, 239 μmol) in ethanol (3.0 mL) and tetrahydrofuran (0.50 mL), sodium borohydride (18.0 mg, 477 μmol) was added under ice-cooling, and the mixture was stirred for 1.5 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 5 (45.5 mg, 53.5%). MS (ESI) m / z: 357 (M+1) + .

[0300] [Step d] To a solution of compound 5 (68.6 mg, 160 μmol) and compound 6 (66.3 mg, 404 μmol) in N,N-dimethylformamide (2.1 mL), sodium hydride (60 wt%, 41.2 mg, 1.03 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 7 (14.6 mg, 28.9%). MS (ESI) m / z: 501 (M+1) + .

[0301] [Step e] To a solution of compound 7 (14.6 mg, 29.2 μmol) in dichloromethane (1.0 mL), trifluoroacetic acid (100 μL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 8 (11.2 mg, 86.4%). MS (ESI) m / z: 445 (M+1) + .

[0302] Example 4 trans-2-[2-Methoxy-5-(6-{2-[4-(trifluoromethoxy)phenyl]ethyl}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid

[0303] [Chemical formula]

[0304] [Step a] To a solution of Compound 1 (80.0 mg, 268 μmol) obtained in Step a of Reference Example 46 and Compound 2 (201 mg, 536 μmol) obtained in Step c of Reference Example 1 in 1,4-dioxane (2.4 mL) were added a solution of potassium carbonate (74.1 mg, 536 μmol) in water (0.24 mL), tris(dibenzylideneacetone)dipalladium(0) (25 mg, 27 μmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (51.1 mg, 107 μmol). The mixture was stirred overnight under heating and reflux in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was purified by NH silica gel chromatography to obtain Compound 3 (52.2 mg, 38.2%). MS (ESI) m / z: 511 (M+1) + 。 [Step b] To a solution of Compound 3 (50 mg, 98 μmol) in methanol (3.0 mL) was added 10%-palladium / carbon (10 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After diluting the reaction solution with chloroform, it was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (3.0 mL), 10%-palladium / carbon (10 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After diluting the reaction solution with chloroform, it was filtered through celite. The filtrate was concentrated under reduced pressure to obtain Compound 4 (44 mg, 88%). MS (ESI) m / z: 515 (M+1) + 。

[0305] [Step c] To a solution of Compound 4 (40 mg, 78 μmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.80 mL), and the mixture was stirred at room temperature for 3 days. The reaction solution was purified by silica gel chromatography to obtain Compound 5 (36 mg). MS (ESI) m / z: 459 (M+1) + 。

[0306] Example 5 (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid

[0307]

Chem.

[0308] [Step a] To a solution of Compound 1 (1.81 g, 6.14 mmol) and bis(pinacolato)diborane (2.49 g, 9.82 mmol) in 1,4-dioxane (61 mL) obtained in Step a of Reference Example 44 were added potassium acetate (1.81 g, 18.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (337 mg, 368 μmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (351 mg, 736 μmol), and the mixture was stirred at 100 °C for 3 hours under heating in a nitrogen atmosphere. The reaction solution was cooled with ice, the resulting solid was diluted with water, filtered, and washed with water. The obtained solid was washed with hexane to obtain Compound 2 (1.78 g, 75.2%). MS(APCI) m / z: 387 (M + 1) + .

[0309] [Step b] To a solution of Compound 3 (384 mg, 1.50 mmol) obtained in Step d of Reference Example 2 and Compound 2 (645 mg, 1.67 mmol) in tetrahydrofuran (15 mL), a solution of tripotassium phosphate (1.95 g, 9.19 mmol) in water (3.0 mL) and X-Phos aminobiphenyl palladium chloride precatalyst (66 mg, 84 μmol) were added, and the mixture was stirred for 4 hours under heating at 80 °C in a nitrogen atmosphere. To the reaction solution, X-Phos aminobiphenyl palladium chloride precatalyst (65.7 mg, 83.5 μmol) was further added, and the mixture was stirred for 2.5 hours under heating at 80 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water (25 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography to obtain Compound 4 (380 mg, 38.0%). MS (ESI) m / z: 480 (M+1) + 。

[0310] [Step c] To a mixed solution of Compound 4 (73.0 mg, 152 μmol) in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), 4M aqueous sodium hydroxide solution (0.50 mL, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (4 mL), neutralized by adding 1M hydrochloric acid (2 mL), and the resulting solid was collected by filtration and washed with water to obtain Compound 5 (57.0 mg, 82.9%). MS (ESI) m / z: 452 (M+1) + 。

[0311] Example 6 (1S,2S)-2-(5-Methoxy-5’-{2-[4-(trifluoromethoxy)phenyl]ethyl}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid

[0312]

Chemical formula

[0313] [Step a] To a solution of Compound 1 (600 mg, 1.74 mmol) obtained in Step b of Reference Example 45 and bis(pinacolato)diboron (487 mg, 1.92 mmol) in 1,4-dioxane (12 mL), potassium acetate (513 mg, 5.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (64 mg, 87 μmol) were added, and the mixture was stirred for 6 hours under heating at 100 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water (40 mL) was added and the mixture was extracted twice with ethyl acetate (40 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain Compound 2 (746 mg), which is a cis / trans mixture. MS(ESI) m / z: 310 (M+1) + .

[0314] [Step b] To a solution of Compound 3 (196 mg, 767 μmol) obtained in Step d of Reference Example 2 and Compound 2 (300 mg, 767 μmol) in 1,4-dioxane (5.4 mL), a solution of tripotassium phosphate (488 mg, 2.30 mmol) in water (0.60 mL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (27 mg, 37 μmol) were added, and the mixture was stirred for 4 hours under heating at 100 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography and further purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM ,RxnCX) to obtain Compound 4 (125 mg, 33.7%) and Compound 5 (75 mg, 20%). MS(ESI) m / z: 485 (M+1) + . 485 (M+1) + .

[0315] [Step c] To a solution of compound 4 (120 mg, 248 μmol) in methanol (2.4 mL) was added 10%-palladium / carbon (24 mg), and the mixture was stirred at room temperature for 1 day under a hydrogen atmosphere. The reaction mixture was filtered through Celite, washed with chloroform, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 6 (87.5 mg, 72.6%). MS (APCI) m / z: 487 (M+1) + .

[0316] [Step d] To a mixed solution of compound 6 (85.0 mg, 175 μmol) in tetrahydrofuran (1.7 mL) and methanol (1.7 mL) was added 4M-sodium hydroxide aqueous solution (218 μL, 0.87 mmol), and the mixture was stirred at room temperature overnight. 1M-hydrochloric acid (0.88 mL) was added to the reaction mixture to neutralize it, and the mixture was diluted with water (10 mL). The resulting solid was collected by filtration and washed with water (15 mL). The obtained solid was washed with ethyl acetate (5.0 mL) to obtain compound 7 (42.5 mg, 53.1%). MS (ESI) m / z: 459 (M+1) + .

[0317] Example 7 (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid (1R,2R)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid

[0318] [Chemical formula]

[0319] [Step a] To a solution of Compound 1 (200 mg, 440 μmol) obtained in Step a of Example 5 and Compound 2 (119 mg, 440 μmol, Reference Example 5) in 1,4-dioxane (4.0 mL), a solution of tripotassium phosphate (93.4 mg, 440 μmol) in water (0.40 mL), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 22 μmol), and tricyclohexylphosphine (18.5 mg, 66 μmol) were added, and the mixture was stirred for 4 hours under heating at 105 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. The filtrate was phase-separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (35 mg, 16%). MS (ESI) m / z: 494 (M+1) + 。

[0320] [Step b] Compound 3 (35 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IF, 30×250, tert-butyl methyl ether:methanol:diethylamine = 96:4:0.1, 20 mL / min) to obtain Compound 3a (13 mg, 99.9% ee, peak with retention time of 15 minutes) and Compound 3b (13 mg, 99.3% ee, peak with retention time of 22 minutes).

[0321] [Step c] To a mixed solution of Compound 3a (13 mg, 26 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.50 mL), 2M aqueous sodium hydroxide solution (0.50 mL, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. To the reaction solution, 0.5M hydrochloric acid (2.1 mL) was added for neutralization, and the mixture was diluted with water (8 mL). The organic solvent was distilled off under reduced pressure from the reaction solution, and the resulting solid was collected by filtration and washed with water to obtain Compound 4a (11 mg, 90%). This enantiomer was designated as Example 7-1. MS (ESI) m / z: 466 (M+1) + 。

[0322] [Step d] To a mixed solution of compound 3b (13 mg, 26 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.50 mL), 2M aqueous sodium hydroxide solution (0.50 mL, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. 0.5M hydrochloric acid (2.1 mL) was added to the reaction solution for neutralization, and then diluted with water (8 mL). The organic solvent was distilled off under reduced pressure from the reaction solution, and the resulting solid was collected by filtration and washed with water to obtain compound 4b (9.0 mg, 73%). This enantiomer was designated as Example 7-2. MS (ESI) m / z: 466 (M+1) + .

[0323] Example 8 (1S,2S)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid (1R,2R)-2-(5’-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3’-bipyridin-6-yl)cyclopropanecarboxylic acid

[0324] [Chemical formula]

[0325] [Step a] To a solution of compound 1 (380 mg, 1.12 mmol) and bis(pinacolato)diboron (342 mg, 1.35 mmol) in dimethyl sulfoxide (2.7 mL) obtained in Step b of Reference Example 42, potassium acetate (331 mg, 3.37 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (41.1 mg, 56.2 μmol) were added, and the mixture was stirred overnight under heating at 80 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 2 (727 mg). MS (ESI) m / z: 304 (M+1 of boronic acid) + .

[0326] [Step b] To a solution of Compound 3 (180 mg, 666 μmol) obtained in Step b of Reference Example 3 and Compound 2 (1.44 g, 2.02 mmol) in 1,4-dioxane (6.0 mL), a solution of tripotassium phosphate (424 mg, 2.00 mmol) in water (1.2 mL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (42 mg, 67 μmol) were added, and the mixture was stirred for 3 hours under heating at 105 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography and NH silica gel chromatography to obtain Compound 4 (400 mg, 100%). MS(ESI) m / z: 449 (M+1) + .

[0327] [Step c] Compound 4 (400 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IF, 30×250, ethanol:diethylamine = 100:0.1, 15 mL / min) to obtain Compound 4a (119 mg, 99.8% ee, peak with retention time of 22 minutes) and Compound 4b (128 mg, 99.9% ee, peak with retention time of 18 minutes).

[0328] [Step d] To a mixed solution of tetrahydrofuran (3.0 mL) and methanol (1.5 mL) of Compound 4a (119 mg, 265 μmol), 2M aqueous sodium hydroxide solution (1.5 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 0.2M hydrochloric acid (15 mL) was added to the reaction solution to neutralize it, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was washed with diethyl ether - hexane to obtain Compound 5a (92.0 mg, 82.5%). This enantiomer was designated as Example 8-1. MS(ESI) m / z: 421 (M+1) + .

[0329] [Step e] To a mixed solution of compound 4b (128 mg, 285 μmol) in tetrahydrofuran (3.0 mL) and methanol (1.5 mL), 2M aqueous sodium hydroxide solution (1.5 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 0.2M hydrochloric acid (15 mL) was added to the reaction solution to neutralize it, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was washed with diethyl ether - hexane to obtain compound 5b (95.0 mg, 79.2%). This enantiomer was designated as Example 8 - 2. MS(ESI) m / z: 421 (M + 1) + 。

[0330] Example 9 (1S,2S)-2-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid (1R,2R)-2-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}-3,4’-bipyridin-2’-yl)cyclopropanecarboxylic acid

[0331]

Chemical Structure

[0332] [Step a] To a solution of Compound 1 (719 mg, 1.11 mmol) obtained in Step a of Example 8 and Compound 2 (200 mg, 740 μmol, Reference Example 6) in 1,4-dioxane (3.6 mL) were added a solution of tripotassium phosphate (472 mg, 2.22 mmol) in water (0.40 mL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (52 mg, 74 μmol), and the mixture was stirred under heating under reflux in a nitrogen atmosphere for 3 hours. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography and silica gel chromatography to obtain Compound 3 (115 mg, 34.5%). MS (ESI) m / z: 449 (M+1) + .

[0333] [Step b] Compound 3 (110 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, methanol:tetrahydrofuran:diethylamine = 90:10:0.1, 20 mL / min) to obtain Compound 3a (54 mg, 99.9% ee, peak with retention time of 18 minutes) and Compound 3b (54 mg, 99.8% ee, peak with retention time of 13 minutes).

[0334] [Step c] To a mixed solution of Compound 3a (54 mg, 122 μmol) in tetrahydrofuran (2.0 mL) and methanol (1.0 mL) was added 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol), and the mixture was stirred at room temperature overnight. 1M hydrochloric acid (2.2 mL) was added to the reaction solution to neutralize it, diluted with saturated brine (10 mL), and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was washed with diethyl ether to obtain Compound 4a (28 mg, 54%). This enantiomer is designated as Example 9-1. MS (ESI) m / z: 421 (M+1) + .

[0335] [Step d] To a mixed solution of compound 3b (54 mg, 122 μmol) in tetrahydrofuran (2.0 mL) and methanol (1.0 mL), 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. 1M hydrochloric acid (2.0 mL) was added to the reaction solution for neutralization, and then diluted with water (10 mL). The organic solvent was distilled off under reduced pressure from the reaction solution, and the resulting solid was collected by filtration and washed with water to obtain compound 4b (16 mg, 33%). This enantiomer was designated as Example 9-2. MS (ESI) m / z: 421 (M+1) + 。

[0336] Example 10 (1S,2S)-2-[4-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid (1R,2R)-2-[4-(6-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid

[0337]

Chemical Structure

[0338] [Step a] Compound 3 was obtained from compound 1 and compound 2 obtained in Step a of Example 5 in the same manner as in Step a of Example 7. MS (ESI) m / z: 450 (M+1) + 。

[0339] [Step b] Compound 3 (30 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IF, 30×250, tert-butyl methyl ether:2-propanol:diethylamine = 93:7:0.1, 20 mL / min, fractionation after 1 recycle) to obtain compound 3a (9.0 mg, 99.9% ee, peak with retention time of 38 minutes) and compound 3b (9.0 mg, 99.9% ee, peak with retention time of 58 minutes).

[0340] [Step c] Compound 4a was obtained from compound 3a in the same manner as in Step c of Example 7. This enantiomer was designated as Example 10-1. MS(ESI) m / z: 422 (M+1) + .

[0341] [Step d] Compound 4b was obtained from compound 3b in the same manner as in Step c of Example 7. This enantiomer was designated as Example 10-2. MS(ESI) m / z: 422 (M+1) + .

[0342] Example 11 (1S,2S)-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid (1R,2R)-2-(5-{[4-(Trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid

[0343] [Chemical Structure]

[0344] [Step a] To a solution of compound 1 (3.00 g, 8.62 mmol, Reference Example 49) and bis(pinacolato)diboron (2.85 g, 11.2 mmol) in 1,4-dioxane (30 mL), potassium acetate (2.11 g, 21.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (352 mg, 431 μmol) were added, and the mixture was stirred for 3 hours under heating at 110 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 2 (5.64 g). MS(ESI) m / z: 314 (M+1 of boronic acid) + . [Step b] Compound 4 was obtained from Compound 2 and Compound 3 in the same manner as in Step a of Example 9. MS (ESI) m / z: 459 (M+1) + 。

[0345] [Step c] Compound 5 was obtained from Compound 4 in the same manner as in Step c of Example 7. MS (ESI) m / z: 431 (M+1) + 。

[0346] [Step d] Compound 5 (60 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, ethanol: acetic acid = 100:0.1, 10 mL / min) to obtain Compound 5a (25 mg, 99.9% ee, peak with retention time of 38 minutes) and Compound 5b (25 mg, 99.9% ee, peak with retention time of 23 minutes). Compound 5a is Example 11-1 and Compound 5b is Example 11-2. Example 11-1: MS (ESI) m / z: 431 (M+1) + 。 Example 11-2: MS (ESI) m / z: 431 (M+1) + 。

[0347] Example 12 1-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)-2,3-dihydro-1H-indole-5-carboxylic acid

[0348]

Chemical Structure

[0349] [Step a] To a solution of Compound 1 (100 mg, 296 μmol) and Compound 2 (78.6 mg, 444 μmol) in 1,4-dioxane (3.0 mL) obtained in Step b of Reference Example 42, cesium carbonate (289 mg, 887 μmol), palladium(II) acetate (3.3 mg, 15 μmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (14 mg, 30 μmol) were added, and the mixture was stirred for 5 hours under heating under reflux in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (109 mg, 84.9%). MS (ESI) m / z: 435 (M+1) + 。

[0350] [Step b] To a mixed solution of Compound 3 (109 mg, 251 μmol) in tetrahydrofuran (3 mL) and methanol (1.0 mL), 4M aqueous sodium hydroxide solution (0.20 mL, 0.80 mmol) was added, and the mixture was stirred at room temperature for 15 hours and then stirred under heating at 60 °C for 4 hours. After allowing the reaction solution to cool to room temperature, 1M hydrochloric acid (0.8 mL) was added for neutralization, water was added, and the resulting solid was collected by filtration and washed with 50% aqueous methanol solution to obtain Compound 4 (85.0 mg, 80.6%). MS (ESI) m / z: 421 (M+1) + 。

[0351] Example 13 3-[4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]benzoic acid

[0352]

Chemical formula

[0353] [Step a] To the hydrochloride of Compound 2 (133 mg, 591 μmol, Reference Example 15), saturated aqueous sodium bicarbonate and chloroform were added and stirred. After that, the organic phase was separated and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (3.0 mL), and Compound 1 (100 mg, 296 μmol) obtained in Step b of Reference Example 42, cesium carbonate (289 mg, 887 μmol), palladium(II) acetate (3.3 mg, 15 μmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (14 mg, 30 μmol) were added. The mixture was stirred for 3 hours under heating at 100 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (100 mg, 75.9%). MS (ESI) m / z: 446 (M+1) + .

[0354] [Step b] To a solution of Compound 3 (100 mg, 225 μmol) in ethylene glycol (3.0 mL), potassium hydroxide (85 wt%, 74 mg, 1.1 mmol) was added, and the mixture was stirred for 3.5 hours under heating at 150 °C. After allowing the reaction solution to cool to room temperature, 1 M - hydrochloric acid was added for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was washed with ethyl acetate - hexane to obtain Compound 4 (80 mg, 76.7%). MS (ESI) m / z: 465 (M+1) + .

[0355] Example 14 3 - [(2S)-4-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin - 3 - yl)morpholin - 2 - yl]propanoic acid

[0356] [Chemical formula]

[0357] [Step a] To a solution of Compound 2 (1.39 g, 4.19 mmol) obtained in Step c of Reference Example 9 and Compound 1 (1.81 g, 5.45 mmol, Reference Example 49) in 1,4-dioxane (28 mL) were added cesium carbonate (3.42 g, 10.5 mmol), palladium(II) acetate (141 mg, 629 μmol), and 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (587 mg, 1.26 mmol). The mixture was stirred under heating under reflux in a nitrogen atmosphere for 4 hours. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (1.93 g, 76.4%). MS (ESI) m / z: 599 (M+1) + .

[0358] [Step b] To a solution of Compound 3 (1.93 g, 3.15 mmol) in ethanol (39 mL) was added potassium hydroxide (85 wt%, 415 mg, 6.29 mmol), and the mixture was stirred at room temperature for 4 days. 1M-Hydrochloric acid (6.29 mL) was added to the reaction solution for neutralization, water (100 mL) was added, and the mixture was extracted with chloroform (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in toluene (35 mL), diisopropylethylamine (545 μL, 3.15 mmol) was added, and the mixture was stirred under heating under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 4 (1.34 g, 90.2%). MS (ESI) m / z: 455 (M+1) + .

[0359] [Step c] To a mixed solution of Compound 4 (1.34 g, 2.83 mmol) in tetrahydrofuran (8.0 mL) and methanol (2.7 mL) was added 4M-aqueous sodium hydroxide solution (2.83 mL, 11.3 mmol), and the mixture was stirred at room temperature overnight. 10% Aqueous citric acid solution (25 mL) was added to the reaction solution for neutralization, and the organic solvent was distilled off under reduced pressure. The solid formed by allowing the residue to stand was collected by filtration and washed with water to obtain Compound 5 (1.13 g, 93.3%). MS (ESI) m / z: 427 (M+1)+ .

[0360] Example 15 3-[(2S)-4-(5-{[4-(trifluoromethyl)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid

[0361] [Chemical formula]

[0362] [Step a] To a solution of Compound 1 (4.80 g, 11.6 mmol) and Compound 2 (4.09 g, 13.9 mmol) obtained in Step c of Reference Example 9 in 1,4-dioxane (120 mL), cesium carbonate (9.44 g, 29.0 mmol), palladium(II) acetate (390 mg, 1.74 mmol), and 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (1.62 g, 3.48 mmol) were added, and the mixture was stirred for 3 hours under heating and reflux in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (5.46 g, 86.5%). MS (ESI) m / z: 545 (M+1) + .

[0363] [Step b] To a solution of compound 3 (5.46 g, 10.0 mmol) in ethanol (150 mL) was added potassium hydroxide (85 wt%, 1.32 g, 20.1 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (500 mL), neutralized by adding 1 M-hydrochloric acid (20 mL), and extracted six times with chloroform (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was suspended in toluene (150 mL), diisopropylethylamine (1.62 mL, 9.36 mmol) was added, and the mixture was stirred under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (2.88 g, 76.8%). MS (ESI) m / z: 401 (M + 1) + .

[0364] [Step c] To a solution of compound 4 (2.88 g, 7.19 mmol) in dichloromethane (150 mL) was added trifluoroacetic acid (10.0 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 5 (1.33 g, 66.0%). MS (ESI) m / z: 281 (M + 1) + .

[0365] [Step d] To a solution of compound 5 (80.0 mg, 285 μmol) and compound 6 (65.4 mg, 371 μmol) in tetrahydrofuran (2.4 mL) were added tributylphosphine (75.1 mg, 371 μmol) and 1,1'-(azodicarbonyl)dipiperidine (93.6 mg, 371 μmol), and the mixture was stirred at room temperature overnight. The reaction suspension was diluted with tetrahydrofuran (6.0 mL) and hexane (12 mL), the insoluble material was filtered off, and then concentrated. After purification of the residue by silica gel chromatography, solid-phase extraction purification was performed using a cation exchange resin column (Waters, PoraPak TM ,RxnCX) to obtain compound 7 (66.9 mg, 53.5%). MS (ESI) m / z: 439 (M + 1) + .

[0366] [Step e] To a mixed solution of compound 7 (60.0 mg, 137 μmol) in tetrahydrofuran (1.8 mL) and methanol (1.8 mL), 4M aqueous sodium hydroxide solution (0.17 mL, 0.68 mmol) was added, and the mixture was stirred at room temperature overnight. 1M hydrochloric acid (0.78 mL) was added to the reaction solution for neutralization, and then diluted with water (12 mL). The resulting solid was collected by filtration and washed with water to obtain compound 8 (46.3 mg, 82.4%). MS (ESI) m / z: 411 (M+1) + 。

[0367] Example 16 3-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid

[0368]

Chemical Structure

[0369] [Step a] To a solution of compound 1 (60.0 mg, 214 μmol) obtained in Step c of Example 15 and compound 2 (72.0 mg, 214 μmol) obtained in Step a of Reference Example 48 in N,N-dimethylformamide (1.8 mL), potassium carbonate (59.2 mg, 428 μmol) was added, and the mixture was stirred under heating at 80 °C for 5 hours. After allowing the reaction solution to cool to room temperature, it was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (63.0 g, 66.2%). MS (ESI) m / z: 445 (M+1) + 。

[0370] [Step b] To a mixed solution of compound 3 (60.0 mg, 135 μmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), 4M aqueous sodium hydroxide solution (0.17 mL, 0.68 mmol) was added, and the mixture was stirred at room temperature for 2 days. 1M hydrochloric acid (0.68 mL) was added to the reaction solution for neutralization, and then diluted with water (20 mL). The resulting solid was collected by filtration and washed with water to obtain compound 4 (44.2 mg, 78.6%). MS (ESI) m / z: 417 (M+1) + 。

[0371] Example 17 2-Methyl-3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid

[0372]

Chemical formula

[0373] [Step a] To a solution of compound 1 (270 mg, 775 μmol, Reference Example 49) and compound 2 (230 mg, 547 μmol, Reference Example 33) in 1,4-dioxane (5.0 mL), cesium carbonate (530 mg, 1.63 mmol), palladium(II) acetate (12 mg, 55 μmol), and 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (51.0 mg, 109 μmol) were added. The mixture was stirred under heating at 105 °C for 7 hours in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (300 mg, 87.2%). MS (ESI) m / z: 541 (M+1) + 。

[0374] [Step b] To a solution of compound 3 (100 mg, 160 μmol) in ethanol (1.0 mL) was added an aqueous solution of 4 M sodium hydroxide (0.50 mL, 2.0 mmol), and the mixture was stirred at 85 °C for 2.5 hours. After allowing the reaction solution to cool to room temperature, acetic acid (114 μL, 2.0 mmol) was added for neutralization, and the mixture was concentrated under reduced pressure. The residue was dissolved in acetic acid (3.0 mL) and stirred at 125 °C for 5.5 hours. After allowing the reaction solution to cool to room temperature, it was purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM , RxnCX) to obtain compound 4 (65.0 g, 92.5%). MS (ESI) m / z: 441 (M + 1) + .

[0375] Example 18 3-[(2S)-4-(5-{2-[4-(Trifluoromethoxy)phenyl]ethyl}pyridin-3-yl)morpholin-2-yl]propanoic acid

[0376] [Chemical formula]

[0377] [Step a] To a solution of compound 1 (190 mg, 552 μmol) obtained in step b of Reference Example 45 and compound 2 (50.0 mg, 267 μmol, Reference Example 39) in 1,4-dioxane (5.0 mL) were added cesium carbonate (220 mg, 675 μmol), palladium(II) acetate (7.0 mg, 31 μmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (25 mg, 54 μmol). The mixture was heated at 160 °C under microwave irradiation and stirred for 30 minutes. After allowing the reaction solution to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (155 mg). MS (ESI) m / z: 451 (M + 1) + .

[0378] [Step b] To a solution of compound 3 (150 mg, 267 μmol) in ethanol (6.0 mL) was added 10%-palladium / carbon (100 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was diluted with chloroform, filtered through celite, and washed with chloroform. The filtrate was concentrated under reduced pressure to obtain compound 4 (135 mg). MS (ESI) m / z: 453 (M+1) + 。

[0379] [Step c] To a mixed solution of compound 4 (135 mg, 267 μmol) in tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was added 2M aqueous sodium hydroxide solution (1.5 mL, 3.0 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 0.5M hydrochloric acid (6.5 mL) for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by solid-phase extraction on a cation exchange resin column (Waters, PoraPak TM ,RxnCX) to obtain compound 5 (70 mg, 61%). MS (ESI) m / z: 425 (M+1) + 。

[0380] [Step d] Compound 5 (170 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, hexane:methanol:tetrahydrofuran:acetic acid = 70:15:15:0.5, 20 mL / min) to obtain compound 5a (28 mg, 99.8% ee, peak with retention time of 17 minutes) and compound 5b (27 mg, 99.9% ee, peak with retention time of 13 minutes). Compound 5a was used as Example 18-1, and compound 5b was used as Example 18-2. Example 18-1: MS (ESI) m / z: 425 (M+1) + 。 Example 18-2: MS (ESI) m / z: 425 (M+1) + 。

[0381] Example 19 (1S,2S)-2-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1R,2R)-2-[(2S)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1R,2R)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1S,2S)-2-[(2R)-4-(5-{[trans-4-(Trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid

[0382] [Chemical formula]

[0383] [Chemical formula]

[0384] [Step a] To a 1,4-dioxane (3.5 mL) solution of Compound 1 (463 mg, 1.37 mmol) obtained in Step b of Reference Example 42 and Compound 2a (140 mg, 702 μmol, a diastereomer of 2b) obtained in Step f of Reference Example 10 were added cesium carbonate (558 mg, 1.71 mmol), palladium(II) acetate (15 mg, 68 μmol), and 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (63.9 mg, 137 μmol). The mixture was stirred for 5 hours under heating at 110 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (220 mg, 65.5%). MS(ESI) m / z: 457 (M+1)+ .

[0385] [Process b] Compound 3 (220 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, tert-butyl methyl ether:ethanol:diethylamine = 85:15:0.1, 20 mL / min), to obtain Compound 3a (95 mg, 99.9% ee, peak with retention time of 12 minutes) and Compound 3b (65 mg, 99.3% ee, peak with retention time of 16 minutes).

[0386] [Process c] To a mixed solution of tetrahydrofuran (2.0 mL) and methanol (1.0 mL) of Compound 3a (95 mg, 0.21 mmol), 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. 1M hydrochloric acid (2.1 mL) was added to the reaction solution for neutralization, saturated brine (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 4a (90 mg, 94%). This enantiomer was designated as Example 19-1. MS (ESI) m / z: 429 (M+1) + .

[0387] [Process d] To a mixed solution of tetrahydrofuran (2.0 mL) and methanol (1.0 mL) of Compound 3b (65 mg, 0.14 mmol), 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. 1M hydrochloric acid (2.1 mL) was added to the reaction solution for neutralization, saturated brine (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 4b (55 mg, 90%). This enantiomer was designated as Example 19-2. MS (ESI) m / z: 429 (M+1) + .

[0388] [Process e] To a solution of Compound 1 (543 mg, 1.61 mmol) obtained in Step b of Reference Example 42 and Compound 2b (160 mg, 803 μmol, a diastereomer of 2a) obtained in Step g of Reference Example 10 in 1,4-dioxane (3.5 mL) were added cesium carbonate (654 mg, 2.01 mmol), palladium(II) acetate (18 mg, 80 μmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (74.9 mg, 161 μmol). The mixture was stirred for 5 hours under heating at 110 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 5 (26 mg, 64.5%). MS (ESI) m / z: 457 (M+1) + 。

[0389] [Step f] Compound 5 (260 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IC, 30×250, methanol:diethylamine = 100:0.1, 20 mL / min) to obtain Compound 5a (186 mg, 99.8% ee, peak with retention time of 14 minutes) and Compound 5b (140 mg, 97.7% ee, peak with retention time of 19 minutes).

[0390] [Step g] To a mixed solution of Compound 5a (186 mg) in tetrahydrofuran (2.4 mL) and methanol (1.2 mL) was added 2M aqueous sodium hydroxide solution (1.2 mL, 2.4 mmol), and the mixture was stirred overnight at room temperature. 1M hydrochloric acid (2.5 mL) was added to the reaction solution to neutralize it, saturated brine (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 6a (125 mg). This enantiomer was designated as Example 19-3. MS (ESI) m / z: 429 (M+1) + 。

[0391] [Step h] To a mixed solution of compound 5b (140 mg) in tetrahydrofuran (2.4 mL) and methanol (1.2 mL), 2M aqueous sodium hydroxide solution (1.2 mL, 2.4 mmol) was added, and the mixture was stirred overnight at room temperature. 1M hydrochloric acid (2.5 mL) was added to the reaction solution to neutralize it, saturated brine (10 mL) was added, and the mixture was extracted with chloroform. After the organic layer was washed with saturated brine, it was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6b (83 mg). This enantiomer was designated as Example 19-4. MS (ESI) m / z: 429 (M+1) + .

[0392] Example 20 trans-1-Methyl-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid

[0393] [Chemical formula]

[0394] [Step a] To a solution of compound 1 (289 mg, 855 μmol) obtained in Step b of Reference Example 42 and compound 2 (91.2 mg, 428 μmol) obtained in Step g of Reference Example 11 in 1,4-dioxane (4.0 mL), cesium carbonate (348 mg, 1.07 mmol), palladium(II) acetate (14 mg, 64 μmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (59.9 mg, 128 μmol) were added. The mixture was stirred for 8 hours under heating at 110 °C in a nitrogen atmosphere. After the reaction solution was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography and silica gel chromatography to obtain compound 3 (130 mg, 60.7%). MS (ESI) m / z: 471 (M+1) + .

[0395] [Step b] To a mixed solution of compound 3 (130 mg, 260 μmol) in tetrahydrofuran (1.3 mL) and methanol (1.3 mL), 4 M aqueous sodium hydroxide solution (1.3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water (7.0 mL) and washed with diisopropyl ether. The aqueous layer was neutralized by adding 4 M hydrochloric acid (1.35 mL), saturated aqueous ammonium chloride solution (5 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 4 (103 mg, 85.1%). MS (ESI) m / z: 443 (M+1) + .

[0396] Example 21 {[(3S)-4-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-3-yl]methoxy}acetic acid

[0397] [Chemical formula]

[0398] [Step a] To a solution of Compound 1 (368 mg, 1.06 mmol, Reference Example 49) and Compound 2 (145 mg, 756 μmol, Reference Example 38) in 1,4-dioxane (4.0 mL), sodium tert-butoxide (182 mg, 1.89 mmol), palladium(II) acetate (17 mg, 76 μmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (70.5 mg, 151 μmol) were added. The mixture was stirred for 3 hours under heating at 105 °C in a nitrogen atmosphere. Further, palladium(II) acetate (17 mg, 76 μmol) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (70.5 mg, 151 μmol) were added to the reaction solution, and the mixture was stirred for 3 hours under heating at 105 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. The filtrate was phase-separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (160 mg, 49.4%). MS (ESI) m / z: 429 (M+1) + 。

[0399] [Step b] To a solution of Compound 3 (155 mg, 362 μmol) in tetrahydrofuran (2.0 mL), 6M-hydrochloric acid (2.0 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 10 hours. After neutralizing the reaction solution with 2M-aqueous sodium hydroxide solution (5.0 mL), the solution was purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM ,RxnCX) to obtain Compound 4 (70 mg, 50%). MS (ESI) m / z: 385 (M+1) + 。

[0400] [Step c] To a solution of compound 4 (60 mg, 156 μmol) in N,N-dimethylformamide (1.0 mL) was added sodium hydride (60 wt%, 9.4 mg, 0.23 mmol) under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. To the reaction solution was added dropwise a solution of tert-butyl bromoacetate (33 mg, 0.17 mmol) in N,N-dimethylformamide (0.50 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 5 (35 mg, 45%). MS (ESI) m / z: 499 (M+1) + 。

[0401] [Step d] To a mixed solution of compound 5 (35 mg, 70 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.50 mL) was added 4M aqueous sodium hydroxide solution (0.50 mL, 2.0 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (20 mL) and washed with diisopropyl ether-hexane. The aqueous layer was neutralized by adding 1M hydrochloric acid (2.1 mL) and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 6 (32 mg, 99%). MS (ESI) m / z: 443 (M+1) +

[0402] Example 22 (2E)-4-[(3R)-4-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-3-yl]-2-butenoic acid

[0403]

Chemical formula

[0404] [Step a] To a solution of Compound 2 (594 mg, 3.39 mmol) obtained in Step c of Reference Example 12 and Compound 1 (1.42 g, 4.07 mmol, Reference Example 49) in 1,4-dioxane (30 mL), cesium carbonate (2.76 g, 8.48 mmol), palladium(II) acetate (114 mg, 508 μmol), and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (475 mg, 1.02 mmol) were added. The mixture was stirred under heating under reflux in a nitrogen atmosphere for 4 hours. After allowing the reaction solution to cool to room temperature, it was diluted with ethyl acetate (200 mL) and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (731 mg, 48.7%). MS (ESI) m / z: 443 (M + 1) + 。

[0405] [Step b] To a solution of Compound 3 (731 mg, 1.65 mmol) in tetrahydrofuran (9.0 mL), 6 M - hydrochloric acid (9.0 mL, 54 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with 1 M - aqueous sodium hydroxide solution and extracted with ethyl acetate (240 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 4 (404 mg, 61.4%). MS (ESI) m / z: 399 (M + 1) + 。

[0406] [Step c] To a mixed solution of Compound 4 (404 mg, 1.01 mmol) in dichloromethane (9.0 mL) and dimethyl sulfoxide (3.0 mL), triethylamine (705 μL, 5.07 mmol) and sulfur trioxide pyridine complex (526 mg, 3.04 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 5 (334 mg, 83.1%). MS (ESI) m / z: 397 (M + 1) + 。

[0407] [Step d] To a solution of ethyl diethylphosphonoacetate (682 mg, 3.04 mmol) in tetrahydrofuran (6.0 mL) was added sodium hydride (60 wt%, 101 mg, 2.54 mmol) under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. To the reaction solution was added dropwise a solution of compound 5 (334 mg, 843 μmol) in tetrahydrofuran (6.0 mL) under ice-cooling, and the mixture was stirred for 1.5 hours while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC (Capcellpak C18 UG80, 30×250, 35 mL / min, 0.05% aqueous TFA / 0.05% TFA acetonitrile solution = 35%→55%, 15 minutes) to obtain compound 6 (212 mg, 44.8%). MS (ESI) m / z: 467 (M+1) + .

[0408] [Step e] To a mixed solution of compound 6 (50.0 mg, 107 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 4M aqueous sodium hydroxide solution (0.5 mL, 2.0 mmol), and the mixture was stirred at room temperature for 60 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (2 mL), and 1M hydrochloric acid (2.0 mL) was added for neutralization. The resulting solid was collected by filtration and washed with water to obtain compound 7 (30.0 mg, 63.8%). MS (ESI) m / z: 439 (M+1) + .

[0409] [Step f] Compound 7 (21 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30×250, hexane:ethanol:tetrahydrofuran:acetic acid = 60:30:10:0.1, 10 mL / min, fractionation after 0.5 recycling) to obtain compound 7a (4.1 mg, 99.8% ee, peak with retention time of 27 minutes) and compound 7b (5.2 mg, 99.1% ee, peak with retention time of 17 minutes). Compound 7a is used as Example 22-1, and compound 7b is used as Example 22-2. Example 22-1: MS(ESI) m / z: 439 (M+1) + 。 Example 22-2: MS(ESI) m / z: 439 (M+1) + 。

[0410] Example 23 4-[1-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin-3-yl)pyrrolidin-2-yl]butanoic acid

[0411]

Chemical formula

[0412] [Step a] To a solution of Compound 2 (197 mg, 1.08 mmol) and Compound 1 (250 mg, 718 μmol, Reference Example 49) obtained in Step c of Reference Example 14 in 1,4-dioxane (7.2 mL), cesium carbonate (702 mg, 2.16 mmol), palladium(II) acetate (8.1 mg, 36 μmol), and 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (34 mg, 72 μmol) were added, and the mixture was stirred for 15 hours under heating at 100 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 3 (138 mg, 42.7%). MS(ESI) m / z: 451 (M+1) + 。

[0413] [Step b] To a solution of compound 3 (138 mg, 306 μmol) in ethanol (2.0 mL) was added 10%-palladium / carbon (30 mg), and the mixture was stirred for 6 hours at room temperature under a hydrogen atmosphere. After filtering the reaction mixture through celite, the filtrate was concentrated. The residue was dissolved in ethanol (2.0 mL), 10%-palladium / carbon (30 mg) was added, and the mixture was stirred for 20 hours at room temperature under a hydrogen atmosphere. After filtering the reaction mixture through celite, the filtrate was concentrated. Compound 4 (97.0 mg, 70.0%) was obtained by purifying the residue by silica gel chromatography. MS(ESI) m / z: 453 (M+1) + 。

[0414] [Step c] To a mixed solution of compound 4 (97.0 mg, 214 μmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was added 4M aqueous sodium hydroxide solution (0.11 mL, 0.44 mmol), and the mixture was stirred for 2 hours at room temperature. 1M hydrochloric acid (0.44 mL) was added to the reaction solution for neutralization, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and compound 5 (81.0 mg, 89.0%) was obtained by purifying the residue by silica gel chromatography. MS(ESI) m / z: 425 (M+1) + 。

[0415] Example 24 {[(2R)-1-(5-{[4-(Trifluoromethoxy)benzyl]oxy}pyridin-3-yl)pyrrolidin-2-yl]methoxy}acetic acid

[0416]

Chemical formula

[0417] [Step a] To a solution of compound 1 (1.89 g, 5.43 mmol, Reference Example 49) and D-proline tert-butyl (2.32 g, 13.5 mmol) in toluene (20 mL) were added sodium tert-butoxide (1.04 g, 10.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (199 mg, 217 μmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (270 mg, 434 μmol). The mixture was stirred for 2.5 hours under heating at 105 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 2 (1.74 g, 67.4%). MS(ESI) m / z: 439 (M+1) + .

[0418] [Step b] To a solution of compound 2 (830 mg, 1.52 mmol) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (86.2 mg, 2.27 mmol) under ice-cooling, and the mixture was stirred for 3 hours under ice-cooling. To the reaction solution was further added lithium aluminum hydride (57.5 mg, 1.52 mmol) under ice-cooling, and the mixture was stirred for 5 hours under ice-cooling. Water (0.15 mL) was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. 4M aqueous sodium hydroxide solution (0.15 mL) was added to the reaction suspension, and the mixture was stirred at room temperature for 15 minutes. Then, water (0.45 mL) was added, and the mixture was stirred at room temperature overnight. The reaction suspension was filtered through Celite and washed with tetrahydrofuran (60 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (490 mg, 79.9%). MS(ESI) m / z: 369 (M+1) + .

[0419] [Step c] To a solution of compound 3 (240 mg, 593 μmol) in dimethyl sulfoxide (2.5 mL) was added sodium hydride (60 wt%, 30.8 mg, 771 μmol) under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. To the reaction solution was added dropwise a solution of tert-butyl bromoacetate (127 mg, 652 μmol) in dimethyl sulfoxide (0.50 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography and NH silica gel chromatography to obtain compound 4 (120 mg, 42.0%). MS (ESI) m / z: 483 (M+1) + 。

[0420] [Step d] To a solution of compound 4 (115 mg, 238 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM ,RxnCX). The residue was dissolved in tetrahydrofuran (2.0 mL) and methanol (1.0 mL), 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 0.5M hydrochloric acid (4.1 mL) was added to the reaction solution to neutralize it, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 5 (95.0 mg, 93.5%). MS (ESI) m / z: 427 (M+1) + 。

[0421] The following compounds were prepared according to Production Methods 1 to 6 and Examples 1 to 11.

[0422]

Table 1

[0423]

Table 2

[0424] The following compounds were prepared according to Production Methods 7 to 8 and Examples 12 to 13.

[0425] [Table 3]

[0426] [Table 4]

[0427] [Table 5]

[0428] [Table 6]

[0429] [Table 7]

[0430] [Table 8]

[0431] The following compounds were prepared according to Production Methods 7, 9 to 11 and Examples 14 to 16.

[0432] [Table 9]

[0433] [Table 10]

[0434] [Table 11]

[0435] The following compounds were prepared according to Production Methods 7, 14 to 17 and Examples 19 to 24.

[0436] [Table 12]

[0437] [Table 13]

[0438] Reference Example 1

[0439] [Chemical Formula]

[0440] [Step a] To a solution of tert-butyl diethylphosphonoacetate (14.1 g, 55.8 mmol) in tetrahydrofuran (200 mL) was added dropwise a solution of 1 M potassium tert-butoxide in tetrahydrofuran (55.8 mL, 55.8 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of Compound 1 (10.0 g, 46.5 mmol) in tetrahydrofuran (100 mL) under ice-cooling, and the mixture was stirred for 3 hours under ice-cooling. 1 M hydrochloric acid (55 mL) and water (100 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 2 (14.8 g, 101%). MS (APCI) m / z: 257, 259 (M-tBu+1) + .

[0441] [Step b] To a solution of potassium tert-butoxide (1.75 g, 15.6 mmol) in dimethyl sulfoxide (40 mL) was added trimethylsulfoxonium iodide (3.43 g, 15.6 mmol), and the mixture was stirred for 30 minutes. A solution of compound 2 (4.07 g, 13.0 mmol) in dimethyl sulfoxide (40 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (2.77 g, 65.2%). MS (APCI) m / z: 327, 329 (M+1) + 。

[0442] [Step c] To a solution of compound 3 (2.72 g, 8.31 mmol) and bis(pinacolato)diborane (3.16 g, 12.5 mmol) in 1,4-dioxane (60 mL) were added potassium acetate (2.45 g, 24.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (243 mg, 333 μmol), and the mixture was stirred overnight under heating at 80 °C in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (3.38 g, 109%). MS (APCI) m / z: 319 (M-tBu+1) + 。

[0443] Reference Example 2

[0444]

Chemical Structure

[0445] [Step a] A solution of compound 1 (12.0 g, 44.5 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of 2M-isopropylmagnesium chloride in tetrahydrofuran (24.5 mL, 49.0 mmol) in tetrahydrofuran (30 mL) under a nitrogen atmosphere at room temperature, and the mixture was stirred for 1 hour. A solution of 2M-isopropylmagnesium chloride in tetrahydrofuran (4.45 mL, 8.91 mmol) was further added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A solution of compound 2 (6.43 g, 46.8 mmol) in tetrahydrofuran (30 mL) was added to the reaction solution under ice-cooling, and after stirring for 2 hours, the mixture was stirred overnight while warming to room temperature. Water (40 mL) and saturated aqueous ammonium chloride solution (160 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was washed with chloroform (50 mL)-hexane (100 mL) to obtain compound 3 (5.84 g, 59.6%). MS(ESI) m / z: 220, 222 (M + 1) + 。

[0446] [Step b] A mixture of formic acid (12.2 mL, 323 mmol) and triethylamine (17.9 mL, 129 mmol) was added dropwise to a solution of compound 3 (14.2 g, 64.5 mmol) and chloro[(1S,2S)-N-(2’,6’-dimethylbenzylsulfonyl)-1,2-diphenylethylenediamine](p-cymene)ruthenium(II) (777 mg, 1.29 mmol) in N-methylpyrrolidone (129 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 7 hours. Water (700 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (700 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (390 mL), water (520 mL), and saturated brine (260 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 4 (14.5 g, 95.3% ee). MS(ESI) m / z: 222, 224 (M + 1) + 。

[0447] [Step c] To a solution of compound 4 (14.5 g, 65.3 mmol) in diethyl ether (140 mL) was added a solution of potassium hydroxide (85 wt%, 11.0 g, 166 mmol) in water (140 mL), and the mixture was stirred overnight. After the reaction suspension was extracted with ethyl acetate (280 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (11.78 g, 99.2%, 90.1% ee). MS (ESI) m / z: 186, 188 (M+1) + 。

[0448] [Step d] To a solution of compound 6 (28.9 mL, 146 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 1M-potassium tert-butoxide in tetrahydrofuran (127 mL, 127 mmol), and then a solution of compound 5 (11.8 g, 63.3 mmol) in tetrahydrofuran (19 mL) was added. The mixture was stirred under heating under reflux in a nitrogen atmosphere for 1 day. After the reaction solution was cooled to room temperature, water (740 mL) was added, and the resulting solid was collected by filtration and washed with water (185 mL). The obtained solid was recrystallized from ethanol (150 mL) to obtain compound 7 (11.8 g, 73.2%, 99.7% ee). MS (ESI) m / z: 256, 258 (M+1) + 。

[0449] Reference Example 3

[0450]

Chemical Structure

[0451] [Step a] A suspension of sodium hydride (60 wt%, 421 mg, 10.5 mmol) in dimethyl sulfoxide (35 mL) was stirred for 30 minutes under heating at 60 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, trimethylsulfoxonium iodide (2.70 g, 12.3 mmol) was added and stirred for 30 minutes. To the reaction solution, a solution of Compound 1 (1.63 g, 8.76 mmol) in dimethyl sulfoxide (15 mL) was added and stirred at room temperature for 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 2 (910 mg, 45.7%). MS (ESI) m / z: 200, 202 (M+1) + 。

[0452] [Step b] To a solution of Compound 3 (2.13 g, 9.50 mmol) in tetrahydrofuran (2.0 mL) was added dropwise a solution of 1 M potassium tert-butoxide in tetrahydrofuran (7.92 mL, 7.92 mmol) under ice-cooling. Then, Compound 2 (900 mg, 3.96 mmol) was added to the reaction solution, and the mixture was stirred under heating under reflux in a nitrogen atmosphere for 1 day. After allowing the reaction solution to cool to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 4 (735 mg, 68.7%). MS (ESI) m / z: 270, 272 (M+1) + 。

[0453] The following compounds were prepared according to Production Methods 18 to 20 and Reference Examples 1 to 3.

[0454]

Table 14

[0455] Reference Example 7

[0456]

Chem.

[0457] [Process a] To a mixed solution of 1,2-dimethoxyethane (122 mL) and water (10 mL) containing compound 1 (3.00 g, 12.2 mmol) and vinylboronic anhydride pyridine complex (2.36 g, 9.79 mmol), potassium carbonate (3.38 g, 24.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (354 mg, 306 μmol) were added, and the mixture was stirred for 2 hours under heating and reflux in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, it was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 2 (2.35 g, 99.9%). MS(ESI) m / z: 193 (M+1) + 。

[0458] [Process b] To a mixed solution of tert-butyl alcohol (30 mL) and water (40 mL) containing compound 2 (2.35 g, 12.2 mmol), N-bromosuccinimide (2.39 g, 13.4 mmol) was added, and the mixture was stirred for 2.5 hours under heating at 45 °C. After allowing the reaction solution to cool to room temperature, 4M aqueous sodium hydroxide solution (23.06 mL, 12.2 mL) was added, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution, 4M aqueous sodium hydroxide solution (3.06 mL, 12.2 mL) was further added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Filtration and concentration gave compound 3 (2.48 g, 97.4%). 1 1H-NMR (400 MHz, CDCl3) δ: 2.76 (1H, m), 3.17 (1H, m), 3.88 (1H, m), 3.88 (3H, s), 3.91 (3H, s), 6.87 (1H, d, J = 1.5 Hz), 6.93 (1H, dd, J = 8.2, 1.5 Hz), 7.78 (1H, d, J = 8.2 Hz).

[0459] [Process c] To a solution of Compound 3 (2.48 g, 11.9 mmol) in 2-methyl-2-butanol (60 mL) was added Compound 4 (1.89 g, 12.5 mmol), and the mixture was stirred overnight under heating at 110 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 5 (2.17 g, 50.7%). MS (APCI) m / z: 360 (M+1) + .

[0460] [Step d] To a solution of Compound 5 (2.17 g, 6.04 mmol) in tetrahydrofuran (60 mL) were added tributylphosphine (2.23 mL, 9.06 mmol) and 1,1'-(azodicarbonyl)dipiperidine (2.29 g, 9.06 mmol), and the mixture was stirred overnight at room temperature. After filtering off the insoluble matter from the reaction suspension, it was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 6 (1.18 g, 57.2%). MS (APCI) m / z: 342 (M+1) + .

[0461] [Step e] To a solution of Compound 6 (307 mg, 899 μmol) in methanol (45 mL) was added 10%-palladium / carbon (92 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain Compound 7 (187 mg, 82.8%). MS (APCI) m / z: 252 (M+1) + .

[0462] Reference Example 8

[0463] [Chemical Structure]

[0464] [Step a] To a mixed solution of compound 1 (400 mg, 1.77 mmol) in tetrahydrofuran (18 mL) and methanol (3.0 mL), di-tert-butyl dicarbonate (425 mg, 1.95 mmol) and triethylamine (377 μL, 2.65 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and phase separation was performed. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 2 (400 mg, 69.3%). 1 1H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.96 (1H, m), 2.25 (1H, m), 3.22 - 3.44 (3H, m), 3.53 - 3.66 (1H, m), 3.75 - 3.85 (1H, m), 7.15 - 7.21 (2H, m), 7.36 - 7.38 (1H, d, J = 7 Hz), 7.38 (1H, s).

[0465] [Step b] To a mixed solution of compound 2 (400 mg, 1.23 mmol) in N,N-dimethylformamide (5.0 mL) and ethanol (15 mL), sodium acetate (168 mg, 2.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (289 mg, 354 μmol), and diisopropylethylamine (918 μL, 5.31 mmol) were added, and the mixture was stirred under heating at 70 °C in a carbon monoxide atmosphere for 2 days. After allowing the reaction solution to cool to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. The filtrate was phase-separated, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (224 mg, 41.5%). MS (ESI) m / z: 250 (M - tBu + 1) + .

[0466] [Step c] To a chloroform (2.0 mL) solution of compound 3 (224 mg, 724 μmol), trifluoroacetic acid (0.56 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was passed through a cation exchange resin column (Waters, PoraPakTM , By subjecting it to solid-phase extraction and purification with (RxnCX), compound 4 (142 mg, 94.3%) was obtained. MS (ESI) m / z: 206 (M+1) + .

[0467] Reference Example 9

[0468] [Chemical formula]

[0469] [Step a] To a solution of compound 1 (20.0 g, 92.1 mmol) and triethylamine (16.6 mL, 120 mmol) in dichloromethane (180 mL), a solution of mesyl chloride (7.84 mL, 101 mmol) in dichloromethane (8.0 mL) was added dropwise under ice-cooling, and then the mixture was stirred for 2 hours under ice-cooling. To the reaction solution, water (60 mL) was added under ice-cooling, and phase separation was carried out. The organic layer was washed with saturated aqueous sodium hydrogen carbonate (40 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2 (30.3 g). MS (ESI) m / z: 296 (M+1) + .

[0470] [Step b] To a solution of compound 2 (30.3 g, 92.3 mmol) and compound 3 (39.2 mL, 185 mmol) in N-methylpyrrolidone (230 mL), potassium carbonate (63.8 g, 462 mmol) and sodium iodide (4.15 g, 27.7 mmol) were added, and the mixture was stirred for 3.5 hours under heating at 120 °C. After allowing the reaction solution to cool to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 4 (41.6 g, 90.4%). MS (ESI) m / z: 432 (M+1) + .

[0471] [Step c] To a solution of compound 4 (2.00 g, 4.17 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (100 mL) was added dropwise to the reaction solution, and the mixture was extracted three times with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (1.40 g). MS(ESI) m / z: 332 (M+1) + 。

[0472] Reference Example 10

[0473]

Chemical Structure

[0474] [Step a] To a mixed solution of compound 1 (5.00 g, 23.0 mmol) in dichloromethane (60 mL) and dimethyl sulfoxide (20 mL) under ice-cooling were added triethylamine (19.2 mL, 138 mmol) and sulfur trioxide pyridine complex (11.0 g, 69.0 mmol), and the mixture was stirred at room temperature for 4 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with chloroform (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (30 mL), and the solution was added dropwise under ice-cooling to a solution of diethyl phosphonoacetate (7.73 g, 34.5 mmol) and sodium hydride (60 wt%, 1.20 g, 34.5 mmol) in tetrahydrofuran (30 mL), and then the mixture was stirred overnight while warming to room temperature. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 2 (2.92 g, 38.3%). MS(ESI) m / z: 286 (M+1) + 。

[0475] [Step b] To a solution of compound 2 (3.32 g, 10.2 mmol) in tetrahydrofuran (35 mL) was added dropwise a dichloromethane solution of 1M-diisobutylaluminum hydride (30.5 mL, 30.5 mmol) under ice-cooling, and the mixture was stirred for one and a half hours under ice-cooling. To the reaction solution was added dropwise a saturated aqueous Rochelle salt solution (30 mL) under ice-cooling, and the mixture was stirred overnight at room temperature, and then extracted three times with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (1.55 g, 57.7%). MS(ESI) m / z: 188 (M-tBu + 1) + 。

[0476] [Step c] To a solution of compound 3 (780 mg, 2.94 mmol) in 1,2-dichloroethane (15 mL) were added dropwise a toluene solution of 1M-diethylzinc (5.90 mL, 5.90 mmol) and chloroiodomethane (860 μL, 11.8 mmol) under ice-cooling, and the mixture was stirred for 5 hours while warming to room temperature. To the reaction solution were added saturated aqueous ammonium chloride solution (5.0 mL), saturated aqueous Rochelle salt solution (30 mL), and chloroform (30 mL), and the mixture was stirred overnight at room temperature, and then extracted twice with chloroform (30 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 4 (145 mg, 19%) and compound 5 (140 mg, 18%). Compounds 4 and 5 are diastereoisomers. Compound 4: MS(ESI) m / z: 258 (M + 1) + 。 Compound 5: MS(ESI) m / z: 258 (M + 1) + 。

[0477] [Step d] To a mixed solution of compound 4 (280 mg, 1.01 mmol) in acetonitrile (6.0 mL) and carbon tetrachloride (6.0 mL), an aqueous solution of sodium periodate (645 mg, 3.02 mmol) in water (9.0 mL) and ruthenium(IV) oxide hydrate (4.6 mg, 30 μmol) were added, and the mixture was stirred at room temperature for 1 hour. 2-Propanol (3.0 mL) was added to the reaction solution, and after stirring at room temperature for 1 hour, the mixture was filtered through celite. Saturated aqueous ammonium chloride solution (9.0 mL) was added to the filtrate, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (4.0 mL), potassium carbonate (443 mg, 3.21 mmol) and iodoethane (257 μL, 3.21 mmol) were added, and the mixture was stirred at room temperature for 2 days. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 6 (290 mg, 64.1%). MS(ESI) m / z: 300 (M+1) + .

[0478] [Step e] To a mixed solution of compound 5 (260 mg, 900 μmol) in acetonitrile (5.0 mL) and carbon tetrachloride (5.0 mL), an aqueous solution of sodium periodate (578 mg, 2.70 mmol) in water (7.5 mL) and ruthenium(IV) oxide hydrate (4.1 mg, 27 μmol) were added, and the mixture was stirred at room temperature for 1 hour. 2-Propanol (2.5 mL) was added to the reaction mixture, and after stirring at room temperature for 1 hour, the mixture was filtered through celite. Saturated aqueous ammonium chloride solution (7.5 mL) was added to the filtrate, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (3.5 mL), potassium carbonate (377 mg, 2.73 mmol) and iodoethane (218 μL, 2.73 mmol) were added, and the mixture was stirred at room temperature for 4 days. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 7 (210 mg, 77.2%). MS(ESI) m / z: 300 (M+1) + 。

[0479] [Step f] To a solution of compound 6 (205 mg, 685 μmol) in dichloromethane (3.5 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 8 (140 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 1.01 (1H, m), 1.15 (1H, m), 1.25 (3H, t, J = 7.2 Hz), 1.50 (1H, m), 1.60 (1H, m), 2.68 (1H, m), 2.78 (1H, m), 2.85 (1H, m), 2.98 (1H, m), 3.09 (1H, m), 3.54 (1H, m), 3.85 (1H, m), 4.12 (2H, m). MS(ESI) m / z: 200 (M+1) + 。

[0480] [Step g] To a solution of compound 7 (210 mg, 701 μmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 9 (160 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 0.87 (1H, m), 1.14 (1H, m), 1.25 (3H, t, J = 7.2 Hz), 1.50 (1H, m), 1.70 (1H, m), 2.71 (1H, m), 2.79 (1H, m), 2.86 (1H, m), 2.94 - 2.99 (2H, m), 3.54 (1H, m), 3.86 (1H, m), 4.11 (2H, m). MS (ESI) m / z: 200 (M + 1) + 。

[0481] Reference Example 11

[0482]

Chemical Structure

[0483] [Step a] To a solution of Compound 1 (2.50 g, 11.5 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (36.0 mg, 230 μmol) in dichloromethane (35 mL), an aqueous solution of sodium bromide (118 mg, 1.15 mmol) in water (2.0 mL), saturated sodium bicarbonate solution (5.5 mL), and 5% aqueous sodium hypochlorite solution (17.1 mL, 11.5 mmol) were added dropwise over 45 minutes under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. Saturated brine (30 mL) was added to the reaction mixture, and the mixture was extracted three times with chloroform (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (20 mL), and the solution was added dropwise to a solution of diethyl ethylphosphonopropionate (3.47 g, 14.6 mmol) and sodium hydride (60 wt%, 499 mg, 12.5 mmol) in tetrahydrofuran (20 mL) under ice-cooling, and then the mixture was stirred overnight while warming to room temperature. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain Compound 2 (1.74 g, 53.6%). MS(ESI) m / z: 300 (M+1) + .

[0484] [Step b] To a solution of compound 2 (1.74 g, 5.81 mmol) in tetrahydrofuran (20 mL) was added dropwise a dichloromethane solution of 1 M diisobutylaluminum hydride (20.3 mL, 20.3 mmol) at -50 °C over 40 minutes, and then the mixture was stirred for 2 hours while warming to -30 °C. To the reaction solution was added dropwise a mixture of methanol (1.0 mL) and tetrahydrofuran (10 mL) at -30 °C, and then the mixture was stirred for 1 hour while warming to -10 °C. To the reaction solution at -10 °C was added saturated Rochelle salt aqueous solution (10 mL), and the mixture was stirred overnight at room temperature, and then extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 3 (950 mg, 58.4%). MS (ESI) m / z: 258 (M+1) + .

[0485] [Step c] To a solution of compound 3 (950 mg, 3.40 mmol) in dichloromethane (15 mL) were added imidazole (694 mg, 10.2 mmol) and tert-butylchlorodiphenylsilane (1.32 mL, 5.10 mmol), and the mixture was stirred at room temperature for 9 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 4 (2.20 g). 1 1H-NMR (400 MHz, CDCl3) δ: 1.06 (9H, s), 1.48 (9H, s), 1.66 (3H, s), 2.71 (1H, m), 2.96 (1H, m), 3.57 (1H, m), 3.84 - 3.91 (3H, m), 4.05 (2H, s), 4.12 (1H, m), 5.52 (1H, d, J = 8 Hz), 7.35 - 7.44 (6H, m), 7.64 - 7.68 (4H, m).

[0486] [Step d] To a solution of compound 4 (2.20 g, 3.40 mmol) in 1,2-dichloroethane (35 mL), a toluene solution of 1M-diethylzinc (11.1 mL, 11.1 mmol) and chloroiodomethane (1.61 mL, 22.1 mmol) were added dropwise over 45 minutes under ice-cooling, and then the mixture was stirred under ice-cooling for 4 hours. To the reaction solution, saturated aqueous ammonium chloride solution (5.0 mL), saturated aqueous Rochelle salt solution (10 mL), and chloroform (10 mL) were added, and the mixture was stirred overnight at room temperature. Then, the mixture was extracted twice with chloroform (30 mL). The organic layer was washed with saturated aqueous Rochelle salt solution (10 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 5 (1.35 g, 70.9%). 1 1H-NMR (400 MHz, CDCl3) δ: 0.36 (1H, t, J = 5 Hz), 0.69 - 0.76 (2H, m), 1.06 (9H, s), 1.20 (3H, s), 1.46 (9H, s), 2.74 (1H, m), 2.93 (1H, m), 3.20 (1H, m), 3.45 - 3.56 (2H, m), 3.84 - 3.98 (3H, m), 7.35 - 7.44 (6H, m), 7.62 - 7.65 (4H, m).

[0487] [Step e] To a solution of compound 5 (1.35 g, 2.41 mmol) in tetrahydrofuran (8.0 mL), a tetrahydrofuran solution of 1M-tetrabutylammonium fluoride (4.82 mL, 4.82 mmol) was added, and the mixture was stirred overnight at room temperature. To the reaction solution, saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 6 (720 mg, 94.7%). MS (ESI) m / z: 272 (M + 1) + .

[0488] [Step f] To a mixed solution of compound 6 (360 mg, 1.33 mmol) in acetonitrile (8.0 mL) and carbon tetrachloride (8.0 mL), an aqueous solution of sodium periodate (851 mg, 3.98 mmol) in water (12 mL) and ruthenium(IV) oxide hydrate (10 mg, 66 μmol) were added, and the mixture was stirred at room temperature for one and a half hours. 2-Propanol (4.0 mL) was added to the reaction solution, and after stirring at room temperature for 1 hour, it was filtered through celite. To the filtrate, saturated aqueous ammonium chloride solution (10 mL) and 10% aqueous citric acid solution (10 mL) were added, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (5.0 mL), potassium carbonate (564 mg, 3.95 mmol) and iodoethane (316 μL, 3.95 mmol) were added, and the mixture was stirred at room temperature for 3 days. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 7 (270 mg, 62.8%). MS(ESI) m / z: 314 (M+1) + 。

[0489] [Step g] To a solution of compound 7 (270 mg, 827 μmol) in dichloromethane (4.5 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 8 (195 mg). MS(ESI) m / z: 214 (M+1) + 。

[0490] Reference Example 12

[0491]

Chemical Structure

[0492] [Step a] To a solution of compound 1 (1.00 g, 4.08 mmol) in 1,2-dimethoxyethane (6.0 mL) were added 4-methylmorpholine (493 μL, 4.48 mmol) and isobutyl chloroformate (586 μL, 4.48 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction suspension was filtered, and to the filtrate were added sodium borohydride (231 mg, 6.12 mmol) and water (3.0 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 2 (836 mg, 88.7%). MS (ESI) m / z: 176 (M-tBu+1) + 。

[0493] [Step b] To a solution of compound 2 (836 mg, 3.61 mmol) in dichloromethane (10 mL) were added diisopropylethylamine (1.88 mL, 10.8 mmol) and chloromethyl methyl ether (851 μL, 11.21 mmol) dropwise under ice-cooling, and the mixture was stirred overnight while warming to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (926 mg, 93.1%). MS (ESI) m / z: 276 (M+1) + 。

[0494] [Step c] To a solution of compound 3 (926 mg, 3.36 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2.6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 2M aqueous potassium carbonate solution and extracted three times with dichloromethane (30 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4 (594 mg). MS (ESI) m / z: 176 (M+1) + 。

[0495] Reference Example 13

[0496]

Chemical Structure

[0497] [Step a] To a solution of Compound 1 (400 mg, 1.73 mmol) in dichloromethane (12 mL) was added Dess-Martin periodinane (1.10 g, 2.59 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution were added saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfite under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 2 (399 mg). MS (ESI) m / z: 174 (M-tBu+1) + 。

[0498] [Step b] To a solution of Compound 2 (399 mg, 1.74 mmol) and diethyl ethylphosphonoacetate (587 mg, 2.62 mmol) in tetrahydrofuran (12.0 mL) was added sodium hydride (60 wt%, 90.7 mg, 2.27 mmol) under ice-cooling, and the mixture was stirred for 15 minutes. The mixture was stirred overnight while warming to room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (325 mg, 2.1%). MS (ESI) m / z: 244 (M-tBu+1) + 。

[0499] [Step c] To a solution of Compound 3 (320 mg, 1.07 mmol) in methanol (13 mL) was added 10%-palladium / carbon (64 mg), and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was diluted with chloroform (10 mL), filtered through celite, and the filtrate was concentrated under reduced pressure to obtain Compound 4 (321 mg, 99.7%). MS (ESI) m / z: 302 (M+1) + 。

[0500] [Step d] To a solution of compound 4 (130 mg, 431 μmol) in dichloromethane (2.6 mL) was added trifluoroacetic acid (0.26 mL), and the mixture was stirred overnight at room temperature. The reaction solution was purified by solid-phase extraction on a cation exchange resin column (Waters, PoraPak TM , RxnCX) to obtain compound 5 (81.6 mg, 94.0%). MS (ESI) m / z: 202 (M + 1) + .

[0501] Reference Example 14

[0502] [Chemical Structure]

[0503] [Step a] To a solution of compound 1 (450 mg, 2.09 mmol) in dichloromethane (21 mL) was added Dess-Martin periodinane (1.33 g, 3.14 mmol) under ice-cooling, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution were added saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium sulfite under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 2 (295 mg, 66.2%). MS (ESI) m / z: 214 (M + 1) + .

[0504] [Step b] To a solution of ethyl diethylphosphonoacetate (457 mg, 2.04 mmol) in tetrahydrofuran (14.0 mL) was added sodium hydride (60 wt%, 70.7 mg, 1.77 mmol) under ice-cooling, and the mixture was stirred for 15 minutes. To the reaction solution was added dropwise compound 2 (290 mg, 1.36 mmol) under ice-cooling, and the mixture was stirred for 1.5 hours under ice-cooling. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3 (612 mg). MS (ESI) m / z: 228 (M - tBu + 1) + .

[0505] [Step c] To a solution of compound 3 (612 mg, 2.04 mmol) in chloroform (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by solid-phase extraction using a cation exchange resin column (Waters, PoraPak TM , RxnCX) to obtain compound 4 (220 mg, 88.2%). MS (ESI) m / z: 184 (M+1) + .

[0506] The following compounds were prepared according to Production Methods 21 to 24 and Reference Examples 7 to 14.

[0507]

Table 15

[0508]

Table 16

[0509]

Table 17

[0510] Reference Example 42

[0511]

Chem.

[0512] [Step a] To a solution of lithium aluminum hydride (2.90 g, 76.5 mmol) in tetrahydrofuran (150 mL) was added compound 1 (10.0 g, 51.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added dropwise a solution of water (3.0 mL) in tetrahydrofuran (150 mL) under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. To the reaction suspension was added 4M aqueous sodium hydroxide solution (3.0 mL), and after stirring at room temperature for 30 minutes, water (3.0 mL) was added and the mixture was stirred at room temperature overnight. The reaction suspension was filtered through celite and washed with tetrahydrofuran (50 mL). The filtrate was concentrated under reduced pressure to obtain compound 2 (8.70 g, 93.7%). 1 1H-NMR (400 MHz, CDCl3) δ: 0.94 - 1.05 (2H, m), 1.27 - 1.38 (3H, m), 1.49 (1H, m), 1.90 - 2.01 (5H, m), 3.48 (2H, t, J = 6 Hz).

[0513] [Step b] To a solution of compound 2 (678 mg, 3.72 mmol) and compound 3 (540 mg, 3.10 mmol) in tetrahydrofuran (20 mL) were added triphenylphosphine (1.22 g, 4.66 mmol) and diisopropyl azodicarboxylate (941 mg, 4.66 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added 50% aqueous N,N-dimethylformamide solution, followed by extraction with heptane. The organic phase was washed with 50% aqueous N,N-dimethylformamide solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (972 mg, 92.6%). MS (ESI) m / z: 338, 340 (M + 1) + .

[0514] Reference Example 43

[0515]

Chemical Structure

[0516] [Step a] To a solution of Compound 1 (2.04 g, 9.48 mmol) and Compound 2 (1.50 g, 8.62 mmol) in tetrahydrofuran (15 mL), triphenylphosphine (2.71 g, 10.3 mmol) and diisopropyl azodicarboxylate (2.18 g, 10.8 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 3 (2.90 g, 90.6%). MS (ESI) m / z: 371, 373 (M+1) + .

[0517] [Step b] To a solution of Compound 3 (2.90 g, 7.81 mmol) in ethyl acetate (10 mL), a 4M solution of hydrochloric acid in ethyl acetate (19.5 mL, 78.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with a 2M aqueous sodium hydroxide solution and phase-separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, Compound 4 (1.94 g, 91.5%) was obtained. MS (ESI) m / z: 271, 273 (M+1) + .

[0518] [Step c] To a mixed solution of Compound 4 (1.29 g, 4.76 mmol) in N,N-dimethylformamide (15 mL) and diisopropylethylamine (1.65 mL, 9.52 mmol), Compound 5 (1.37 mL, 9.52 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain Compound 6 (1.61 g, 95.5%). MS (ESI) m / z: 353, 355 (M+1) + .

[0519] Reference Example 44

[0520] [Chemical Structure]

[0521] [Step a] To a solution of compound 1 (12.6 g, 61.7 mmol) obtained in step a of Reference Example 42 in tetrahydrofuran (225 mL) was added sodium hydride (60 wt%, 2.69 g, 67.3 mmol) portionwise under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of compound 2 (8.35 g, 56.1 mmol) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred overnight while warming to room temperature. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (4.95 g, 30.0%). MS (ESI) m / z: 295, 297 (M+1) + 。

[0522] Reference Example 45

[0523]

Chemical formula

[0524] [Step a] To a solution of compound 1 (5.00 g, 19.6 mmol) in toluene (100 mL) was added triphenylphosphine (5.66 g, 21.6 mmol), and the mixture was stirred under heating under reflux for 1 hour. The reaction solution was diluted with toluene (50 mL), and further stirred under heating under reflux for 1 hour. After allowing the reaction solution to cool to room temperature, it was diluted with hexane (150 mL), and the resulting solid was collected by filtration and washed with hexane (100 mL) to obtain compound 2 (8.78 g, 86.6%). MS (ESI) m / z: 437

[0525] [Step b] To a mixed solution of compound 2 (3.62 g, 6.99 mmol) in tetrahydrofuran (40 mL) and N,N-dimethylformamide (10 mL) under ice-cooling, sodium hydride (60 wt%, 155 mg, 6.45 mmol) was added, and the mixture was stirred for 30 minutes under ice-cooling. To the reaction solution under ice-cooling, compound 3 (1.00 g, 5.38 mmol) was added portionwise, and the mixture was stirred for 30 minutes under ice-cooling. Insoluble matters were filtered off from the reaction suspension and washed with ethyl acetate (50 mL). The filtrate was diluted with ethyl acetate (50 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (864 mg, 46.7%), compound 5 (193 mg, 10.5%), and compound 6 (619 mg, 33.5%), which is a cis / trans mixture. Compound 4: MS(ESI) m / z: 344, 346 (M+1) + 。 Compound 5: MS(ESI) m / z: 344, 346 (M+1) + 。 Compound 6: MS(ESI) m / z: 344, 346 (M+1) + 。

[0526] Reference Example 46

[0527]

Chemical Structure

[0528] [Step a] To a mixed solution of Compound 1 (200 mg, 1.34 mmol), Compound 2 (250 mg, 1.34 mmol), N,N-dimethylformamide (4.0 mL) and triethylamine (2.0 mL), bis(triphenylphosphine)palladium(II) dichloride (94.2 mg, 134 μmol), triphenylphosphine (70.4 mg, 268 μmol) and copper(I) iodide (25.6 mg, 134 μmol) were added. The mixture was stirred for 6 hours under heating at 50 °C in a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (160 mg, 40.0%). MS(ESI) m / z: 299, 301 (M+1) + 。

[0529] Reference Example 47

[0530]

Chemical formula

[0531] [Step a] To a solution of Compound 1 (200 mg, 1.06 mmol) and Compound 2 (224 mg, 1.38 mmol) in tetrahydrofuran (6.0 mL), tributylphosphine (341 μL, 1.38 mmol) and 1,1'-(azodicarbonyl)dipiperidine (349 mg, 1.38 mmol) were added little by little, and the mixture was stirred overnight at room temperature. The reaction suspension was diluted with hexane (6.0 mL), the insoluble matter was filtered off, and then concentrated. The residue was purified by silica gel chromatography to obtain Compound 3 (324 mg, 91.8%). MS(ESI) m / z: 332, 334 (M+1) + 。

[0532] Reference Example 48

[0533]

Chemical formula

[0534] [Process a] To a solution of Compound 1 (100 mg, 549 μmol) obtained in Process a of Reference Example 42 in dichloromethane (2.0 mL), pyridine (133 μL, 1.65 mmol) and p-toluenesulfonyl chloride (126 mg, 659 μmol) were added, and the mixture was stirred at room temperature for 6 hours. Further, p-toluenesulfonyl chloride (62.8 mg, 329 μmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (20 mL), washed with 1 M hydrochloric acid (10 mL) and saturated aqueous sodium bicarbonate (10 mL), and concentrated under reduced pressure to obtain Compound 2 (176 mg, 95.2%). 1 1H-NMR (400 MHz, CDCl3) δ: 0.92 - 1.03 (2H, m), 1.22 - 1.33 (2H, m), 1.68 (1H, m), 1.81 - 1.86 (2H, m), 1.89 - 2.00 (3H, m), 2.46 (3H, s), 3.84 (2H, d, J = 6.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz).

[0535] The following compounds were produced according to Production Methods 25 to 29 and Reference Examples 42 to 48.

[0536] [Table 18]

[0537] Experimental Example 1: [Enzyme Inhibition Test Method] A substrate and a set of choline quantification reagents prepared with assay buffer (50 mM Tris (pH 8.0), 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.1% BSA (Albumin from bovine serum, SIGMA), 0.0025% Triton X-100) (200 μM LPC (1-Oleoyl-sn-glycero-3-phosphocholine Sigma #L1881), 25 μM Amplex UltraRed reagent (Invitrogen), 0.1 U / mL Peroxidase (TOYOBO), 1 U / mL Choline oxidase (TOYOBO)) 10 μL, enzyme (0.4 ng / μL human recombinant ATX) 10 μL, and compound-containing solution 100 nL were dispensed into a 384-well plate, and fluorescence (Ex. 525 nm / Em. 598 nm) was measured after incubation at room temperature for 1 hour. Choline chloride was used as a standard. A blank without enzyme was set as 100% inhibition rate, and a control without inhibitor was set as 0% inhibition rate. The inhibition rate was calculated, and the IC50 value was calculated from the percentage of inhibitory activity at each concentration.

[0538] Experimental Example 2: [Measurement of ATX activity in plasma (ex vivo)] The compound administration solution prepared to a predetermined concentration with 0.5% aqueous carboxymethylcellulose solution by wet grinding for 10 minutes using a mixer mill (model: MM400) was orally administered to male Wistar rats (5 weeks old at the time of use) at a rate of 5 mL / kg. Blood was collected over time from the jugular vein 8 to 24 hours after administration. The blood was heparinized using a small blood collection container Capject (CJ-AL, Terumo), and plasma was separated by centrifugation (4°C, 12,000 rpm, 2 minutes) and then stored at -80°C. After blood collection, the rats were euthanized by bleeding from the posterior vena cava under isoflurane inhalation anesthesia. The measurement of ATX activity in plasma was evaluated using the plasma choline concentration released from lysophosphatidylcholine (substrate of ATX) by the lysophospholipase D activity of ATX as an index. 12 μL of plasma was added with an equal volume of 2× assay buffer (200 mM Tris-HCl pH 9.0, 10 mM MgCl2, 1 M NaCl, 0.1% Triton X-100) and reacted at 37°C for 6 hours. 10 μL of the reaction solution reacted for 6 hours and 45 μL of reagent R1 solution (100 mM Tris-HCl pH 8.0, 0.5 mM TOOS, 10 U / mL peroxidase, 0.01% Triton X-100) were added and mixed, and then the absorbance at 550 - 700 nm was measured as a pre-value. Choline chloride was used as a standard. 1 mM choline chloride was diluted with 2× assay buffer in a two-fold serial dilution up to 7 steps, and the R1 solution was treated similarly to measure the absorbance. Further, 15 μL of reagent R2 solution (100 mM Tris-HCl pH 8.0, 1 mM 4-aminoantipyrine, 10 U / mL choline oxidase, 0.01% Triton X-100) was added, reacted at room temperature for 10 minutes, and the absorbance at 550 - 700 nm was measured. The choline concentration per reaction time was calculated from the difference between the absorbance after adding the R2 solution and the pre-value measured before adding R2, and used as the ATX activity value. <Calculation formula> Inhibitory activity (%) = 100 × {1 - [choline concentration (μM) in the test substance-administered group / choline concentration (μM) in the solvent control group]} The results obtained in Experimental Examples 1 and 2 are shown in the following table.

[0539]

Table 19

[0540]

Table 20

[0541]

Table 21

[0542]

Table 22

[0543]

Table 23

[0544] Experimental Example 3: [Examination of the effect of an ATX inhibitor on a mouse bleomycin-induced pulmonary fibrosis model] The efficacy of an ATX inhibitor (Example 5, hereinafter referred to as example 5 in the figure) against a bleomycin (BLM)-induced pulmonary fibrosis model was evaluated using the changes in each fibrosis index marker in plasma or BALF, or the fibrosis-related genes in the lung as indicators. As a result, it suppressed SP-D in plasma (Figure 1), and with regard to the genes in the lung, it showed an inhibitory effect on the expression of Col1a1 (Figure 2), CTGF (Figure 3), and IL-6 (Figure 4). In addition, it completely suppressed the ATX activity in plasma (Figure 5) and also showed an inhibitory effect on the production of LPA (C18:2) in BALF (Figure 6). [Creation of a bleomycin-induced pulmonary fibrosis model] Eight-week-old mice were grouped using a simulation method so that their weights would be uniform by the day before bleomycin administration according to the group composition shown in Table 24 (SOP / STA / RA-0003). The mice were anesthetized with isoflurane, and a bleomycin-induced pulmonary fibrosis model was established by intratracheally administering a 0.5 mg / mL bleomycin solution at 50 μL / head (1.25 U / kg). In the Saline group, physiological saline was administered instead of bleomycin. The ATX inhibitor (Example 5) was orally administered twice a day starting from the day of bleomycin administration. Also, body weight was measured once a day starting from the day of grouping.

[0545]

Table 24

[0546] <Preparation method of ATX inhibitor> To the ATX inhibitor (Example 5), a mixture of 1 equivalent of 1N NaOH and 0.5% CMC solution (100 μL in total) was added, 10 zirconia beads with a diameter of 3 mm were added, and it was pulverized using a mixer mill MM400 (frequency 28.01 / min, pulverization time 10 minutes). 0.5% CMC was added to make it 30 mg / mL and suspended, and ultrasonic treatment was performed for 10 minutes. The administration volume was carried out at 10 mL / Kg, and the administration dose was 30 mg / kg. It was administered twice a day, and the first administration was performed 30 minutes before BLM administration.

[0547] <Reagents> Bleomycin hydrochloride for injection (BLM, product name: Bleo (5 mg / ampoule), manufacturer: Nippon Kayaku Co., Ltd., manufacturing number: 250590, preparation method: BLM was dissolved in physiological saline to a concentration of 1 mg / mL, diluted with physiological saline, and then a 0.5 mg / mL solution was prepared and administered intratracheally at a rate of 50 μL / head. Otsuka natural drinking water (Otsuka Pharmaceutical Factory, Inc., storage condition: stored at room temperature). Sircol Soluble / Insoluble Collagen Assay kit (Biocolor, S1111). Rat / Mouse SP-D Kit "Yamasa" EIA (Yamasa Soy Sauce, 80072).

[0548] <Test Animals> Animal Species: Female C57BL / 6J Mice, Supplier: Charles River Laboratories Japan, Inc., Number of Animals Used: 10 mice / group (7 weeks old at the time of arrival).

[0549] <Breeding Environment> Set Temperature (Allowable Range): 23°C (20 - 26°C), Set Humidity (Allowable Range): 55% (30 - 70%), Set Light / Dark Cycle: 12 hours of lighting (AM 7:00 - PM 7:00 light), Water and Food: Free access.

[0550] <Sampling and Measurement of Each Index> Fourteen days after bleomycin administration, plasma, BALF, and lung tissue were sampled. BALF was collected, and the concentration of LPA(18:2) (Figure 6) in BALF was measured. Plasma was collected by blood sampling from the abdominal vena cava. After anticoagulating the whole blood with heparin, it was centrifuged and collected. Then, the ATX activity (Figure 5) and SP-D (Figure 1) in plasma were measured. Furthermore, the chest was opened to collect the whole lung tissue, and gene expression analysis of Col1a1 (Figure 2), CTGF (Figure 3), and IL-6 (Figure 4) in the lung was performed. For gene expression analysis, mRNA in the lung tissue was extracted using TRIzol, reverse transcription was performed using a kit from Life technologies, and qPCR was carried out using Taqman probe.

[0551] <Measurement of LPA Concentration in BALF> To 200 μL of the sampled BALF, an organic solvent and an LPA(17:0) solution as an internal standard substance were added, and vacuum drying was performed at 35°C. After drying, 50 μL of 50% ethanol aqueous solution was added to the residue, and the redissolved solution was used as an analytical sample. The analytical sample was separated using a reverse-phase column, and LPA(18:2) was detected using a QTRAP6500 system (ABSciex). Also, an LPA(18:2) synthetic standard was added to the PBS buffer used for collecting BALF, and the concentration of LPA(18:2) contained in BALF was calculated by comparing with a calibration sample that had undergone the same pretreatment (Figure 6).

[0552] <Measurement of ATX Activity in Plasma> The ATX activity value was measured and calculated from the collected plasma by the same method as in Experimental Example 2 (Figure 5).

[0553] <Statistical Analysis> The differences between the Saline group and the BLM-administered group and between the BLM-administered group and the compound-administered group were analyzed by Student's t-test, and the significance level was set at 5% for both sides. Statistical analysis was performed using SAS.

[0554] Experimental Example 4: [Examination of the Effect of an ATX Inhibitor on Intraocular Pressure in Cynomolgus Monkeys] The efficacy of an ATX inhibitor (Example 5, hereinafter referred to as example5 in the figure) against a cynomolgus monkey laser-induced ocular hypertension model was evaluated using the intraocular pressure lowering effect as an index. As a result, the ATX inhibitor (Example 5) showed a statistically significant intraocular pressure lowering effect in both the single oral administration (Figure 7) and single eye drop administration (Figure 8) of the test drug. <Establishment of a Cynomolgus Monkey Laser-Induced Ocular Hypertension Model> Only the left eye was uniformly irradiated with green laser light with a wavelength of 532 nm around 360° of the trabecular meshwork, which is the aqueous humor drainage pathway, to induce ocular hypertension. The right eye was maintained normal. After a 7-day acclimation period, the animals were grouped according to the group composition shown in Table 25. In addition, administration was performed by a crossover test in which animals were repeatedly used for the ATX inhibitor, vehicle, and positive control substance as shown in Table 26.

[0555]

Table 25

[0556]

Table 26

[0557] <Method for Preparing an Oral Administration Solution of an ATX Inhibitor> Weighed the required amount of the ATX inhibitor (Example 5), transferred it to an agate mortar, and gently ground it. A few drops of the oral medium (0.5% w / v CMC-Na) were added dropwise and mixed with the ATX inhibitor (Example 5). The addition and mixing of the oral medium to the mixture were repeated to make a paste. The paste was transferred to a graduated cylinder, and the oral medium was added up to 60% of the final preparation volume. While stirring with a stirrer, the medium (0.5% w / v CMC-Na containing 0.5 mol / L NaOH) was added (so that the amount of NaOH was 0.75 mol per 1 mol in Example 5). The oral medium was added to make up the volume, and it was confirmed that the pH did not exceed 11.0 (measured value: pH 10.55 - 10.88).

[0558] <Method for Preparing Ophthalmic Administration Solution of ATX Inhibitor> After mixing 307 mL of a 0.04 mol / L boric acid / phosphoric acid / acetic acid mixed solution and 193 mL of a 0.2 mol / L aqueous sodium hydroxide solution (pH about 8.4), a Britton-Robinson buffer solution (pH 8.5) adjusted to pH 8.5 with 1 mol / L hydrochloric acid was prepared. A solution in which 5% of kolliphor EL was dissolved was used as the ophthalmic administration medium (5% w / v kolliphor EL solution (pH 8.5)). 4.5 mg of the ATX inhibitor (Example 5) was weighed into a 10 mL volumetric flask, 9.6 mL of the ophthalmic administration medium was added, and ultrasonic treatment was carried out for 30 minutes in an ultrasonic cleaner set at a temperature around 40°C. After confirming that it was uniformly suspended, the volumetric flask was made up to the calibration line with the ophthalmic administration medium and ultrasonic treatment was carried out for 40 minutes as above, and complete dissolution was visually confirmed. If it was suspended at this point, ultrasonic treatment was continued until complete dissolution.

[0559] <Reagents> · CMC-Na (Sigma-Aldrich Co. LLC) · Kolliphor EL (Sigma-Aldrich Co. LLC, C5156) · Boric acid (Sigma-Aldrich Co. LLC, B6768) · Phosphoric acid (FUJIFILM Wako Pure Chemical Corporation, 162 - 20492) · Acetic acid (FUJIFILM Wako Pure Chemical Corporation, 017-00256) · Water for injection (Otsuka Pharmaceutical Factory, Inc.) · Granatic eye drops 0.4% (Kowa Company, Ltd.): Positive control substance

[0560] <Test animals> Animal species: Male cynomolgus monkeys Supplier: Shin Nippon Science Co., Ltd. Number of animals used: 10 animals (age 7 - 8 years at the start of domestication)

[0561] <Breeding environment> Temperature: Measured value: 25.4 - 27.5°C, Allowable range 23 - 29°C Humidity: Measured value: 47 - 74%, Allowable range 30 - 70% Ventilation rate: 15 times / hour Illumination: Artificial lighting for 12 hours a day (lighting from 07:00 to 19:00) Feed: Solid feed (Purina Mills LLC, HF Primate J 12G 5K9J) about 108 g (about 12 g × 9 pieces) was given once a day at 14:00 - 16:00, and the remaining feed until 11:00 the next day (on the dosing day, before dosing) was collected. Drinking water: Animals were allowed to freely ingest using an automatic water supply device.

[0562] <Measurement of intraocular pressure> Intraocular pressure was measured 3 times using a rebound tonometer (TonoVet Tonometer TV01, Tiolat Oy) with the animals immobilized without anesthesia. The adopted value was the median of the 3 measured values. Considering the irritation to the cornea caused by frequent administration of topical anesthetics, topical anesthetics were not used.

[0563] <Points for intraocular pressure measurement> Before compound administration, and at about 1, 2, 4, 8, and 24 hours after administration (6 points on each dosing day)

[0564] <Statistical analysis> For the intraocular pressure of the left eye (high intraocular pressure eye), the mean value and standard error of the adopted values, the mean value and standard error of the change rate from before each administration, and the mean value and standard error of the change amount from before each administration were calculated for each measurement time point. [Regarding topical administration] 1) In order to examine the presence or absence of the effect of the intraocular pressure-lowering action after administration for each time point, an analysis of covariance was performed for each time point after administration, with the individual as the variable, the administration group as the fixed factor, and the intraocular pressure before administration as the covariate. A comparative test was conducted between the topical vehicle (topical administration) group, the test substance (topical administration) group, and the positive control substance group (multiplicity was not adjusted). 2) Regarding the change rate and change amount of the intraocular pressure from before each administration, an analysis of variance was performed for each time point after administration, with the individual as the variable and the administration group and administration date as the fixed factors. A comparative test was conducted between the topical vehicle (topical administration) group, the test substance (topical administration) group, and the positive control substance group. [Regarding oral administration] 1) In order to examine the presence or absence of the effect of the intraocular pressure-lowering action after administration for each time point, an analysis of covariance was performed for each time point after administration, with the individual as the variable, the administration group as the fixed factor, and the intraocular pressure before administration as the covariate. A comparative test was conducted between the oral vehicle (oral administration) group and the test substance (oral administration) group. 2) Regarding the change rate and change amount of the intraocular pressure from before each administration, an analysis of variance was performed for each time point after administration, with the individual as the variable and the administration group and administration date as the fixed factors. A comparative test was conducted between the oral vehicle (oral administration) group and the test substance (oral administration) group. SAS System for windows, Release 9.3 (SAS Institute Inc.) was used for these tests. The significance level of the test was set at 5% two-sided.

Industrial Applicability

[0565] The compound of the present invention has an excellent autotaxin inhibitory effect and is useful as a prophylactic or therapeutic agent for various diseases caused by autotaxin, such as cancer or tumors (e.g., malignant melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostate intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor, renal cell carcinoma, etc.), fibrotic diseases (e.g., pulmonary fibrosis, scleroderma, liver fibrosis, renal fibrosis, diabetic nephropathy, atherosclerosis, etc.), inflammatory diseases (e.g., asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, obesity associated with type II diabetes, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, itching, etc.), eye diseases (e.g., glaucoma, etc.), urological diseases (e.g., benign prostatic hyperplasia, etc.). This application is based on Japanese Patent Application No. 2018-141254 filed in Japan, the content of which is incorporated herein in its entirety.

Claims

1. A pharmaceutical composition for the treatment or prevention of a disease involving autotaxin, which contains a carboxylic acid compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier: 【Chemical 1】 {In the formula, R １ is 【Chemical 2】 [In the formula, X １ａ is -C(R １ａ ) ２ - (wherein, R １ａ may be the same or different, each of which is a hydrogen atom, a halogen atom, or C １ ~C ２ Perfluoroalkyl, C １ ~C ２ Perfluoroalkoxy or C １ ~C ６ represents an alkyl group or R １ａ is bonded to 1,1-C ３ ~C ６ forming a cycloalkylene) or -NR １ｂ - (wherein, R １ｂ is a hydrogen atom or C １ ~C ２ perfluoroalkyl), X １ｂ and X １ｃ are the same or different and each represents —O— or —CH ２ — (provided that X １ｂ and X １ｃ do not simultaneously represent —O—), R １ｃ represents a hydrogen atom, a halogen atom, C １ to C ２ perfluoroalkyl, C １ to C ２ perfluoroalkoxy, C １ to C ６ alkyl or C １ to C ２ perfluoroalkylthio, R １ｄ represents a hydrogen atom, a halogen atom or C １ to C ６ alkyl, and R １ｅ represents a hydrogen atom, C １ to C ２ perfluoroalkyl or C １ to C ２ represents perfluoroalkoxy], and X represents -N= or -CH=, Ring A is [Chemical 3] [wherein, X ２ａ is -N= or -CR ２ａ =(wherein, R ２ａ is a hydrogen atom, a halogen atom, C １ to C ６ alkyl or C １ to C ６ alkoxy), is shown, R ２ｂ represents a hydrogen atom, a halogen atom, C １ to C ６ alkyl or C １ to C ６ alkoxy, and R ２ｃ represents a hydrogen atom or C １ to C ６ alkyl, and X ２ｂ is -O-, -NR ２ｄ -(wherein R ２ｄ is a hydrogen atom or C １ to C ２ perfluoroalkyl) or -CHR ２ｅ -(wherein R ２ｅ is a hydrogen atom or C １ to C ６ alkyl), and X ２ｃ represents - (CH ２ ) ｎ’ - (wherein n' represents 0 or 1) or -O-]. L is -(CHR ３ａ ). ｎ -(wherein n represents 0, 1, 2 or 3, and R ３ａ may be the same or different and each represents a hydrogen atom or C １ to C ６ alkyl), -(CH ２ ). ｍ -O-(CH ２ ). ｍ’ -(wherein m and m' are the same or different and each represents 0, 1 or 2), C ２ to C ３ alkenylene,[[]] 【Chemical 4】 (wherein, R ３ｂ and R ３ｃ may be the same or different and each represents a hydrogen atom or a C １ to C ６ alkyl, R ３ｄ represents a hydrogen atom, a C １ to C ６ alkoxy, a C １ to C ６ alkyl or a C １ to C ２ perfluoroalkyl, and R ３ｅ represents a hydrogen atom, a C １ to C ６ alkoxy, a C １ to C ６ alkyl or a C １ to C ２ perfluoroalkyl).}.

2. R １ is [Chemical Formula 5] (wherein X １ａａ is -C(R １ａａ ) ２ - (wherein R １ａａ is the same or different and each represents a hydrogen atom, C １ -C ２ perfluoroalkyl or C １ -C ６ alkyl, or R １ａａ are bonded to form 1,1-C ３ -C ６ cycloalkylene), or -NR １ｂａ - (wherein R １ｂａ represents a hydrogen atom or C １ -C ２ perfluoroalkyl), R １ｃａ is C １ -C ２ perfluoroalkyl, C １ -C ２ perfluoroalkoxy or C １ -C ２ perfluoroalkylthio, and R １ｄａ represents a halogen atom or C １ -C ６ alkyl). The pharmaceutical composition according to claim 1.

3. where Ring A is [Chemical Formula 6] (wherein, R ２ａｂ represents a hydrogen atom, C １ to C ６ alkoxy or C １ to C ６ alkyl, R ２ｂｂ represents a hydrogen atom, C １ to C ６ alkoxy or C １ to C ６ alkyl, R ２ｃｂ represents a hydrogen atom or C １ to C ６ alkyl). The pharmaceutical composition according to any one of claims 1 or 2.

4. where Ring A is 【Chemical Formula 7】 (wherein, R ２ａｃ represents a hydrogen atom, C １ to C ６ alkoxy or C １ to C ６ alkyl, R ２ｂｃ represents a hydrogen atom, C １ to C ６ alkoxy or C １ to C ６ alkyl, R ２ｃｃ represents a hydrogen atom or C １ to C ６ alkyl). The pharmaceutical composition according to any one of claims 1 to 3.

5. where Ring A is 【Chemical Formula 8】 (wherein, R ２ａｄ represents a hydrogen atom, C １ - C ６ alkoxy or C １ - C ６ alkyl, R ２ｂｄ represents a hydrogen atom, C １ - C ６ alkoxy or C １ - C ６ alkyl, R ２ｃｄ represents a hydrogen atom or C １ - C ６ alkyl) The pharmaceutical composition according to any one of claims 1 to 4.

6. L is, -(CH ２ ) ｎ -(wherein n represents 1 or 2) or 【Chemical Formula 9】 (wherein R ３ａｂ and R ３ｂｂ may be the same or different and each represents a hydrogen atom or C １ - C ６ alkyl), the pharmaceutical composition according to any one of claims 1 to 5.

7. The pharmaceutical composition according to any one of Claims 1 to 6, wherein X is -N=.

8. The pharmaceutical composition according to Claim 1, wherein the compound represented by the general formula (1) is any of the following: trans-2-[2-Methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-Methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1R,2R)-2-[2-Methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-Methoxy-5'-{[4-(trifluoromethoxy)benzyl]oxy}-2,3'-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-Methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridin-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5'-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3'-bipyridin-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5'-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3'-bipyridin-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1R,2R)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid, (1S,2S)-2-[2-ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-Methyl-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-Chloro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, 3-[(2S,6R)-6-Methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, or (1S,2S)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid. The pharmaceutical composition according to claim 1, wherein the disease involving autotaxin is cancer or tumor, fibrosis disease, inflammatory disease, eye disease, urinary disease, obesity related to type II diabetes or acute coronary syndrome. The pharmaceutical composition according to claim 9, wherein the cancer or tumor is melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostate intraepithelial neoplasia, prostate tumor, thyroid tumor, follicular lymphoma, liver tumor or renal cell carcinoma. The pharmaceutical composition according to claim 9, wherein the fibrosis disease is pulmonary fibrosis, liver fibrosis, scleroderma, renal fibrosis, diabetic nephropathy or atherosclerosis. The pharmaceutical composition according to claim 11, wherein the fibrosis disease is pulmonary fibrosis, scleroderma, liver fibrosis or renal fibrosis. ​ ​ ​ ​ ​ The pharmaceutical composition according to claim 9, wherein the inflammatory disease is asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain or pruritus.

14. The pharmaceutical composition according to claim 13, wherein the inflammatory disease is asthma or COPD.

15. The pharmaceutical composition according to claim 13, wherein the inflammatory disease is rheumatoid arthritis or osteoarthritis.

16. The pharmaceutical composition according to claim 13, wherein the inflammatory disease is NASH or NAFLD.

17. The pharmaceutical composition according to claim 13, wherein the inflammatory disease is inflammatory bowel disease, Crohn's disease or ulcerative colitis.

18. The pharmaceutical composition according to claim 13, wherein the inflammatory disease is neuropathic pain or pruritus.

19. The pharmaceutical composition according to claim 9, wherein the acute coronary syndrome is angina pectoris or myocardial infarction.

20. The pharmaceutical composition according to claim 9, wherein the eye disease is glaucoma.

21. The pharmaceutical composition according to claim 9, wherein the urinary disease is benign prostatic hyperplasia.

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