Novel 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives and pharmaceutical use of the same

Abstract

To provide a compound superior in an ATX inhibitory action and useful for the prophylaxis or treatment of a disease involving ATX.SOLUTION: The invention provides a carboxylic acid compound represented by the general formula (1), or a pharmaceutically 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 that have an autotaxin inhibitory effect and are effective in preventing or treating diseases caused by autotaxin in mammals, including humans. [Background technology]

[0002] Autotaxin (ATX) was isolated from the culture supernatant of the human melanoma cell line A2058 and identified as a cell migration-promoting factor. ATX, also known as secreted lysophospholipase D (lysoPLD) and ENPP2 (Ectonucleotide Pyrophosphatase / Phosphodiesterase 2), is the main component of lysoPLD activity and hydrolyzes lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA), a lipid mediator with diverse physiological activities.

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

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

[0005] Furthermore, it has become clear that intracellular signaling pathways mediated by ATX and LPA receptors are involved in various fibrotic diseases.

[0006] Regarding the involvement of LPA in the above diseases, it has been shown that the concentration of LPA is elevated in the alveolar lavage fluid of patients with idiopathic pulmonary fibrosis, and that the concentration of ATX is elevated in the lung tissue of a bleomycin-induced pulmonary fibrosis model. Furthermore, in LPA1-deficient mice, the bleomycin-induced pulmonary fibrosis is reduced. It has been shown that the progression of pulmonary fibrosis and death 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 serum autotaxin activity and plasma LPA levels increase with the progression of liver fibrosis in patients with chronic hepatitis C (Non-Patent Documents 16-18).

[0008] Regarding renal fibrosis, it has been shown that LPA production and LPA1 expression are increased in a unilateral ureteral ligation model, LPA1-deficient mice are resistant to fibrosis, and LPA receptor antagonists suppress the progression of fibrosis (Non-patent Document 19).

[0009] Regarding scleroderma, ATX expression is elevated in the skin of scleroderma patients. Furthermore, in a bleomycin-induced scleroderma model, ATX expression in the skin is elevated, and an ATX inhibitor has been shown to suppress IL-6 production and CD3-positive cell infiltration in the skin, as well as skin thickening and hydroxyproline production (Non-Patent Document 20).

[0010] Regarding urinary outflow disorders associated with benign prostatic hyperplasia, a urological disease, it has been shown that the application of LPA to isolated rat urethra causes urethral contraction, and furthermore, it has been shown that the administration of an ATX inhibitor to rats can reduce intraurethral pressure (Non-Patent Document 21).

[0011] Regarding glaucoma, ATX and LPA concentrations are elevated in the aqueous humor of patients with normal-tension glaucoma, primary open-angle glaucoma, secondary open-angle glaucoma, and exfoliation glaucoma, and it has been shown that LPA concentration, ATX concentration, and LysoPLD activity are positively correlated with intraocular pressure. Furthermore, ATX inhibitors have been shown to reduce intraocular pressure in rabbit intraocular pressure tests (Dutch belted rabbits) (Non-Patent Documents 22 and 23).

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

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

[0014] Regarding inflammatory diseases such as NASH and NAFLD, serum ATX concentrations have been shown to be elevated in patients with liver cirrhosis, and furthermore, serum ATX concentrations have been shown to be positively correlated with Child-Pugh stage and MELD score (Non-Patent Document 26). Furthermore, in a mouse STAM-NASH model combining streptozotocin (STZ) administration with a high-fat diet, ATX inhibitors showed improvement in NAS scores through their anti-inflammatory effects and inhibitory effects on hepatocyte ballooning. Furthermore, in a mouse NASH model using a choline-deficient high-fat diet (CDAHFD), ATX inhibitors have been shown to suppress liver fibrosis (Non-Patent Document 27).

[0015] Regarding rheumatoid arthritis, it has been shown that ATX levels are elevated in fibroblast-like synoviocytes (SFCs) of rheumatoid arthritis patients (Non-patent Document 28). Furthermore, ATX levels in the synovium are elevated in a collagen-induced arthritis model (Non-patent Document 5), and ATX inhibitors have been shown to be effective against rheumatoid arthritis. It has been shown to improve joint pathology scores (Non-Patent Document 29).

[0016] Regarding osteoarthritis, it has been shown that ATX levels are elevated 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 level in synovial fluid (Non-Patent Document 30). Furthermore, it has been shown that ATX inhibitors suppress pain in a monoiodoacetate-induced osteoarthritis model (Non-Patent Document 31).

[0017] Known ATX inhibitors include lipid analogues (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), and 2-amino-pyridine and 2-amino-pyrimidine derivatives (Patent Document 5). These have structures different from those of the 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives of the present invention. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] International Patent Publication WO2012 / 005227 [Patent Document 2] International Patent Publication WO2012 / 024620 [Patent Document 3] International Patent Publication WO2009 / 046841 [Patent Document 4] International Patent Publication WO2013 / 061297 [Patent Document 5] International Patent Publication WO2015 / 163435 [Patent Document 6] International Patent Publication WO2014 / 139882 [Patent Document 7] International Patent Gazette WO2014 / 202458

Non-licensed literature

[0019]

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[0020] An objective of the present invention is to provide a compound that has excellent ATX inhibitory activity and is useful for preventing or treating diseases in which ATX is involved. [Means for solving the problem]

[0021] As a result of intensive research to solve the above problems, the present inventors have discovered a compound that inhibits ATX, and have found that it is possible to provide a preventive or therapeutic agent for diseases in which ATX is involved, thereby completing the present invention.

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

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

[0023] [ka]

[0024] {where, R 1 teeth,

[0025] [ka]

[0026] [where, 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, a C1-C2 perfluoroalkyl, a C1-C2 perfluoroalkoxy, or a C1-C6 alkyl, or R 1a are bonded to form 1,1-C3-C6 cycloalkylene) or -NR 1b -(In the formula, R 1b represents a hydrogen atom or a C1-C2 perfluoroalkyl), X 1b and X 1c are the same or different and each represents -O- or -CH2- (provided that X 1b and X 1c and do not simultaneously represent -O-), R 1c represents a hydrogen atom, a halogen atom, a C1-C2 perfluoroalkyl, a C1-C2 perfluoroalkoxy, a C1-C6 alkyl, or a C1-C2 perfluoroalkylthio, R 1d represents a hydrogen atom, a halogen atom or a C1-C6 alkyl, R1e represents a hydrogen atom, a C1-C2 perfluoroalkyl group, or a C1-C2 perfluoroalkoxy group, X represents -N= or -CH=; Ring A is

[0027] [ka]

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

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

[0031] [2]R 1 but

[0032] [ka]

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

[0034] [3] Ring A is

[0035] [ka]

[0036] (In the formula, R 2abrepresents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2bb represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2cb represents a hydrogen atom or a C1-C6 alkyl), or a pharmacologically acceptable salt thereof according to either [1] or [2] above.

[0037] [4] Ring A is

[0038] [ka]

[0039] (In the formula, R 2ac represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2bc represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2cc represents a hydrogen atom or a C1-C6 alkyl), or a pharmacologically acceptable salt thereof.

[0040] [5] Ring A is

[0041] [ka]

[0042] (In the formula, R 2ad represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2bd represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2cd represents a hydrogen atom or a C1-C6 alkyl), or a pharmacologically acceptable salt thereof.

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

[0044] [ka]

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

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

[0047] [8] The carboxylic acid compound or a pharmacologically acceptable salt thereof according to the above [1], wherein the compound represented by the general formula (1) is any one 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]o (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 the above [1] to [8] or a pharmacologically 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], which is used for the treatment or prevention of a disease in which autotaxin is involved.

[0051]

[12] The pharmaceutical composition according to

[11] , wherein the disease in which autotaxin is involved is cancer or tumor, fibrotic disease, inflammatory disease, eye disease, urinary tract 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's lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostatic 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 fibrotic 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] above, 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] above, wherein the inflammatory disease is asthma or COPD.

[0057]

[18] The pharmaceutical composition according to

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

[0058]

[19] The pharmaceutical composition according to

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

[0059]

[20] The pharmaceutical composition according to

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

[0060]

[21] The pharmaceutical composition according to

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

[0061]

[22] The pharmaceutical composition according to

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

[0062]

[23] The pharmaceutical composition according to

[12] above, wherein the eye disease is glaucoma.

[0063]

[24] The pharmaceutical composition according to

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

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

[26] The method according to

[25] , wherein the disease in which autotaxin is involved is cancer or tumor, fibrotic disease, inflammatory disease, eye disease, urinary tract disease, obesity associated with type II diabetes, or acute coronary syndrome.

[27] Use of the carboxylic acid compound or pharmacologically acceptable salt thereof according to any one of [1] to [8] above for the manufacture of a therapeutic or preventive agent for a disease in which autotaxin is involved.

[28] The use according to

[27] above, wherein the disease in which autotaxin is involved is cancer or tumor, fibrotic disease, inflammatory disease, eye disease, urinary tract disease, obesity associated with type II diabetes, or acute coronary syndrome. [Effects of the Invention]

[0064] The present invention can provide compounds that have excellent ATX inhibitory activity and are effective as prophylactic or therapeutic drugs for diseases in which ATX is involved, such as cancer, tumor, fibrotic disease, inflammatory disease, eye disease, urinary tract disease, obesity associated with type II diabetes, or acute coronary syndrome. [Brief explanation of the drawings]

[0065] [Figure 1] 1 is a graph showing the amount of SP-D in plasma as a result of Experimental Example 3. [Figure 2] 1 is a graph showing the amount of Col1a1 mRNA in lung tissue as a result of Experimental Example 3. [Figure 3] 1 is a graph showing the amount of CTGF mRNA in lung tissue as a result of Experimental Example 3. [Figure 4] 1 is a graph showing the amount of IL-6 mRNA in lung tissue as a result of Experimental Example 3. [Figure 5] 1 is a graph showing the ATX activity in plasma as a result of Experimental Example 3. [Figure 6] 1 is a graph showing the amount of LPA (18:2) in BALF as a result of Experimental Example 3. [Figure 7] 1 is a graph showing the effect of oral administration of an ATX inhibitor on intraocular pressure in cynomolgus monkeys as a result of Experimental Example 4. [Figure 8] 1 is a graph showing the effect of instillation of an ATX inhibitor on intraocular pressure in cynomolgus monkeys as a result of Experimental Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0066] The definitions of each group in this specification can be freely combined unless otherwise specified.

[0067] The definitions of the symbols used 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 the above means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Groups having 1 to 4 carbon atoms (C1-C4) are particularly preferred. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. Methyl, ethyl, isopropyl, and tert-butyl are particularly preferred.

[0069] R 1a , R 1c , R 1d , R 2a , R 2b and R 1da The halogen atom in the 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 , R2d , R 3d , R 3e , R 1aa , R 1ba and R 1ca The C1-C2 perfluoroalkyl in the above formula is a methyl or ethyl group substituted with 1 to 5 fluorines. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc. Trifluoromethyl or 2,2,2-trifluoroethyl is particularly 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. Trifluoromethoxy or 2,2,2-trifluoroethoxy is particularly preferred.

[0072] R 1a and R 1aa The 1,1-C3-C6 cycloalkylene in the above formula represents 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 1ca The C1-C2 perfluoroalkylthio in the above means a monovalent group in which the perfluoroalkyl is bonded to sulfur, and examples thereof include perfluoroalkyl-S- having 1 to 2 carbon atoms (C1-C2). Specific examples include fluoromethylthio, difluoromethylthio, trifluoromethylthio, 2,2,2-trifluoroethylthio, etc. Trifluoromethylthio or 2,2,2-trifluoroethylthio is particularly preferred.

[0074] R 2a , R2b , R 3d , R 3e , R 2ab , R 2bb , R 2ac , R 2bc , R 2ad and R 2bd The C1-C6 alkoxy in R 1a It refers to a monovalent group in which the C1-C6 alkyl shown in the above is bonded to oxygen, and examples thereof include straight-chain or branched-chain alkyl-O- having 1 to 6 carbon atoms (C1 to C6). In particular, alkyl-O- having 1 to 4 carbon atoms (C1 to C4) is preferred, and alkyl-O- having 1 to 2 carbon atoms (C1 to C2) is particularly preferred. Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, etc. In particular, methoxy or ethoxy is preferred.

[0075] The C2-C3 alkenylene in L refers to a linear divalent hydrocarbon group having 2 to 3 carbon atoms (C2-C3) and at least one double bond. Specific examples include vinylene and propenylene.

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

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

[0078] [ka]

[0079] (In the formula, R A is preferably a hydrogen atom, a C1-C2 perfluoroalkyl or a C1-C6 alkyl, more preferably a C1-C2 perfluoroalkyl or a C1-C6 alkyl, R B is preferably C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C2 perfluoroalkylthio, more preferably C1-C2 perfluoroalkyl or C1-C2 perfluoroalkoxy; R Cis preferably a halogen atom or C1 to C6 alkyl, and more preferably C1 to C6 alkyl.

[0080] In another embodiment of the present invention, R 1 is preferably

[0081] [ka]

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

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

[0084] [ka]

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

[0086] [ka]

[0087] (In the formula, R Dis 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 of the groups represented by the following general formulas:

[0089] [ka]

[0090] (In the formula, R D and R E is the same as above)

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

[0092] [ka]

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

[0094] [ka]

[0095] (In the formula, R 2ac represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2bc represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, and R 2ccrepresents a hydrogen atom or a C1-C6 alkyl), and more preferably

[0096] [ka]

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

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

[0099] L in the general formula (1) is preferably —(CH) n - (wherein n is 1 or 2) or

[0100] [ka]

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

[0102] [ka]

[0103] (In the formula, R 3ab and R 3bb is the same as above).

[0104] Suitable examples of compound (1) include the following compounds: [Compound 1-A] R1 but,

[0105] [ka]

[0106] [where, 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., a fluorine atom), a C1-C2 perfluoroalkyl (e.g., trifluoromethyl), or a 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 -(In the formula, R 1b is C1-C2 perfluoroalkyl (e.g., trifluoroethyl), X 1b and X 1c are the same or different and each represents -O- or -CH2- (provided that X 1b and X 1c and do not simultaneously represent -O-), R 1c is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom), a C1-C2 perfluoroalkyl (e.g., trifluoromethyl), a C1-C2 perfluoroalkoxy (e.g., trifluoromethoxy) or a C1-C2 perfluoroalkylthio (e.g., trifluoromethylthio), R 1d is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom), or a C1-C6 alkyl (e.g., methyl), R 1e is C1-C2 perfluoroalkoxy (e.g., trifluoromethoxy); X is -N= or -CH=; Ring A is

[0107] [ka]

[0108] [where, X 2a -CR 2a =(In the formula, 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 -O-, -NR 2d -(In the formula, R 2d is C1-C2 perfluoroalkyl (e.g., trifluoroethyl) or —CHR 2e -(In the formula, R 2e is a hydrogen atom), X 2c Ha-(CH2) n’ - (wherein n' is 0 or 1) or -O-; L is -(CHR 3a ) n where n is 0, 1, 2, or 3; and R 3a may be the same or different, and each is a hydrogen atom or a 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] [ka]

[0110] (In the formula, R 3b and R 3c may be the same or different and each represents a hydrogen atom or a C1-C6 alkyl (e.g., methyl), and 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), and R 3eis a hydrogen atom or C1-C6 alkoxy (e.g., methoxy); Compound (1).

[0111] Specific examples of compound (1) include the compounds of Examples 1 to 101 described below, and 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]cyclopropan-2-yl propanecarboxylic 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, (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]cyclohexyl Isopropanecarboxylic 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" refers to the act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has not yet developed a disease, disorder, or symptom. "Treatment" refers to the act of administering the compound of the present invention or a pharmaceutical composition containing the compound to an individual who has already developed a disease, disorder, or symptom. Therefore, administering the compound to an individual who has already developed a disease, disorder, or symptom to prevent the worsening of symptoms, attacks, or recurrence is one aspect 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 agent, injection, etc.) obtained by mixing the compound of the present invention with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, odorant, emulsifier, diluent, solubilizing agent, etc.). The pharmaceutical composition can be formulated according to a conventional method.

[0114] Examples of formulations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. Examples of formulations suitable for parenteral administration include injections, drip infusions, and suppositories. Formulations suitable for oral administration may contain additives such as excipients, disintegrants, binders, lubricants, coating agents, or bases. Furthermore, 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 drugs appropriate for treating the target disease.

[0115] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion, or local administration (transdermal administration, transocular administration, transpulmonary / bronchial administration, transnasal administration, transrectal administration, etc.).

[0116] The compound of the present invention can be used in combination with other drugs, etc., depending on the case. The administration timing of the compound of the present invention or a pharmacologically acceptable salt thereof, or a solvate thereof and a concomitant drug is not limited, and they may be administered to a subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two different preparations containing the respective active ingredients, or as a single preparation containing both active ingredients.

[0117] The dosage of the compound of the present invention is determined taking into consideration the age, body weight, general health condition, sex, administration time, administration method, excretion rate, and the severity of the patient's condition currently being treated, as well as other factors. The daily dosage of the compound of the present invention varies depending on the patient's condition and body weight, the type of compound, the administration route, etc., but is, for example, about 0.0001 to 500 mg / person / day administered parenterally via subcutaneous, intravenous, intramuscular, transdermal, ocular, pulmonary / bronchial, nasal, or rectal routes, and about 0.001 to 5,000 mg / person / day administered orally.

[0118] 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] [ka]

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

[0122] Examples of transition metal complexes include tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)dipalladium(0), and

[0033] Examples of the palladium complex include palladium (0), bis(tri-tert-butylphosphine)palladium (0), bis(tricyclohexylphosphine)palladium (0), and divalent palladium complexes such as palladium acetate (II), 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).

[0123] Furthermore, a suitable ligand may be added to the transition metal complex. Suitable ligands include, for example, 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-(diphenyl)diphenylphosphine]-n ...

[0033] 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 bases include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. The amount of the transition metal complex used can be 0.01 to 0.5 equivalents, preferably 0.03 to 0.1 equivalents, relative to compound (A1). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (A1). In particular, the compound can be suitably produced by a method using reaction conditions such as those described in J. Org. Chem., 1995, 60, 7508-7510.

[0125] [Step 1b] Compound (A4) can be produced by reacting Compound (A2) with Compound (A3) in the presence of a transition metal complex and a base in a solvent, such as 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. Examples of transition metal complexes 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), 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-butylphosphine)palladium(II) dichloride. A divalent palladium complex such as t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) is used.

[0126] Furthermore, a suitable ligand may be added to the transition metal complex. Suitable ligands include, for example, 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-(diphenyl)diphenylphosphine]-n ...

[0033] 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 bases include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and dipotassium hydrogen phosphate. The amount of the transition metal complex used can be 0.01 to 0.5 equivalents, preferably 0.03 to 0.1 equivalents, relative to compound (A3). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (A3). In particular, the compound can be suitably produced by a method using reaction conditions such as those described in Acc. Chem. Res., 2008, 41, 1461-1473. The compound can also be suitably produced by a method using a palladium catalyst precursor containing an appropriate ligand, such as those described in J. Am. Chem. Soc., 2010, 132, 14073-14075.

[0128] [Process 1c] Compound (A5) can be produced by hydrolyzing compound (A4) using a commonly used method. It can be produced by hydrolysis in an appropriate mixed aqueous solution in the presence of a base. Suitable solvents include methanol, ethanol, and tetrahydrofuran. Suitable bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide.

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

[0130] [ka]

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

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

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

[0134] [ka]

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

[0136] [Step 3b] Compound (C4) can be produced by reacting compound (C2) with 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, and di-2-methoxyethyl azodicarboxylate. Examples of phosphine reagents include triphenylphosphine, tri-n-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, and diphenyl-2-pyridylphosphine. Furthermore, when using a Tsunoda reagent such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane, this reaction proceeds favorably even in the absence of a phosphine reagent. Examples of solvents 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, and N-methylpyrrolidone. This reaction proceeds favorably at temperatures between -40°C and 100°C, preferably between 0°C and 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] [ka]

[0140] (In the formula, R 4 and R 5 is alkyl and X A and X B is a halogen atom, and Q 1 is a borate ester, and the other symbols are as above.) [Step 4a] Compound (D2) can be produced by reacting compound (D1) with compound (B1) in the same manner 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 may also be 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 transition metal complexes 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), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tolyl A divalent palladium complex such as [1,1'-bis(diphenylphosphine)ferrocene]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, or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) is used.

[0142] Furthermore, a suitable ligand may be added to the transition metal complex. Suitable ligands include, for example, 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-(diphenyl)diphenylphosphine]-n ...

[0033] 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 bases include sodium bicarbonate, 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, and 1,4-diazabicyclo[2.2.2]octane. The amount of the transition metal complex used can be 0.01 to 0.3 equivalents, preferably 0.03 to 0.1 equivalents, relative to compound (D2). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (D2). In particular, the compound can be suitably produced by a method using reaction conditions such as those 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, and diethyl ether. Mixtures of these solvents with alcoholic solvents such as methanol, ethanol, and 2-propanol are also acceptable. Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride. This reaction proceeds favorably at temperatures between -78°C and 100°C, preferably between -10°C and room temperature.

[0144] [Process 4d] Compound (D6) can be produced by reacting Compound (D4) with Compound (D5) in a solvent in the presence of a base, with or without 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, and sodium Examples of suitable phase transfer catalysts include tetrahydrofuran, ...

[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 aryl or heteroaryl such as phenyl or pyridyl)

[0147] [ka]

[0148] (In the formula, R 4 is alkyl and X B is a halogen atom, and Q 1 is a borate ester, and the other symbols are as 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 catalytic hydrogenation of compound (E2) in a solvent in the presence of a transition metal catalyst under a hydrogen atmosphere. Any solvent that does not interfere with the reaction can be used, including methanol, ethanol, ethyl acetate, and tetrahydrofuran. Examples of transition metal catalysts that can be used include palladium on carbon (Pd / C) and palladium hydroxide on carbon (Pd(OH)2 / C). This reaction proceeds favorably at temperatures between 0°C and 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 an aryl or heteroaryl such as phenyl or pyridyl)

[0153] [ka]

[0154] (In the formula, R 4 is alkyl and X A and X B is a halogen atom, and Q1 is a borate ester, and the other symbols are as above.) [Step 6a] Compound (F2) can be produced by reacting compound (F1) with bis(pinacolato)diborane in the same manner 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) in the same manner as in [Step 5b].

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

[0158] [ka]

[0159] (In the formula, R 4 is alkyl and X B is a halogen atom, and other symbols are as above.) [Step 7a] Compound (G2) can be produced by reacting Compound (G1) with Compound (A1) in the presence of a transition metal complex and a base in a suitable solvent, such as toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N 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), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tolyl) palladium(II). A divalent palladium complex such as [1,1'-bis(diphenylphosphine)ferrocene]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, or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) is used.Furthermore, a suitable ligand may be added to the transition metal complex. Suitable ligands include, for example, 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-(diphenyl)diphenylphosphine]-n ...

[0033] 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 bases 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, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. The amount of the transition metal complex used is 0.01 to 0.5 equivalents, preferably 0.03 to 0.1 equivalents, relative to Compound (A1). The amount of the base used is 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to Compound (A1). In particular, it can be suitably produced under reaction conditions such as those described in Angew. Chem. Int. Ed., 2008, 47, 6338-6361. It can also be suitably produced by a method using a palladium catalyst precursor containing an appropriate ligand, such as that described in Chemical Science, 2013, 4, 916-920.

[0161] [Step 7b] Compound (G3) can be produced by hydrolyzing 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] [ka]

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

[0165] [Step 8b] Compound (G3) can be produced by hydrolyzing compound (H2) in an appropriate mixed aqueous solution in the presence of a base. Suitable solvents include 1,4-dioxane and ethylene glycol. Suitable bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide. This reaction proceeds at temperatures between 0°C and 200°C, preferably between room temperature and 120°C.

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

[0167] [ka]

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

[0169] [Step 9b] Compound (I3) can be produced by reacting compound (I2) in a suitable solvent in the presence of two equivalents of a base. The solvent used is an alcoholic solvent such as methanol or ethanol. The base that can be used is lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. This reaction proceeds suitably at 0°C to 100°C, preferably 0°C to room temperature.

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

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

[0172] [ka]

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

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

[0175] [Step 10c] Compound (J4) is the PG of compound (J3). 1 can be prepared by removing the

[0176] [Step 10d] Compound (J5) was prepared by reacting compound (J4) and compound (C3) in the same manner as in [Step 3b]. It can be produced by reacting

[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] [ka]

[0180] (In the formula, R 4 is alkyl, and R 5 is alkyl or aryl, and the other symbols are as defined above. [Step 11a] Compound (K3) can be produced by reacting compound (K1) with compound (K2) in a solvent in the presence of a base. Examples of solvents 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 bases include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. This reaction proceeds favorably at temperatures between −40°C and 100°C, preferably between 0°C and room temperature.

[0181] [Step 11b] Compound (K4) can be produced by reacting compound (K3) with compound (J4) in a solvent in the presence of a base, with or without 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, and sodium Examples of suitable phase transfer catalysts include tetrahydrofuran, ...

[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] [ka]

[0185] (In the formula, R 4 is alkyl and X B is a halogen atom, and other symbols are as above.) [Step 12a] Compound (L2) can be produced by reacting compound (L1) with compound (A1) in the same manner 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, followed by heating in the presence of an acid. An alcoholic solvent such as methanol or ethanol can be used as the solvent. Lithium hydroxide, potassium hydroxide, sodium hydroxide, or the like can be used as the base. Acetic acid, hydrochloric acid, sulfuric acid, or the like can be used as the acid. This reaction proceeds favorably by first proceeding at 0°C to room temperature in the presence of a base, and then heating to 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)

[0188] [ka]

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

[0190] [Step 13b] Compound (M2) can be produced by reacting compound (M1) in the same manner 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] [ka]

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

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

[0196] [Step 14b] Compound (N3) can be produced by reacting compound (N2) in the same manner 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] [ka]

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

[0201] [Step 15b] Compound (O3) is the PG of compound (O2) 1 can be prepared by removing the

[0202] [Step 15c] Compound (O5) can be produced by reacting compound (O3) with compound (O4) in a solvent in the presence of a base, with or without a phase-transfer catalyst. Examples of solvents include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of bases 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 phase-transfer catalysts include quaternary ammonium halide salts and crown ethers. This reaction proceeds favorably at temperatures between −40°C and 120°C, preferably between 0°C and 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] [ka]

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

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

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

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

[0210] [ka]

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

[0212] [Step 17b] Compound (Q3) is a PG of compound (Q2). 1 can be prepared by removing the [Step 17c] Compound (Q4) can be produced by a conventional method of oxidizing the primary alcohol of compound (Q3) to an aldehyde. In particular, it can be suitably produced under 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, or oxidation reaction conditions using Dess-Martin periodinane as described in J. Org. Chem., 1983, 48, 4155-4156.

[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, and N-methylpyrrolidone. Examples of the base include sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and sodium bis(trimethylsilyl). Examples of suitable reaction temperatures include potassium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc. This reaction proceeds suitably 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] [ka]

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

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

[0219] Production Method 19 (When A is an aryl or heteroaryl such as phenyl or pyridyl)

[0220] [ka]

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

[0222] [Step 19b] Compound (S4) can be produced by treating compound (S3) with a reducing agent in a solvent. The solvent can be a mixture of an ethereal solvent such as tetrahydrofuran and an alcoholic solvent such as methanol, ethanol, or 2-propanol. Sodium borohydride or the like can be used as the reducing agent. This reaction proceeds favorably at temperatures between −78°C and 100°C, preferably between −10°C and room temperature. Alternatively, optically active compounds can be produced favorably by using the Noyori asymmetric hydrogen transfer reaction 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 of a base, with or without a phase transfer catalyst. Examples of solvents include toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of bases 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, and potassium hydroxide. Examples of phase transfer catalysts include quaternary ammonium halide salts and crown ethers. This reaction proceeds suitably at temperatures between -40°C and 120°C, preferably between 0°C and 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 solvents include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of bases include sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. This reaction proceeds favorably at 0°C to 120°C, preferably room temperature to 60°C.

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

[0226] [ka]

[0227] (In the formula, R 4 and R 5 is alkyl and X A and X B is a halogen atom, and other symbols are as above.) [Step 20a] Compound (T2) can be produced by the Corey-Chaykovsky reaction of compound (T1) with compound (R3), particularly by a method using reaction conditions such as those 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) in the same manner as in [Step 19d].

[0229] Production Method 21 (When A is a heterocyclic group such as morpholinyl)

[0230] [ka]

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

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

[0233] [Step 21c] Compound (T5) is a PG of compound (T4). 2 can be prepared by removing the

[0234] Production Method 22 (When A is a heterocyclic group such as morpholinyl)

[0235] [ka]

[0236] (In the formula, R 4 and R 5 is alkyl, and PG 1 is a protecting group for the hydroxyl group, and PG 2 is a protecting group for an amino group, and other symbols are as defined 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) was prepared by converting the hydroxyl group of compound (U2) to PG using a conventional method. 1 It can be produced by protecting it with

[0238] [Step 22c] Compound (U4) can be produced by subjecting compound (U3) to the Simmons-Smith reaction. It can be suitably produced by a method using reaction conditions such as those described in J. Chem. Soc., 3353-3354.

[0239] [Step 22d] Compound (U5) is a PG of compound (U4). 1 can be prepared by removing the

[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 suitably 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 for converting a carboxylic acid to an ester, such as reacting compound (U6) with an alcohol in the presence of a condensing agent, or reacting it with an alkylating agent in the presence of a base.

[0242] [Process 22g] Compound (U8) is a PG of compound (U7). 2 can be prepared by removing the

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

[0244] [ka]

[0245] (In the formula, Z 1 is -N= or -CH=, and R 4 is alkyl and X A is a halogen atom, and 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 vinylboronic acid ester in the same manner as in [Step 1b].

[0246] [Step 23b] Compound (V3) can be produced by reacting compound (V2) with a halogenating agent in a solvent, followed by treatment with a base. Suitable solvents include a mixed aqueous solution of tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, and tert-butyl alcohol. Examples of halogenating agents include N-iodosuccinimide and N-bromosuccinimide. 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 proceeds suitably at -20°C to 100°C, preferably 0°C to 60°C.

[0247] [Step 23c] Compound (V5) can be produced by reacting compound (V3) with compound (V4) in a solvent in the presence or absence of a base. Examples of solvents include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. This reaction proceeds favorably 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 with a Mitsunobu reagent and a phosphine reagent, such as 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, or di-2-methoxyethyl azodicarboxylate. Examples of phosphine reagents include triphenylphosphine, tri-n-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, and diphenyl-2-pyridylphosphine. Furthermore, when using a Tsunoda reagent such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane, this reaction proceeds favorably even in the absence of a phosphine reagent. Examples of solvents include toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. This reaction proceeds favorably at temperatures between -40°C and 100°C, preferably between 0°C and 70°C.

[0249] [Step 23e] Compound (V7) is a PG of compound (V6). 2 can be prepared by removing the

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

[0251] [ka]

[0252] (In the formula, R 4 and R 5 is alkyl, and 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) in the same manner as in [Step 17c].

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

[0254] [Step 24c] Compound (W4) is the PG of compound (W3) 2 can be prepared by removing the

[0255] Manufacturing method 25

[0256] [ka]

[0257] (In the formula, X A and X B is a halogen atom, and ring B is

[0258] [ka]

[0259] and other symbols are as above.) [Step 25a] Compound (X3) can be produced by reacting compound (X1) with compound (X2) in a solvent in the presence of a base, with or without a phase-transfer catalyst. Examples of solvents 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 bases 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 proceeds particularly favorably using sodium hydride or butyllithium. Examples of phase-transfer catalysts include quaternary ammonium halide salts and crown ethers. This reaction proceeds suitably at 0°C to 120°C, preferably at room temperature to 60°C.

[0260] Manufacturing method 26

[0261] [ka]

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

[0263] [ka]

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

[0265] Manufacturing method 27

[0266] [ka]

[0267] (In the formula, X A and X B is a halogen atom, and other symbols are as above.) [Step 27a] Compound (E1) can be produced by reacting compound (Z1) with compound (D1) in a solvent in the presence or absence of a catalytic amount of copper iodide, in the presence of a transition metal complex and a base. Examples of solvents that can be used include toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Examples of transition metal complexes 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), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tolyl). A divalent palladium complex such as [1,1'-bis(diphenylphosphine)ferrocene]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, or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) is used.

[0268] Furthermore, a suitable ligand may be added to the transition metal complex. Suitable ligands include, for example, 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-(diphenyl)diphenylphosphine]-n ...

[0033] Examples of the base include 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, etc. Examples of the base include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and triethylamine. , diisopropylethylamine, diisopropylamine, etc. The amount of the transition metal complex used can be 0.01 to 0.5 equivalents, preferably 0.03 to 0.1 equivalents, relative to compound (Z1). The amount of the base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (Z1). In particular, it can be suitably produced by a method using reaction conditions such as those described in J. Organomet. Chem., 2002, 653, 46-49.

[0269] Manufacturing method 28

[0270] [ka]

[0271] (In the formula, X A and X B is a halogen atom, and other symbols are as above.) [Step 28a] Compound (F1) can be produced by reacting compound (AA1) with 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 proceeds favorably at temperatures between -78°C and 60°C, preferably between -10°C and room temperature.

[0272] Manufacturing method 29

[0273] [ka]

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

[0275] The compound of the present invention thus obtained can be separated by known separation means, for example, concentration, vacuum concentration, They can be isolated and purified by 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 it is 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 compound of the present invention has a basic group and an acidic group in the molecule, examples of its pharmacologically acceptable salts 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, etc.

[0277] Suitable examples of 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; and aluminum salts. Suitable examples of 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. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of 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. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0278] Furthermore, the compounds of the present invention include the above compound (1) and its pharmacologically acceptable salts, as well as their hydrates and solvates.

[0279] When the compound of the present invention has isomers such as optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or a mixture thereof is also included in the compound of the present invention. For example, when the compound of the present invention has optical isomers, optical isomers resolved from the racemate are also included in the compound of the present invention. These isomers can be obtained individually by known synthesis and separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization).

[0280] Additionally, chiral HPLC against standards can be used to determine the enantiomeric excess (% ee). The enantiomeric excess can be calculated as follows: [(moles R - mols S) / (moles R + mols S)] x 100% where R moles and S moles are the R and S mole fractions in the mixture, such that R moles + S moles = 1. Alternatively, the enantiomeric excess can 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 in the form of a crystal, and both a single crystalline form and a mixture of crystalline forms are encompassed in the compound of the present invention. The crystal can be produced by crystallization using a crystallization method known per se. The compound of the present invention may also be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or co-crystal salt refers to two or more unique co-crystals or co-crystal salts that are formed at room temperature and have different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, stability). It means a crystalline substance that is composed of a solid. Co-crystals or co-crystalline salts can be prepared according to known co-crystallization methods.

[0282] Isotopes (e.g. 2 H, 3 H, 13 C. 14 C. 15 N, 35 Compounds labeled with, for example, S) are also included in the compounds of the present invention. [Example]

[0283] The present invention will be described in detail below with reference to examples and experimental examples, but the present invention is not limited to these examples at all. The following abbreviations are used in the following examples: 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] [ka]

[0286] [Step a] To a 1,4-dioxane (10 mL) 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, 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 stirred overnight under reflux in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, 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 give compound 3 (207 mg, 60.2%). MS(ESI)m / z:507(M+1) + .

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

[0288] [Process c] To a solution of compound 3a (82.4 mg, 160 μmol) in dichloromethane (2.0 mL), trifluoroacetic acid (249 μL) was added and 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 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), trifluoroacetic acid (245 μL) was added and stirred at room temperature for 4 hours. Trifluoroacetic acid (122 μL) was further added to the reaction solution, 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 is referred to 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] [ka]

[0292] [Step a] To a solution of compound 1 (2.37 g, 6.33 mmol) obtained in step c of Reference Example 1 and compound 2 (1.00 g, 5.75 mmol) in 1,4-dioxane (20 mL), 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) were added and stirred overnight at 80°C under a nitrogen atmosphere. The reaction mixture was neutralized with 1 M hydrochloric acid and 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 give 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), triphenylphosphine (115 mg, 439 μmol) and bis(2-methoxyethyl) azodicarboxylate (103 mg, 439 μmol) were added and stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 5 (46.2 mg, 51.0%). MS (ESI) m / z: 516 (M+1). + .

[0294] [Process c] To a solution of compound 5 (44.0 mg, 85.4 μmol) in dichloromethane (1.0 mL), trifluoroacetic acid (653 μL) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was then purified by a cation exchange resin column (Waters, PoraPak TM After purification by solid-phase extraction using HPLC (RxnCX), compound 6 (23.9 mg, 61.0%) was obtained by silica gel chromatography. 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] [ka]

[0297] [Step a] To a toluene (13 mL) solution of compound 1 (1.26 g, 3.36 mmol) obtained in step c of Reference Example 1 and compound 2 (500 mg, 3.36 mmol), a solution of potassium fluoride (487 mg, 8.39 mmol) in water (3.4 mL), 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 a nitrogen atmosphere at 70°C. The reaction mixture was allowed to cool to room temperature, 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 give compound 3 (398 mg, 32.9%). MS (ESI) m / z: 361, 363 (M+1). + .

[0298] [Step b] To a 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 stirred for 4 hours under a carbon monoxide atmosphere at 90°C. To the reaction mixture, ethanol (1.0 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (83.7 mg, 103 μmol) were added and stirred overnight under a carbon monoxide atmosphere at 90°C. After allowing the reaction mixture 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), then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography. Compound 4 (98.3 mg, 24.1%) was obtained by this procedure. MS (ESI) m / z: 399 (M+1). + .

[0299] [Process c] To a 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 give compound 5 (45.5 mg, 53.5%). MS (ESI) m / z: 357 (M+1). + .

[0300] [Step d] Sodium hydride (60% by weight, 41.2 mg, 1.03 mmol) was added 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) and stirred at 100°C for 2 hours. After allowing the reaction mixture 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 give compound 7 (14.6 mg, 28.9%). MS (ESI) m / z: 501 (M+1). + .

[0301] [Process 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 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 give 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] [ka]

[0304] [Step a] 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 were dissolved in 1,4-dioxane ( To the (2.4 mL) solution, 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) were added, and the mixture was stirred overnight under reflux in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and purified by NH silica gel chromatography to give 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), 10% palladium / carbon (10 mg) was added and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction solution was diluted with chloroform, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (3.0 mL), and 10% palladium / carbon (10 mg) was added. The mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction solution was diluted with chloroform and filtered through Celite. The filtrate was concentrated under reduced pressure to give compound 4 (44 mg, 88%). MS (ESI) m / z: 515 (M+1). + .

[0305] [Process c] To a solution of compound 4 (40 mg, 78 μmol) in dichloromethane (1.6 mL), trifluoroacetic acid (0.80 mL) was added and stirred at room temperature for 3 days. The reaction solution was purified by silica gel chromatography to give 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] [ka]

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

[0309] [Step b] 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) was added with a solution of potassium phosphate tripotassium (1.95 g, 9.19 mmol) in water (3.0 mL), X-Phos Aminobiphenyl palladium chloride precatalyst (66 mg, 84 μmol) was added, and the mixture was stirred for 4 hours under a nitrogen atmosphere at 80°C. X-Phos aminobiphenyl palladium chloride precatalyst (65.7 mg, 83.5 μmol) was further added to the reaction mixture, and the mixture was stirred for 4 hours under a nitrogen atmosphere at 80°C. The mixture was heated to 80°C and stirred for 2.5 hours. After allowing the reaction mixture 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 give compound 4 (380 mg, 38.0%). MS (ESI) m / z: 480 (M+1) + .

[0310] [Process 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 mixture was diluted with water (4 mL) and diluted with 1M The mixture was neutralized with 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] [ka]

[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)diborane (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 stirred for 6 hours under a nitrogen atmosphere at 100°C. After cooling 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 give compound 2 (746 mg), 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) was added tricarboxylic acid triphosphate. A solution of palladium (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 a nitrogen atmosphere at 100°C. After the reaction mixture was allowed 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 cation exchange resin column (Waters, PoraPak TM Compound 4 (125 mg, 33.7%) and compound 5 (75 mg, 20%) were obtained by solid-phase extraction and purification using a HPLC column (RxnCX). MS (ESI) m / z: 485 (M+1). + . 485(M+1) + .

[0315] [Process c] To a solution of compound 4 (120 mg, 248 μmol) in methanol (2.4 mL), 10% palladium on carbon (24 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 day. 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 give 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), 4M aqueous sodium hydroxide solution (218 μL, 0.87 mmol) was added and stirred overnight at room temperature. The reaction mixture was neutralized with 1M hydrochloric acid (0.88 mL) and diluted with water (10 mL). The resulting solid was collected by filtration and washed with water (15 mL). The resulting solid was washed with ethyl acetate (5.0 mL) to give 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] [ka]

[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 stirred for 4 hours at 105°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and water and ethyl acetate were added. The mixture was then filtered through Celite. The filtrate was phase-separated, and 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 give Compound 3 (35 mg, 16%). MS (ESI) m / z: 494 (M+1). + .

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

[0321] [Process c] A solution of compound 3a (13 mg, 26 μmol) in a mixture of tetrahydrofuran (1.0 mL) and methanol (0.50 mL) was added to 2 M aqueous sodium hydroxide solution (0.50 mL, 1 0.0 mmol) was added and stirred overnight at room temperature. The reaction solution was neutralized with 0.5 M hydrochloric acid (2.1 mL) and diluted with water (8 mL). The organic solvent was removed from the reaction solution by distillation under reduced pressure, and the resulting solid was collected by filtration and washed with water to obtain compound 4a (11 mg, 90%). The enantiomer is Example 7-1. MS (ESI) m / z: 466 (M+1) + .

[0322] [Step d] A solution of compound 3b (13 mg, 26 μmol) in a mixture of tetrahydrofuran (1.0 mL) and methanol (0.50 mL) was added to 2 M aqueous sodium hydroxide solution (0.50 mL, 1 0.0 mmol) was added and stirred overnight at room temperature. The reaction solution was neutralized with 0.5 M hydrochloric acid (2.1 mL) and diluted with water (8 mL). The organic solvent was removed from the reaction solution by distillation under reduced pressure, and the resulting solid was collected by filtration and washed with water to obtain compound 4b (9.0 mg, 73%). This enantiomer is designated 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] [ka]

[0325] [Step a] To a solution of compound 1 (380 mg, 1.12 mmol) obtained in Step b of Reference Example 42 and bis(pinacolato)diborane (342 mg, 1.35 mmol) in dimethyl sulfoxide (2.7 mL), 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 at 80°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. Compound 2 (727 mg) was obtained by filtration and concentration under reduced pressure. 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 stirred for 3 hours under a nitrogen atmosphere at 105°C. The reaction mixture was allowed to cool to room temperature, then water was added and 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 give compound 4 (400 mg, 100%). MS (ESI) m / z: 449 (M+1). + .

[0327] [Process c] Compound 4 (400 mg) was subjected to chiral separation 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 at 22 min retention time) and compound 4b (128 mg, 99.9% ee, peak at 18 min retention time).

[0328] [Step d] A solution of compound 4a (119 mg, 265 μmol) in a mixture of tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was added to 2 M aqueous sodium hydroxide solution (1.5 mL, 3 0.0 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was neutralized with 0.2 M hydrochloric acid (15 mL) and 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 is designated Example 8-1. MS (ESI) m / z: 421 (M+1) + .

[0329] [Process e] A solution of compound 4b (128 mg, 285 μmol) in a mixture of tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was added to 2 M aqueous sodium hydroxide solution (1.5 mL, 3 0.0 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was neutralized with 0.2 M hydrochloric acid (15 mL) and 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 is designated 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] [ka]

[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), a solution of tripotassium phosphate (472 mg, 2.22 mol) in water (0.40 mL) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (52 mg, 74 μmol) were added, and the mixture was stirred under reflux in a nitrogen atmosphere for 3 hours. After cooling 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 give Compound 3 (115 mg, 34.5%). MS (ESI) m / z: 449 (M+1). + .

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

[0334] [Process c] A solution of compound 3a (54 mg, 122 μmol) in a mixture of tetrahydrofuran (2.0 mL) and methanol (1.0 mL) was added to a 2 M aqueous solution of sodium hydroxide (1.0 mL, 2. 0 mmol) was added and stirred overnight at room temperature. The reaction solution was neutralized with 1 M hydrochloric acid (2.2 mL), diluted with saturated saline (10 mL), and extracted with chloroform. The organic layer was washed with saturated saline, 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] A solution of compound 3b (54 mg, 122 μmol) in a mixture of tetrahydrofuran (2.0 mL) and methanol (1.0 mL) was added to a 2 M aqueous solution of sodium hydroxide (1.0 mL, 2. 0 mmol) was added and stirred overnight at room temperature. The reaction solution was neutralized with 1 M hydrochloric acid (2.0 mL) and diluted with water (10 mL). The organic solvent was removed from the reaction solution by distillation under reduced pressure, and the resulting solid was collected by filtration and washed with water to obtain compound 4b (16 mg, 33%). This enantiomer is 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] [ka]

[0338] [Step a] Compound 3 was obtained from Compound 1 and Compound 2 obtained in Step a of Example 5 by the same method 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 separation using chiral HPLC (CHIRAL PAK IF, 30 × 250, tert-butyl methyl ether:2-propanol:diethylamine=93:7:0.1, 20 mL / min, separated after one recycle) to give compound 3a (9.0 mg, 99.9% ee, peak at 38 min retention time) and compound 3b (9.0 mg, 99.9% ee, peak at 58 min retention time).

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

[0341] [Step d] Compound 4b was obtained from compound 3b by the same method as in step c of Example 7. This enantiomer is 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] [ka]

[0344] [Step a] To a solution of compound 1 (3.00 g, 8.62 mmol, Reference Example 49) and bis(pinacolato)diborane (2.85 g, 11.2 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (2.11 g, 21.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (352 mg, 431 μmol). The mixture was stirred for 3 hours under a nitrogen atmosphere at 110°C. After allowing the reaction mixture 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. Compound 2 (5.64 g) was obtained by filtration and concentration under reduced pressure. 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] [Process 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 separation 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 at 38 min) and compound 5b (25 mg, 99.9% ee, peak at 23 min). Compound 5a is designated as Example 11-1, and compound 5b is designated as 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] [ka]

[0349] [Step a] To a solution of compound 1 (100 mg, 296 μmol) obtained in step b of Reference Example 42 and compound 2 (78.6 mg, 444 μmol) in 1,4-dioxane (3.0 mL), 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 under reflux for 5 hours in a nitrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography. Compound 3 (109 mg, 84.9%) was obtained by purification with HPLC. MS (ESI) m / z: 435 (M+1). + .

[0350] [Step b] To a solution of compound 3 (109 mg, 251 μmol) in tetrahydrofuran (3 mL) and methanol (1.0 mL), 4M aqueous sodium hydroxide (0.20 mL, 0.80 mmol) was added and stirred at room temperature for 15 hours, followed by stirring at 60°C for 4 hours. The reaction mixture was allowed to cool to room temperature, neutralized with 1M hydrochloric acid (0.8 mL), and water was added. The resulting solid was filtered and washed with 50% aqueous methanol to give 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] [ka]

[0353] [Step a] To the hydrochloride salt of compound 2 (133 mg, 591 μmol, Reference Example 15), saturated aqueous sodium bicarbonate and chloroform were added and stirred. 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 at 100°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to give 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, it was neutralized with 1 M hydrochloric acid and 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 give 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] [ka]

[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), 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) were added, and the mixture was stirred under reflux for 4 hours in a nitrogen atmosphere. After cooling 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 give 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), potassium hydroxide (85 wt %, 415 mg, 6.29 mmol) was added and stirred at room temperature for 4 days. The reaction solution was neutralized with 1 M hydrochloric acid (6.29 mL), 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 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] [Process c] A solution of compound 4 (1.34 g, 2.83 mmol) in a mixture of tetrahydrofuran (8.0 mL) and methanol (2.7 mL) was added to 4 M aqueous sodium hydroxide solution (2.83 mL, 11.3 mmol) was added and stirred at room temperature overnight. The reaction solution was neutralized by adding 10% aqueous citric acid solution (25 mL), and the organic solvent was evaporated under reduced pressure. The residue was allowed to stand, and the resulting solid 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] [ka]

[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 under reflux in a nitrogen atmosphere for 3 hours. The reaction mixture was allowed to cool to room temperature and then 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 give 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), potassium hydroxide (85 wt %, 1.32 g, 20.1 mmol) was added and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (500 mL). 1 M hydrochloric acid (20 mL) was added to neutralize the solution, and the solution was 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), and diisopropylethylamine (1.62 mL, 9.36 mmol) was added. The mixture was heated under reflux and stirred 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] [Process c] To a solution of compound 4 (2.88 g, 7.19 mmol) in dichloromethane (150 mL), trifluoroacetic acid (10.0 mL) was added 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 give compound 5 (1.33 g, 66.0%) was obtained. 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), tributylphosphine (75.1 mg, 371 μmol) and 1,1'-(azodicarbonyl)dipiperidine (93.6 mg, 371 μmol) were added and stirred at room temperature overnight. The reaction suspension was diluted with tetrahydrofuran (6.0 mL) and hexane (12 mL), insoluble matter was removed by filtration, and the mixture was concentrated. The residue was purified by silica gel chromatography and then loaded onto a cation exchange resin column (Waters, PoraPak). TM Compound 7 (66.9 mg, 53.5%) was obtained by solid-phase extraction and purification using a column chromatography column (RxnCX). MS (ESI) m / z: 439 (M+1). + .

[0366] [Process e] A solution of compound 7 (60.0 mg, 137 μmol) in a mixture of tetrahydrofuran (1.8 mL) and methanol (1.8 mL) was added to 4 M aqueous sodium hydroxide solution (0.17 mL, 0.68 mmol) was added and stirred at room temperature overnight. The reaction solution was neutralized with 1 M hydrochloric acid (0.78 mL) and 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] [ka]

[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 stirred at 80°C for 5 hours. The reaction mixture was allowed to cool to room temperature, 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 give compound 3 (63.0 g, 66.2%). MS (ESI) m / z: 445 (M+1). + .

[0370] [Step b] A solution of compound 3 (60.0 mg, 135 μmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added to 4 M aqueous sodium hydroxide solution (0.17 mL, 0.68 mmol) was added and stirred at room temperature for 2 days. The reaction solution was neutralized with 1 M hydrochloric acid (0.68 mL) and 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] [ka]

[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, and the mixture was stirred for 7 hours under a nitrogen atmosphere at 105°C. After cooling 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 give 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), 4 M aqueous sodium hydroxide solution (0.50 mL, 2.0 mmol) was added and stirred for 2.5 hours under heating at 85°C. After allowing the reaction solution to cool to room temperature, acetic acid (114 μL, 2.0 mmol) was added to neutralize the solution, and the solution was concentrated under reduced pressure. The residue was dissolved in acetic acid (3.0 mL) and stirred for 5.5 hours under heating at 125°C. After allowing the reaction solution to cool to room temperature, the solution was loaded onto a cation exchange resin column (Waters, PoraPak TM Compound 4 (65.0 g, 92.5%) was obtained by solid-phase extraction and purification using a HPLC column (RxnCX). 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] [ka]

[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) was added cesium carbonate (220 mg, 675 μmol), palladium(II) acetate (7.0 mg, 31 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2' 4',6'-Triisopropyl-1,1'-biphenyl (25 mg, 54 μmol) was added, and the mixture was heated to 160°C under microwave irradiation and stirred for 30 minutes. After allowing the reaction mixture 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 give 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), 10% palladium / carbon (100 mg) was added and stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was diluted with chloroform, filtered through Celite, and washed with chloroform. The filtrate was concentrated under reduced pressure to give compound 4 (135 mg). MS (ESI) m / z: 453 (M+1). + .

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

[0380] [Step d] Compound 5 (170 mg) was purified by chiral HPLC (CHIRAL PAK IA, 30 × 25 Compound 5a (28 mg, 99.8% ee, peak at 17 min) and compound 5b (27 mg, 99.9% ee, peak at 13 min) were obtained by chiral separation using a hexane:methanol:tetrahydrofuran:acetic acid = 70:15:15:0.5 (20 mL / min). Compound 5a is designated as Example 18-1, and compound 5b is designated 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] [ka]

[0383] [ka]

[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, diastereomer of 2b) obtained in Step f of Reference Example 10, 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) were added and stirred for 5 hours at 110°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and water was added, followed by extraction 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 give compound 3 (220 mg, 65.5%). MS (ESI) m / z: 457 (M+1).+ .

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

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

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

[0388] [Process e] To a 1,4-dioxane (3.5 mL) solution of compound 1 (543 mg, 1.61 mmol) obtained in Step b of Reference Example 42 and compound 2b (160 mg, 803 μmol, diastereomer of 2a) obtained in Step g of Reference Example 10, 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) were added and stirred for 5 hours under a nitrogen atmosphere at 110°C. The reaction mixture was allowed to cool to room temperature, and water was added, followed by extraction 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 give compound 5 (26 mg, 64.5%). MS (ESI) m / z: 457 (M+1). + .

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

[0390] [Process g] To a mixed solution of compound 5a (186 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 stirred overnight at room temperature. The reaction solution was neutralized with 1M hydrochloric acid (2.5 mL), saturated saline (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6a (125 mg). This enantiomer is designated Example 19-3. MS (ESI) m / z: 429 (M+1). + .

[0391] [Process 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 stirred overnight at room temperature. The reaction solution was neutralized with 1M hydrochloric acid (2.5 mL), saturated saline (10 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6b (83 mg). This enantiomer is designated 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] [ka]

[0394] [Step a] To a 1,4-dioxane (4.0 mL) solution of compound 1 (289 mg, 855 μmol) obtained in Step b of Reference Example 42 and compound 2 (91.2 mg, 428 mol) obtained in Step g of Reference Example 11, 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 and stirred for 8 hours at 110°C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and water was added and 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 give 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), 4M aqueous sodium hydroxide solution (1.3 mL) was added and 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 with 4M 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 give 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] [ka]

[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, and the mixture was stirred for 3 hours under a nitrogen atmosphere at 105°C. Palladium(II) acetate (17 mg, 76 μmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (70.5 mg, 151 μmol) were further added to the reaction solution, and the mixture was stirred for 3 hours under a nitrogen atmosphere at 105°C. After allowing the reaction mixture to cool to room temperature, water and ethyl acetate were added and the mixture was filtered through Celite. The filtrate was separated into phases, and 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 give 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), 6 M hydrochloric acid (2.0 mL, 12 mmol) was added and stirred at room temperature for 10 hours. The reaction solution was neutralized with 2 M aqueous sodium hydroxide solution (5.0 mL) and then loaded onto a cation exchange resin column (Waters, PoraPak TM Compound 4 (70 mg, 50%) was obtained by solid-phase extraction and purification using a column chromatography column (RxnCX). MS (ESI) m / z: 385 (M+1). + .

[0400] [Process 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. A saturated aqueous ammonium chloride solution was added to the reaction solution, and ethyl acetate was added. 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 give 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), 4 M aqueous sodium hydroxide solution (0.50 mL, 2.0 mmol) was added and 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 with 1 M 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 give 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] [ka]

[0404] [Step a] 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 to a 1,4-dioxane (30 mL) 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). The mixture was heated under reflux in a nitrogen atmosphere to give 4 The reaction mixture was stirred for 3 hours. After allowing it 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 give 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 stirred overnight at room temperature. 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 give compound 4 (404 mg, 61.4%). MS (ESI) m / z: 399 (M+1). + .

[0406] [Process 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 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 give compound 5 (334 mg, 83.1%). MS (ESI) m / z: 397 (M+1). +.

[0407] [Step d] Sodium hydride (60 wt%, 101 mg, 2.54 mmol) was added to a solution of ethyl diethylphosphonoacetate (682 mg, 3.04 mmol) in tetrahydrofuran (6.0 mL) under ice cooling, and the mixture was stirred for 20 minutes under ice cooling. A solution of compound 5 (334 mg, 843 μmol) in tetrahydrofuran (6.0 mL) was added dropwise to the reaction solution 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, and concentrated under reduced pressure. The residue was purified by HPLC (Capcellpak C18 UG80, 30 × 250, 35 mL / min, 0.05% TFA aqueous solution / 0.05% TFA acetonitrile solution = 35% → 55%, 15 minutes) to give compound 6 (212 mg, 44.8%). MS(ESI)m / z:467(M+1) + .

[0408] [Process e] A solution of compound 6 (50.0 mg, 107 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added to 4 M aqueous sodium hydroxide solution (0.5 mL, 2 0.0 mmol) was added and stirred at room temperature for 60 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (2 mL) and neutralized with 1 M hydrochloric acid (2.0 mL). 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] [Process f] Compound 7 (21 mg) was subjected to chiral separation using chiral HPLC (CHIRAL PAK IA, 30 × 250, hexane:ethanol:tetrahydrofuran:acetic acid = 60:30:10:0.1, 10 mL / min, 0.5 recycles followed by preparative separation) to obtain compound 7a (4.1 mg, 99.8% ee, peak at 27 min) and compound 7b (5.2 mg, 99.1% ee, peak at 17 min). Compound 7a is designated as Example 22-1, and compound 7b is designated 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] [ka]

[0412] [Step a] To a solution of compound 2 (197 mg, 1.08 mmol) obtained in step c of Reference Example 14 and compound 1 (250 mg, 718 μmol, Reference Example 49) 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 stirred for 15 hours under nitrogen atmosphere at 100°C. The reaction mixture was allowed to cool to room temperature, then water was added and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 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), 10% palladium / carbon (30 mg) was added and stirred in a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in ethanol (2.0 mL), and 10% palladium / carbon (30 mg) was added. The mixture was stirred in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to give compound 4 (97.0 mg, 70.0%). MS (ESI) m / z: 453 (M+1) + .

[0414] [Process c] A solution of compound 4 (97.0 mg, 214 μmol) in a mixture of tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was added to 4 M aqueous sodium hydroxide solution (0.11 mL, 0.44 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was neutralized with 1 M hydrochloric acid (0.44 mL) and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 5 (81.0 mg, 89.0%). 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] [ka]

[0417] [Step a] A solution of compound 1 (1.89 g, 5.43 mmol, Reference Example 49) and tert-butyl D-proline (2.32 g, 13.5 mmol) in toluene (20 mL) was added with sodium tert-butoxide (1.04 g, 10.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (199 mg, 217 μmol), 2,2′-bis(diphenylphosphine) (phino)-1,1'-binaphthalene (270 mg, 434 μmol) was added, and the mixture was placed under a nitrogen atmosphere. The mixture was stirred for 2.5 hours under heating at 105°C. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride and water were added, followed by extraction 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 give 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, lithium aluminum hydride (57.5 mg, 1.52 mmol) was further added 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. 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 give compound 3 (490 mg, 79.9%). MS (ESI) m / z: 369 (M+1). + .

[0419] [Process c] Sodium hydride (60 wt%, 30.8 mg, 771 μmol) was added to a solution of compound 3 (240 mg, 593 μmol) in dimethyl sulfoxide (2.5 mL) under ice cooling, and the mixture was stirred for 20 minutes under ice cooling. A solution of tert-butyl bromoacetate (127 mg, 652 μmol) in dimethyl sulfoxide (0.50 mL) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous ammonium chloride solution and water 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, and concentrated. The residue was purified by silica gel chromatography and NH silica gel chromatography to give 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), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was applied to a cation exchange resin column (Waters, PoraPak TM The residue was dissolved in tetrahydrofuran (2.0 mL) and methanol (1.0 mL), and 2M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 0.5 M hydrochloric acid (4.1 mL) and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 5 (95.0 mg, 93.5%). MS (ESI) m / z: 427 (M+1). + .

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

[0422] [Table 1]

[0423] [Table 2]

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

[0425] [Table 3]

[0426] [Table 4]

[0427] [Table 5]

[0428] [Table 6]

[0429] [Table 7]

[0430] [Table 8]

[0431] The following compounds were produced 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 produced according to Production Methods 7, 14 to 17 and Examples 19 to 24.

[0436] [Table 12]

[0437] [Table 13]

[0438] Reference example 1

[0439] [ka]

[0440] [Step a] A 1M solution of potassium tert-butoxide in tetrahydrofuran (55.8 mL, 55.8 mmol) was added dropwise to a solution of tert-butyl diethylphosphonoacetate (14.1 g, 55.8 mmol) in tetrahydrofuran (200 mL) under ice cooling, and the mixture was stirred for 30 minutes. A solution of compound 1 (10.0 g, 46.5 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred for 3 hours under ice cooling. 1M 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, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 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), trimethylsulfoxonium iodide (3.43 g, 15.6 mmol) was added and stirred for 30 minutes. To the reaction solution, a solution of compound 2 (4.07 g, 13.0 mmol) in dimethyl sulfoxide (40 mL) was added and stirred overnight at room temperature. Saturated aqueous ammonium chloride and water 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, and concentrated. The residue was purified by silica gel chromatography to give compound 3 (2.77 g, 65.2%). MS (APCI) m / z: 327, 329 (M+1). + .

[0442] [Process 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), potassium acetate (2.45 g, 24.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (243 mg, 333 μmol) were added and stirred overnight at 80°C under 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 give compound 4 (3.38 g, 109%). MS (APCI) m / z: 319 (M-tBu+1). + .

[0443] Reference example 2

[0444] [ka]

[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 2 M isopropylmagnesium chloride in tetrahydrofuran (24.5 mL, 49.0 mmol) in tetrahydrofuran (30 mL) under a nitrogen atmosphere at room temperature and stirred for 1 hour. A solution of 2 M isopropylmagnesium chloride in tetrahydrofuran (4.45 mL, 8.91 mmol) was then added dropwise to the reaction solution and 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 stirred for 2 hours, then stirred overnight while warming to room temperature. Water (40 mL) and saturated aqueous ammonium chloride (160 mL) were added to the reaction solution and 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) and hexane (100 mL) to give compound 3 (5.84 g, 59.6%). MS (ESI) m / z: 220, 222 (M+1). + .

[0446] [Step b] To a solution of compound 3 (14.2 g, 64.5 mmol) and chloro[(1S,2S)-N-(2',6'-dimethylbenzylsulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium(II) (777 mg, 1.29 mmol) in N-methylpyrrolidone (129 mL), a mixture of formic acid (12.2 mL, 323 mmol) and triethylamine (17.9 mL, 129 mmol) was added dropwise under ice cooling, and the mixture was stirred for 7 hours under ice cooling. Water (700 mL) was added to the reaction solution, 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 give compound 4 (14.5 g, 95.3% ee). MS(ESI)m / z:222,224(M+1) + .

[0447] [Process c] To a solution of compound 4 (14.5 g, 65.3 mmol) in diethyl ether (140 mL), a solution of potassium hydroxide (85 wt %, 11.0 g, 166 mmol) in water (140 mL) was added and stirred overnight. The reaction suspension was extracted with ethyl acetate (280 mL), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5 ( Obtained 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), a 1 M solution of potassium tert-butoxide in tetrahydrofuran (127 mL, 127 mmol) was added dropwise, followed by the addition of a solution of compound 5 (11.8 g, 63.3 mmol) in tetrahydrofuran (19 mL). The mixture was stirred under reflux for 1 day under a nitrogen atmosphere. After allowing the reaction mixture to cool to room temperature, water (740 mL) was added, and the resulting solid was filtered and washed with water (185 mL). The resulting solid was recrystallized from ethanol (150 mL) to give compound 7 (11.8 g, 73.2%, 99.7% ee). MS (ESI) m / z: 256, 258 (M+1). + .

[0449] Reference example 3

[0450] [ka]

[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 a nitrogen atmosphere at 60°C. 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. A solution of compound 1 (1.63 g, 8.76 mmol) in dimethyl sulfoxide (15 mL) was added to the reaction solution and stirred at room temperature for 2 hours. Water (200 mL) 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 give 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 1 M solution of potassium tert-butoxide in tetrahydrofuran (7.92 mL, 7.92 mmol) under ice cooling. Compound 2 (900 mg, 3.96 mmol) was then added to the reaction solution, and the mixture was stirred under reflux for 1 day in a nitrogen atmosphere. After allowing the reaction mixture 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 give compound 4 (735 mg, 68.7%). MS (ESI) m / z: 270, 272 (M+1). + .

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

[0454] [Table 14]

[0455] Reference example 7

[0456] [ka]

[0457] [Step a] A solution of compound 1 (3.00 g, 12.2 mmol) and vinylboronic anhydride pyridine complex (2.36 g, 9.79 mmol) in 1,2-dimethoxyethane (122 mL) and water (10 mL) was added to potassium carbonate (3.38 g, 24.5 mmol) and tetrakis(trimethylsilyl)boronic acid. (phenylphosphine)palladium(0) (354 mg, 306 μmol) was added and the mixture was stirred under a nitrogen atmosphere. The mixture was stirred under reflux for 2 hours under atmospheric pressure. 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 give compound 2 (2.35 g, 99.9%). MS (ESI) m / z: 193 (M+1). + .

[0458] [Step b] Compound 2 (2.35 g, 12.2 mmol) was dissolved in a mixture of tert-butyl alcohol (30 mL) and water (40 mL) and N-bromosuccinimide (2.39 g, 13.4 mmol) was added. mol) was added and stirred for 2.5 hours under heating at 45°C. After the reaction solution was allowed to cool to room temperature, 4M aqueous sodium hydroxide solution (23.06 mL, 12.2 mL) was added and stirred at room temperature for 10 minutes. Further 4M aqueous sodium hydroxide solution (3.06 mL, 12.2 mL) was added to the reaction solution and stirred at room temperature overnight. Water was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydroxide, and After washing with brine, the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 3 (2.48 g, 97.4%). 1 H-NMR(400MHz,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=1.5Hz), 6.93(1H,dd,J=8.2,1.5Hz), 7.78(1H,d,J=8.2Hz).

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

[0460] [Step d] A solution of compound 5 (2.17 g, 6.04 mmol) in tetrahydrofuran (60 mL) was treated with tributylphosphine (2.23 mL, 9.06 mmol) and 1,1'-(azodicarbamate). To the mixture was added (bornyl)dipiperidine (2.29 g, 9.06 mmol), and the mixture was stirred at room temperature overnight. After removing insoluble matter from the reaction suspension by filtration, the mixture 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] [Process e] To a solution of compound 6 (307 mg, 899 μmol) in methanol (45 mL), 10% palladium on carbon (92 mg) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 7 (187 mg, 82.8%). MS (APCI) m / z: 252 (M+1). + .

[0462] Reference example 8

[0463] [ka]

[0464] [Step a] Compound 1 (400 mg, 1.77 mmol) in a mixed solution of tetrahydrofuran (18 mL) and methanol (3.0 mL) was added with di-tert-butyl dicarbonate (425 mg , 1.95 mmol) and triethylamine (377 μL, 2.65 mmol) were added, and the The mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue, followed by phase separation. 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 give compound 2 (400 mg, 69.3%). 1 H-NMR(400MHz,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=7Hz), 7.38(1H,s).

[0465] [Step b] To a 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 stirred for 2 days at 70°C under a carbon monoxide atmosphere. After cooling to room temperature, water and ethyl acetate were added and the mixture was filtered through Celite. The filtrate was phase-separated, and 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 give compound 3 (224 mg, 41.5%). MS (ESI) m / z: 250 (M-tBu+1). + .

[0466] [Process c] Trifluoroacetic acid (0.56 mL) was added to a solution of compound 3 (224 mg, 724 μmol) in chloroform (2.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was then applied to a cation exchange resin column (Waters, PoraPak TM Compound 4 (142 mg, 94.3%) was obtained by solid-phase extraction and purification using a HPLC column (RxnCX). MS (ESI) m / z: 206 (M+1). + .

[0467] Reference example 9

[0468] [ka]

[0469] [Step a] To a solution of compound 1 (20.0 g, 92.1 mmol) and triethylamine (16.6 mL, 120 mol) 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 the mixture was stirred for 2 hours under ice cooling. Water (60 mL) was added to the reaction solution under ice cooling, and the phases were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 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 the reaction mixture was cooled to room temperature, water (500 mL) was added, and ethyl acetate was added. The mixture was extracted with chilled water (400 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give compound 4 (41.6 g, 90.4%). MS (ESI) m / z: 432 (M+1). + .

[0471] [Process c] To a solution of compound 4 (2.00 g, 4.17 mmol) in dichloromethane (20 mL), trifluoroacetic acid (4.0 mL) was added and 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 give compound 5 (1.40 g). MS (ESI) m / z: 332 (M+1). + .

[0472] Reference example 10

[0473] [ka]

[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), triethylamine (19.2 mL, 138 mmol) and sulfur trioxide pyridine complex (11.0 g, 69.0 mmol) were added under ice cooling, 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), then dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (30 mL) and ethyl diethylphosphonoacetate (7.73 g, 34.5 mmol) and sodium hydride. The resulting mixture was added dropwise to a solution of 1.20 g (34.5 mmol) of 1,000 mg ... + .

[0475] [Step b] To a solution of compound 2 (3.32 g, 10.2 mmol) in tetrahydrofuran (35 mL), a 1 M diisobutylaluminum hydride solution in dichloromethane (30.5 mL, 30.5 mmol) was added dropwise under ice cooling, and the mixture was stirred for 1.5 hours under ice cooling. A saturated aqueous solution of Rochelle salt (30 mL) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was then extracted three times with ethyl acetate (30 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 give compound 3 (1.55 g, 57.7%). MS (ESI) m / z: 188 (M-tBu+1). + .

[0476] [Process c] To a solution of compound 3 (780 mg, 2.94 mmol) in 1,2-dichloroethane (15 mL), 1 M diethylzinc in toluene (5.90 mL, 5.90 mmol) and chloroiodomethane (860 μL, 11.8 mmol) were added dropwise under ice cooling, and the mixture was stirred for 5 hours while warming to room temperature. Saturated aqueous ammonium chloride (5.0 mL), saturated aqueous Rochelle salt (30 mL), and chloroform (30 mL) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The mixture was 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 give 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 solution of compound 4 (280 mg, 1.01 mmol) in acetonitrile (6.0 mL) and carbon tetrachloride (6.0 mL), a 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 stirred at room temperature for 1 hour. 2-Propanol (3.0 mL) was added to the reaction mixture, which was stirred at room temperature for 1 hour and then filtered through Celite. Saturated aqueous ammonium chloride solution (9.0 mL) was added to the filtrate, which 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), and potassium carbonate (443 mg, 3.21 mmol) and iodoethane (257 μL, 3.21 mmol) were added. The mixture was stirred at room temperature for 2 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 give compound 6 (290 mg, 64.1%). MS (ESI) m / z: 300 (M+1). +.

[0478] [Process e] To a mixed solution of compound 5 (260 mg, 900 μmol) in acetonitrile (5.0 mL) and carbon tetrachloride (5.0 mL), a 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 stirred at room temperature for 1 hour. 2-Propanol (2.5 mL) was added to the reaction mixture, which was stirred at room temperature for 1 hour and then filtered through Celite. The filtrate was diluted with saturated aqueous ammonium chloride (7 0.5 mL) was added and 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), and potassium carbonate (377 mg, 2.73 mmol) and iodoethane (218 μL, 2.73 mmol) were added, followed by stirring at room temperature for 4 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 7 (210 mg, 77.2%). MS (ESI) m / z: 300 (M+1) + .

[0479] [Process f] To a solution of compound 6 (205 mg, 685 μmol) in dichloromethane (3.5 mL), trifluoroacetic acid (1.0 mL) was added and 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 sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give compound 8 (140 mg). 1 H-NMR(400MHz,CDCl3)δ:1.01(1H,m), 1.15(1H,m), 1.25(3H,t,J=7.2Hz), 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] [Process g] To a solution of compound 7 (210 mg, 701 μmol) in dichloromethane (3.5 mL), trifluoroacetic acid (1.0 mL) was added and 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 give compound 9 (160 mg). 1 H-NMR(400MHz,CDCl3)δ:0.87(1H,m), 1.14(1H,m), 1.25(3H,t,J=7.2Hz), 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] [ka]

[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), a solution of sodium bromide (118 mg, 1.15 mmol) in water (2.0 mL), saturated aqueous sodium bicarbonate (5.5 mL), and 5% aqueous sodium hypochlorite (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, which was then extracted three times with chloroform (30 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 (20 mL) and added dropwise to a solution of ethyl diethylphosphonopropionate (3.47 g, 14.6 mmol) and sodium hydride (60 wt %, 499 mg, 12.5 mmol) in tetrahydrofuran (20 mL) under ice cooling. The mixture was then 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 give 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), a 1 M solution of diisobutylaluminum hydride in dichloromethane (20.3 mL, 20.3 mmol) was added dropwise at -50°C over 40 minutes, followed by stirring for 2 hours while warming to -30°C. A mixture of methanol (1.0 mL) and tetrahydrofuran (10 mL) was added dropwise at -30°C, followed by stirring for 1 hour while warming to -10°C. A saturated aqueous solution of Rochelle salt (10 mL) was added to the reaction solution at -10°C, followed by stirring overnight at room temperature, followed by extraction 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 give compound 3 (950 mg, 58.4%). MS (ESI) m / z: 258 (M+1). + .

[0485] [Process c] To a solution of compound 3 (950 mg, 3.40 mmol) in dichloromethane (15 mL), imidazole (694 mg, 10.2 mmol) and tert-butylchlorodiphenylsilane (1.32 mL, 5.10 mmol) were added and 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 give compound 4 (2.20 g). 1 H-NMR(400MHz,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=8Hz), 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), 1M diethylzinc toluene solution (11.1 mL, 11.1 mmol) and chloroiodomethane (1.61 mL, 22.1 mmol) were added dropwise over 45 minutes under ice-cooling, and the mixture was stirred for 4 hours under ice-cooling. Saturated ammonium chloride aqueous solution (5.0 mL), saturated Rochelle salt aqueous solution (10 mL), and chloroform (10 mL) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The mixture was then extracted twice with chloroform (30 mL). The organic layer was separated using saturated Rochelle salt aqueous solution ( The residue was purified by silica gel chromatography to give compound 5 (1.35 g, 70.9%). 1 H-NMR(400MHz,CDCl3)δ:0.36(1H,t,J=5Hz), 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] [Process e] A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.82 mL, 4.82 mmol) was added to a solution of compound 5 (1.35 g, 2.41 mmol) in tetrahydrofuran (8.0 mL) and stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction solution, followed by extraction 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 give compound 6 (720 mg, 94.7%). MS (ESI) m / z: 272 (M+1). + .

[0488] [Process f] To a mixed solution of compound 6 (360 mg, 1.33 mmol) in acetonitrile (8.0 mL) and carbon tetrachloride (8.0 mL), a 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 stirred at room temperature for 1.5 hours. 2-Propanol (4.0 mL) was added to the reaction mixture, which was stirred at room temperature for 1 hour and then filtered through Celite. Saturated aqueous ammonium chloride solution (10 mL) and 10% aqueous citric acid solution (10 mL) were added to the filtrate, which was then 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 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 under reduced pressure. The residue was purified by silica gel chromatography to give compound 7 (270 mg, 62.8%). MS (ESI) m / z: 314 (M+1). + .

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

[0490] Reference example 12

[0491] [ka]

[0492] [Step a] Compound 1 (1.00 g, 4.08 mmol) in 1,2-dimethoxyethane (6.0 mL 4-Methylmorpholine (493 μL, 4.48 mmol) and isobutyl chloroformate (586 μL, 4.48 mmol) were added to the solution under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. The reaction suspension was filtered, and sodium borohydride (231 mg, 6.12 mmol) and water (3.0 mL) were added to the filtrate under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. 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) was added dropwise diisopropylethylamine (1.88 mL, 10.8 mmol) and chloromethyl methyl ether (851 μL, 11.21 mmol) 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 give compound 3 (926 mg, 93.1%). MS (ESI) m / z: 276 (M+1). + .

[0494] [Process c] To a solution of compound 3 (926 mg, 3.36 mmol) in dichloromethane (20 mL), trifluoroacetic acid (2.6 mL) was added and stirred at room temperature for 3 hours. The reaction solution was neutralized with 2 M 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 give compound 4 (594 mg). MS (ESI) m / z: 176 (M+1). + .

[0495] Reference example 13

[0496] [ka]

[0497] [Step a] Dess-Martin periodinane (1.10 g, 2.59 mmol) was added to a solution of compound 1 (400 mg, 1.73 mmol) in dichloromethane (12 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfite were added to the reaction solution 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 give 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 ethyl diethylphosphonoacetate (587 mg, 2.62 mmol) in tetrahydrofuran (12.0 mL), sodium hydride (60 wt%, 90.7 mg, 2.27 mmol) was added under ice cooling, and the mixture was stirred for 15 minutes. The mixture was stirred overnight while warming to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was cooled to room temperature. 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 give compound 3 (325 mg, 2.1%). MS (ESI) m / z: 244 (M-tBu+1). + .

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

[0500] [Step d] Trifluoroacetic acid (0.26 mL) was added to a solution of compound 4 (130 mg, 431 μmol) in dichloromethane (2.6 mL), and the mixture was stirred at room temperature overnight. The reaction solution was applied to a cation exchange resin column (Waters, PoraPakTM Compound 5 (81.6 mg, 94.0%) was obtained by solid phase extraction and purification using a HPLC column (RxnCX). MS (ESI) m / z: 202 (M+1). + .

[0501] Reference example 14

[0502] [ka]

[0503] [Step a] Dess-Martin periodinane (1.33 g, 3.14 mmol) was added to a solution of compound 1 (450 mg, 2.09 mmol) in dichloromethane (21 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfite were added to the reaction solution under ice cooling, 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 give 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), sodium hydride (60 wt%, 70.7 mg, 1.77 mmol) was added under ice cooling and stirred for 15 minutes. Compound 2 (290 mg, 1.36 mmol) was added dropwise to the reaction solution under ice cooling and 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 give compound 3 (612 mg). MS (ESI) m / z: 228 (M-tBu+1). + .

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

[0506] The following compounds were produced 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] [ka]

[0512] [Step a] Compound 1 (10.0 g, 51.0 mmol) was added to a solution of lithium aluminum hydride (2.90 g, 76.5 mmol) in tetrahydrofuran (150 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. A solution of water (3.0 mL) in tetrahydrofuran (150 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 45 minutes. A 4M aqueous solution of sodium hydroxide (3.0 mL) was added to the reaction suspension, and the mixture was stirred at room temperature for 30 minutes. Water (3.0 mL) was then 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 give compound 2 (8.70 g, 93.7%). 1 H-NMR (400MHz, 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=6Hz).

[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), triphenylphosphine (1.22 g, 4.66 mmol) and diisopropyl azodicarboxylate (941 mg, 4.66 mmol) were added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and 50% N,N-dimethylformamide aqueous solution was added to the residue, followed by extraction with heptane. The organic phase was washed with 50% N,N-dimethylformamide aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 4 (972 mg, 92.6%). MS (ESI) m / z: 338, 340 (M+1). + .

[0514] Reference example 43

[0515] [ka]

[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 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 give 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 4 M solution of hydrochloric acid in ethyl acetate (19.5 mL, 78.0 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2 M aqueous sodium hydroxide solution and the phases were separated. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 4 (1.94 g, 91.5%). MS (ESI) m / z: 271, 273 (M+1). + .

[0518] [Process c] Compound 5 (1.37 mL, 9.52 mmol) was added to a solution of compound 4 (1.29 g, 4.76 mmol) in N,N-dimethylformamide (15 mL) and diisopropylethylamine (1.65 mL, 9.52 mmol), 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 give compound 6 (1.61 g, 95.5%). MS (ESI) m / z: 353, 355 (M+1). + .

[0519] Reference example 44

[0520] [ka]

[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), sodium hydride (60 wt %, 2.69 g, 67.3 mmol) was added portionwise under ice cooling, and the mixture was stirred for 30 minutes. A solution of compound 2 (8.35 g, 56.1 mmol) in tetrahydrofuran (30 mL) was added dropwise 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, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 3 (4.95 g, 30.0%). MS (ESI) m / z: 295, 297 (M+1). + .

[0522] Reference example 45

[0523] [ka]

[0524] [Step a] To a solution of compound 1 (5.00 g, 19.6 mmol) in toluene (100 mL), triphenylphosphine (5.66 g, 21.6 mmol) was added and stirred under reflux for 1 hour. The reaction mixture was diluted with toluene (50 mL) and further stirred under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, then diluted with hexane (150 mL). The resulting solid was filtered and washed with hexane (100 mL) to give compound 2 (8.78 g, 86.6%). MS (E SI) m / z: 437

[0525] [Step b] To a mixture of compound 2 (3.62 g, 6.99 mmol) in tetrahydrofuran (40 mL) and N,N-dimethylformamide (10 mL), sodium hydride (60 wt%, 155 mg, 6.45 mmol) was added under ice-cooling and stirred for 30 minutes. Compound 3 (1.00 g, 5.38 mmol) was added in small portions to the reaction solution under ice-cooling and stirred for 30 minutes under ice-cooling. Insoluble matter was removed from the reaction suspension by filtration 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, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 4 (864 mg, 46.7%), compound 5 (193 mg, 10.5%), and a cis / trans mixture of compound 6 (619 mg, 33.5%). 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] [ka]

[0528] [Step a] To a mixture of compound 1 (200 mg, 1.34 mmol) and compound 2 (250 mg, 1.34 mmol) in N,N-dimethylformamide (4.0 mL) and triethylamine (2.0 mL), bistriphenylphosphinepalladium(II) dichloride (94.2 mg, 134 μmol), triphenylphosphine (70.4 mg, 268 μmol), and copper iodide (25.6 mg, 134 μmol) were added and stirred at 50°C under a nitrogen atmosphere for 6 hours. After cooling 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 give compound 3 (160 mg, 40.0%). MS (ESI) m / z: 299, 301 (M+1). + .

[0529] Reference example 47

[0530] [ka]

[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 in small portions and stirred at room temperature overnight. The reaction suspension was diluted with hexane (6.0 mL), insoluble matter was removed by filtration, and the mixture was concentrated. The residue was purified by silica gel chromatography to give compound 3 (324 mg, 91.8%). MS (ESI) m / z: 332, 334 (M+1). + .

[0532] Reference example 48

[0533] [ka]

[0534] [Step a] To a dichloromethane (2.0 mL) solution of compound 1 (100 mg, 549 μmol) obtained in step a of Reference Example 42, pyridine (133 μL, 1.65 mmol) and p-toluenesulfonyl chloride (126 mg, 659 μmol) were added and stirred at room temperature for 6 hours. To the reaction solution, p-toluenesulfonyl chloride (62.8 mg, 329 μmol) was further added and 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 then concentrated under reduced pressure to give compound 2 (176 mg, 95.2%). 1 H-NMR(400MHz,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=6.2Hz), 7.35(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz).

[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 mixture of substrate and choline quantification reagents (200 μM LPC (1-oleoyl-sn-glycero-3-phosphocholine Sigma #L1881), 25 μM Amplex UltraRed re) was prepared in 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). 10 μL of the compound-containing solution (Invitrogen, 0.1 U / mL peroxidase (TOYOBO), 1 U / mL choline oxidase (TOYOBO)), 10 μL of enzyme (0.4 ng / μL human recombinant ATX), and 100 nL of the compound-containing solution were dispensed into a 384-well plate and incubated at room temperature for 1 hour. Fluorescence (Ex. 525 nm / Em. 598 nm) was measured after incubation. Choline chloride was used as a standard. The inhibition rate was calculated using a blank sample without enzyme as 100% inhibition and a control sample without inhibitor as 0% inhibition. The IC50 value was calculated from the percentage of inhibitory activity at each concentration.

[0538] Experimental Example 2: [ATX activity measurement in plasma (ex vivo)] The compound was wet-ground for 10 minutes in a mixer mill (type: MM400) and the compound administration solution was prepared to a predetermined concentration with 0.5% carboxymethylcellulose aqueous solution and orally administered at a rate of 5 mL / kg to male Wistar rats (5 weeks old at the time of use). Blood was collected periodically from the jugular vein 8 to 24 hours after administration. The blood was heparinized using a small blood collection container, Capiject (CJ-AL, Terumo), and plasma was separated by centrifugation (4°C, 12,000 rpm, 2 minutes) and stored at -80°C. After blood collection, the rats were treated with isofluor- Animals were euthanized by exsanguination via the caudal vena cava under orchid inhalation anesthesia. Plasma ATX activity was assessed by measuring the concentration of choline liberated from lysophosphatidylcholine (the substrate of ATX) by the lysophospholipase D activity of ATX. An equal volume of 2x assay buffer (200 mM Tris-HCl pH 9.0, 10 mM MgCl2, 1 M NaCl, 0.1% Triton X-100) was added to 12 μL of plasma and incubated at 37°C for 6 hours. After 6 hours of incubation, 10 μL of the reaction mixture was mixed with 45 μL of Reagent R1 (100 mM Tris-HCl pH 8.0, 0.5 mM TOOS, 10 U / mL peroxidase, 0.01% Triton X-100), and the absorbance was measured at 550-700 nm to obtain a baseline value. Choline chloride was used as a standard. 1 mM choline chloride was diluted 2-fold with 2x assay buffer up to seven times, and R1 solution was treated in the same manner to measure the absorbance. 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, and the mixture was incubated at room temperature for 10 minutes, after which the absorbance at 550-700 nm was measured. The choline concentration per reaction time was calculated from the difference between the absorbance after adding R2 solution and the initial value measured before adding R2, and this was used as the ATX activity value. <Calculation formula> Inhibitory activity (%) = 100 × {1 - [choline concentration (μM) in the test substance-treated group / choline concentration (μM) in the solvent control group]} The results obtained in Experiments 1 and 2 are shown in the table below.

[0539] [Table 19]

[0540] [Table 20]

[0541] [Table 21]

[0542] [Table 22]

[0543] [Table 23]

[0544] Experimental Example 3: [Effect of ATX inhibitors on bleomycin-induced pulmonary fibrosis in mice] The ATX inhibitor (Example 5, hereinafter referred to as Example 5 in the figures) bleomycin ( The efficacy of the compound against the BLM-induced pulmonary fibrosis model was evaluated by measuring the fibrosis index in plasma or BALF. The results were evaluated using changes in markers and pulmonary fibrosis-related genes. The results showed that SP-D in plasma (Fig. 1) was suppressed, and the expression of Col1a1 (Fig. 2), CTGF (Fig. 3), and IL-6 (Fig. 4) in lungs was suppressed. Furthermore, ATX activity in plasma was completely suppressed (Fig. 5), and LPA (C18:2) production in BALF was also suppressed (Fig. 6). <Creation of a bleomycin-induced pulmonary fibrosis model> Eight-week-old mice were grouped using a simulation method to ensure uniform weight distribution by the day before bleomycin administration, as shown in Table 24 (SOP / STA / RA-0003). Mice were anesthetized with isoflurane, and a 0.5 mg / mL bleomycin solution was administered intratracheally at 50 μL / head to create a bleomycin-induced pulmonary fibrosis model (1.25 U / kg). The saline group received saline instead of bleomycin. An ATX inhibitor (Example 5) was orally administered twice daily starting from the day of bleomycin administration. Body weights were measured once daily starting from the day of grouping.

[0545] [Table 24]

[0546] <Preparation Method of ATX Inhibitor> To the ATX inhibitor (Example 5), a mixed solution of 1 equivalent of 1N NaOH and 0.5% CMC solution (total 100 μL) was added, 10 zirconia beads with a diameter of φ3 mm were added, and pulverization was performed using a mixer mill MM400 (frequency 28.01 / min, pulverization time 10 minutes). 0.5% CMC was added to make a suspension at a concentration of 30 mg / mL, 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. Administration was performed twice a day, and the first administration was carried out 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 solution of 0.5 mg / mL was prepared and administered intratracheally at a rate of 50 μL / head. Otsuka Pharmaceutical Factory Co., Ltd. drinking water (preservation 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, supply company: Charles River Laboratories Japan, Inc., number of animals used: 10 animals / group (age at arrival: 7 weeks old).

[0549] <Rearing 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: freely available.

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

[0551] <Measurement of LPA concentration in BALF> Organic solvent and LPA(17:0) solution as an internal standard substance were added to 200 μL of the collected BALF, and evaporation to dryness was carried out under reduced pressure at 35°C. After evaporation to dryness, 50 μL of 50% ethanol aqueous solution was added to the residue, and the re-dissolved 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). In addition, an LPA(18:2) synthetic standard was added to the PBS buffer used for BALF recovery, and the concentration of LPA(18:2) contained in BALF was calculated by comparing with a calibration sample subjected to the same pretreatment (Figure 6).

[0552] <Measurement of ATX activity in plasma> Measurement and calculation were performed from the collected plasma using the same method as in Experimental Example 2, and the ATX activity value was obtained (Figure 5).

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

[0554] Experimental Example 4: [Examination of the effect of an ATX inhibitor on the intraocular pressure of cynomolgus monkeys] The efficacy of an ATX inhibitor (Example 5, hereinafter referred to as "example5" in the figures) against the cynomolgus monkey laser-induced ocular hypertension model was evaluated using the reduction of intraocular pressure as an index. As a result, the ATX inhibitor (Example 5) showed a statistically significant intraocular pressure-lowering effect in both single oral administration (Figure 7) and single topical administration (Figure 8) of the test drug. <Creation of the 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 in a crossover test using animals repeatedly 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 triturated it. Added a few drops of an oral vehicle (0.5% w / v CMC-Na) and mixed it with the ATX inhibitor (Example 5). Repeatedly added drops of the oral vehicle and mixed the mixture until it became a paste. Transferred the paste to a graduated cylinder and added the oral vehicle up to 60% of the final preparation volume. Added the vehicle (0.5% w / v CMC-Na containing 0.5 mol / L NaOH) while stirring with a stirrer (so that the amount of NaOH was 0.75 mol per 1 mol of Example 5). Added the oral vehicle to make up the volume and confirmed that the pH did not exceed 11.0 (measured value: pH 10.55 - 10.88).

[0558] <Method for preparing a topical administration solution of an ATX inhibitor> 307 mL of a 0.04 mol / L boric acid / phosphoric acid / acetic acid mixture and 193 mL of a 0.2 mol / L aqueous sodium hydroxide solution were mixed (pH approximately 8.4), and then adjusted to pH 8.5 with 1 mol / L hydrochloric acid to prepare a Britton-Robinson buffer solution (pH 8.5). A 5% solution of Kolliphor EL was dissolved in the above solution to prepare the ophthalmic administration vehicle (5% w / v Kolliphor EL solution (pH 8.5)). 4 mL of the solution was placed in a 10 mL measuring flask. 0.5 mg of the ATX inhibitor (Example 5) was weighed out, 9.6 mL of the ophthalmic administration vehicle was added, and the mixture was sonicated for 30 minutes in an ultrasonic cleaner set at a temperature of approximately 40°C. After confirming that the mixture was uniformly suspended, the marked line on the volumetric flask was cut with the ophthalmic administration vehicle, and the mixture was sonicated for 40 minutes in the same manner as above, and complete dissolution was confirmed visually. If the mixture was suspended at this point, the sonication 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 Industries, Ltd., 162-20492) Acetic acid (Fujifilm Wako Pure Chemical Industries, Ltd., 017-00256) Water for injection (Otsuka Pharmaceutical Factory, Inc.) Glanatec eye drops 0.4% (Kowa Co., Ltd.): positive control substance

[0560] <Test animals> Animal species: Male cynomolgus monkey Supplier: Shin Nippon Scientific Co., Ltd. Number of animals used: 10 (age 7-8 years old when acclimatization starts)

[0561] <Breeding environment> Temperature: Actual measurement: 25.4-27.5°C, allowable range: 23-29°C Humidity: Actual measured value: 47-74%, allowable range: 30-70% Ventilation rate: 15 times / hour Lighting: Artificial lighting for 12 hours a day (7:00-19:00) Feed: Approximately 108 g (approximately 12 g x 9 pieces) of solid feed (Purina Mills LLC, HF Primate J 12G 5K9J) was given once a day from 14:00 to 16:00, and any remaining feed was collected by 11:00 the following day (before administration on the administration day). Drinking water: Water was provided ad libitum using an automatic water supply system.

[0562] <Intraocular pressure measurement> Intraocular pressure was measured three times using a rebound tonometer (TonoVet Tonometer TV01, Tiolat Oy) with the animals restrained without anesthesia. The median of the three measurements was used as the accepted value. Furthermore, topical anesthetics were not used due to the irritation that frequent administration of topical anesthetics may cause to the cornea.

[0563] <Intraocular pressure measurement points> Before compound administration, approximately 1, 2, 4, 8, and 24 hours after administration (6 points on each administration day)

[0564] <Statistical analysis> For the intraocular pressure of the left eye (high intraocular pressure eye), the mean and standard error of the adopted value at each measurement time point, the mean and standard error of the rate of change from before each administration, and the mean and standard error of the amount of change from before each administration were calculated. [About eye drops] 1) In order to examine the effect of reducing intraocular pressure after administration at each time point, an analysis of covariance was performed for each post-administration time point, with the individual as the variable, the administration group as the fixed factor, and the intraocular pressure before administration as the covariate, and a comparative test was performed between the ophthalmic vehicle (administered by eye drop) group, the test substance (administered by eye drop) group, and the positive control substance group (multiplicity was not adjusted). 2) The rate and amount of change in intraocular pressure from before administration were determined by dividing the individual by the time point after administration. Analysis of variance was performed with the administration group and administration date as fixed factors, and a comparative test was performed between the ophthalmic vehicle (administered by eye drop) group, the test substance (administered by eye drop) group, and the positive control substance group. [Oral administration] 1) In order to examine the effect of reducing intraocular pressure after administration at each time point, a covariance analysis was performed for each post-administration time point, with the individual as the variable, the administration group as the fixed factor, and the intraocular pressure before administration as the covariate, and a comparative test was performed between the oral vehicle (oral administration) group and the test substance (oral administration) group. 2) Regarding the rate and amount of change in intraocular pressure from before each administration, an analysis of variance was performed with individuals as variables for each post-administration time point and the administration group and administration date as fixed factors, and a comparative test was performed between the oral vehicle (oral administration) group and the test substance (oral administration) group. These tests are supported by SAS System for Windows, Release 9.3 (SAS Institute Inc.) was used. The significance level of the test was set at 5% on both sides. [Industrial Applicability]

[0565] The compound of the present invention has an excellent autotaxin inhibitory effect and is useful as a preventive 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's lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovarian tumor, pancreatic tumor, prostatic 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, type II diabetes-related obesity, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, pruritus, etc.), eye diseases (e.g., glaucoma, etc.), and urinary diseases (e.g., benign prostatic hyperplasia, etc.). This application is based on patent application No. 2018-141254 filed in Japan, the contents of which are incorporated in full herein.

Claims

1. The following general formula (A5): 【Chemical 1】 {In the formula, R １ teeth, 【Chemistry 2】 [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, or C １ ~C ２ Perfluoroalkyl, C １ ~C ２ Perfluoroalkoxy or C １ ~C ６ represents alkyl, 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 represents a perfluoroalkyl group, X １ｂ and X １ｃ are the same or different and each represents —O— or —CH ２ - (However, X １ｂ and X １ｃ and do not simultaneously represent -O-), R １ｃ represents a hydrogen atom, a halogen atom, or C １ ~C ２ Perfluoroalkyl, C １ ~C ２ Perfluoroalkoxy, C １ ~C ６ Alkyl or C １ ~C ２ represents perfluoroalkylthio, R １ｄ is a hydrogen atom, a halogen atom or C １ ~C ６ represents an alkyl group, R １ｅ is a hydrogen atom, C １ ~C ２ Perfluoroalkyl or C １ ~C ２ represents perfluoroalkoxy], X represents -N= or -CH=; Ring A is 【Chemistry 3】 [In the formula, X ２ａ is -N= or -CR ２ａ = (in the formula, R ２ａ represents a hydrogen atom, a halogen atom, or C １ ~C ６ Alkyl or C １ ~C ６ alkoxy), R ２ｂ represents a hydrogen atom, a halogen atom, or C １ ~C ６ Alkyl or C １ ~C ６ represents an alkoxy group, L is -(CHR ３ａ ) ｎ - (wherein n is 0, 1, 2 or 3, and R ３ａ may be the same or different, and each represents a hydrogen atom or C １ ~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 ~C ３ Alkenylene, 【Chemistry 4】 (In the formula, R ３ｂ and R ３ｃ may be the same or different, and each represents a hydrogen atom or C １ ~C ６ represents alkyl, and R ３ｄ is a hydrogen atom, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl or C １ ~C ２ represents perfluoroalkyl, and R ３ｅ is a hydrogen atom, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl or C １ ~C ２ (represents perfluoroalkyl). or a pharmacologically acceptable salt thereof, The following general formula (A4): 【Chemistry 5】 (In the formula, R ４ is alkyl, and the other symbols are as defined above. in the presence of a base in a mixed aqueous solution; A manufacturing method comprising the steps of:

2. The following general formula (A2): 【Chemistry 6】 (In the formula, Q １ is a borate ester, and the other symbols are as defined in claim 1. The compound represented by the following general formula (A3): 【Chemistry 7】 (In the formula, X Ａ is a halogen atom, and other symbols are as defined in claim 1. with a compound represented by general formula (A4) in a solvent in the presence of a transition metal complex and a base, to obtain a compound represented by general formula (A4).

3. The following general formula (A1): 【Chemistry 8】 (In the formula, X Ｂ is a halogen atom, and other symbols are as defined in claim 1. with bis(pinacolato)diborane in a solvent in the presence of a transition metal complex and a base to obtain a compound represented by general formula (A2).

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