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

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 pharmaceutically acceptable salts thereof that have autotaxin inhibitory activity and are effective in preventing or treating autotaxin-related diseases in mammals, including humans. [Background technology]

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

[0003] LPA produced by ATX binds to G protein-coupled receptors (GPCRs) to transmit signals within cells, exhibiting various physiological effects. Six subtypes of LPA receptors are known, from LPA1 to LPA6. While LPA receptor subtypes are distributed throughout the body, their localization differs depending on the subtype, and each receptor subtype is involved in different biological functions depending on the tissue. 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 and are similar to the purinergic receptor family (Non-Patent Literature 1 and 2). Through these LPA receptors, LPA is involved in a wide range of physiological life phenomena (both in terms of maintaining homeostasis and pathological conditions).

[0004] On the other hand, in terms of its relationship with disease, it has been revealed that intracellular signaling pathways mediated by ATX and LPA receptors are involved in various cancers and inflammatory diseases. Specifically, it is associated with various cancers such as cancer, tumors, neoplasms, malignant melanoma, brain tumors, neuroblastoma, glioblastoma pleomorphic, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumors, breast tumors, ovarian tumors, pancreatic tumors, prostatic intraepithelial neoplasia, prostate tumors, thyroid tumors, follicular lymphoma, liver tumors, and renal cell carcinoma; various fibroses such as pulmonary fibrosis, scleroderma, hepatic fibrosis, renal fibrosis, diabetic nephropathy, or atherosclerosis; various inflammatory diseases such as asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, obesity associated with type II diabetes, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, and pruritus; eye diseases such as glaucoma; and urinary tract diseases such as benign prostatic hyperplasia (Non-patent Literature 2-13).

[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 the aforementioned diseases, it has been shown that LPA concentrations increase in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis, and that ATX concentrations increase in the lung tissue of bleomycin-induced pulmonary fibrosis models. Furthermore, in LPA1-deficient mice, bleomycin-induced The progression and mortality of pulmonary fibrosis have been shown to be significantly suppressed (Non-patent documents 14 and 15).

[0007] Regarding hepatic fibrosis, it has been shown that LPA promotes the contraction and proliferation of hepatic stellate cells, which play a central role in hepatic fibrosis, and suppresses apoptosis, and that serum autotaxin activity and plasma LPA levels are elevated in patients with chronic hepatitis C as hepatic fibrosis progresses (Non-patent documents 16-18).

[0008] Regarding renal fibrosis, it has been shown that LPA production and LPA1 expression are enhanced in a unilateral ureteral ligation model, LPA1-deficient mice are resistant to fibrosis, and LPA receptor antagonists suppress the progression of fibrosis (Non-Patent Literature 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 ATX inhibitors have been shown to suppress IL-6 production and CD3-positive cell infiltration in the skin, thereby suppressing skin hardening and hydroxyproline production (Non-patent Literature 20).

[0010] Regarding urinary voiding disorders in benign prostatic hyperplasia, a urinary tract disease, it has been shown that urethral constriction can be induced by applying LPA to the isolated rat urethra. Furthermore, it has been shown that urethral pressure can be reduced by administering ATX inhibitors to rats (Non-Patent Literature 21).

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

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

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

[0014] Regarding inflammatory diseases such as NASH and NAFLD, it has been shown that serum ATX concentrations are elevated in patients with cirrhosis, and that serum ATX concentrations are positively correlated with the Child-Pugh stage and MELD score (Non-Patent Literature 26). In addition, in a mouse STAM-NASH model combining streptozotocin (STZ) administration with a high-fat diet, ATX inhibitors showed improvement in the NAS score through anti-inflammatory effects and inhibition of ballooning hepatocyte hypertrophy. Furthermore, in a mouse NASH model using a choline-deficient high-fat diet (CDAHFD), it has been shown that ATX inhibitors suppress hepatic fibrosis (Non-Patent Literature 27).

[0015] Regarding rheumatoid arthritis, it has been shown that ATX concentrations are elevated in fibroblast-like synovial cells (SFCs) of rheumatoid arthritis patients (Non-Patent Literature 28). Furthermore, in a collagen-induced arthritis model, synovial ATX concentrations are elevated (Non-Patent Literature 5), and ATX inhibitors are effective. It has been shown to improve joint pathology scores (Non-Patent Document 29).

[0016] Regarding osteoarthritis, it has been shown that ATX concentrations are elevated in the synovial fluid of patients with osteoarthritis. Furthermore, a positive correlation has been shown between the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and synovial fluid ATX concentration (Non-Patent Literature 30). In addition, it has been shown that ATX inhibitors suppress pain in a monoiodacetate-induced osteoarthritis model (Non-Patent Literature 31).

[0017] Known ATX inhibitors include lipid analogs (Non-Patent Document 32), tetrahydrocarborine derivatives (Patent Document 1), 1H-indole compounds (Patent Document 2), piperidine or piperazine derivatives (Patent Document 3), pyridazine derivatives (Patent Document 4), and 2-aminopyridine and 2-aminopyrimidine derivatives (Patent Document 5). These have different structures from the 3,5-disubstituted pyridine and 3,5-disubstituted pyridazine derivatives, which are the compounds of the present invention. [Prior art documents] [Patent Documents]

[0018] [Patent Document 1] 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] [Non-licensed Document 1] Choiら,Annu Rev Pharmacol Toxicol.2010,50:157-186 [Non-licensed Document 2] Houbenら,Cancer Metastasis Rev.2011,30(3-4):557-565 [Non-licensed Document 3] Benesch, FEBS Lett.2014;588:2712-2727 [Non-licensed Document 4] Inoueら, Mol Pain. 2008;4:6 [Non-licensed Document 5] Nikitopoulouら,J Exp Med.2012;209(5):925-933 [Non-licensed Document 6] Siess, Proc Natl Acad Sci USA.1999;96(12):6931-6936 [Non-licensed Document 7] Zhouら,Cell Metab.2011;13(5):592-600 [Non-licensed Document 8] Imら,Clinical Lipidology 2015;10(2):177-190 [Non-licensed Document 9] Valdes-Rivesら,Mediators Inflamm. 2017;2017:9173090 [Non-licensed Document 10] D´Souzaら, Nutrients. 2018;10(4):E399 [Non-licensed Document 11] Kremer,Hepatology 2012;56(4):1391-1400 [Non-licensed Document 12] Hegadeら,Frontline Gastroenterol. 2016;7(3):158-166

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

Non-licensed Document 22

Non-licensed Document 23

Non-licensed Document 24

[0020] The present invention aims to provide a compound that exhibits excellent ATX inhibitory activity and is useful for the prevention or treatment of diseases involving ATX. [Means for solving the problem]

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

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

[24] , but is not limited thereto. [1] A carboxylic acid compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof (hereinafter sometimes abbreviated as "Compound (1)").

[0023] [Chemical formula]

[0024] [In the formula, R 1 is

[0025] [Chemical formula]

[0026] [In the formula, X 1a is -C(R 1a )2- (wherein R 1a may be the same or different and each represents a hydrogen atom, a halogen atom, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or C1-C6 alkyl, or R 1a is bonded to form 1,1-C3-C6 cycloalkylene) or -NR 1b - (wherein R 1b represents a hydrogen atom or 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 do not simultaneously represent -O-), R 1c represents a hydrogen atom, a halogen atom, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, C1-C6 alkyl or C1-C2 perfluoroalkylthio, R 1d represents a hydrogen atom, a halogen atom or C1-C6 alkyl, R1e [This indicates a hydrogen atom, a C1-C2 perfluoroalkyl group, or a C1-C2 perfluoroalkoxy group] X indicates -N= or -CH=, Ring A is,

[0027] [ka]

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

[0029] [ka]

[0030] (In the formula, R 3b and R 3c These may be the same or different, and each represents a hydrogen atom or a C1-C6 alkyl group, R 3d R represents a hydrogen atom, a C1-C6 alkoxy, a C1-C6 alkyl, or a C1-C2 perfluoroalkyl, 3e (This 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 -C(R 1aa )2-(wherein, R 1aa These represent, either identically or differently, a hydrogen atom, a C1-C2 perfluoroalkyl group, or a C1-C6 alkyl group, or R 1aa (These combine to form 1,1-C3~C6 cycloalkylenes) or -NR 1ba -(In the formula, R 1ba (represents a hydrogen atom or a C1-C2 perfluoroalkyl group), R 1ca R represents C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, or C1-C2 perfluoroalkylthio. 1da The carboxylic acid compound described in [1] above (where is a halogen atom or a C1-C6 alkyl group) or a pharmaceutically acceptable salt thereof.

[0034] [3] Ring A is

[0035] [ka]

[0036] (In the formula, R 2abR represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, 2bb R represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, 2cb A carboxylic acid compound according to either [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein (represents a hydrogen atom or a C1-C6 alkyl group).

[0037] [4] Ring A is

[0038] [ka]

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

[0040] [5] Ring A is

[0041] [ka]

[0042] (In the formula, R 2ad R represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, 2bd R represents a hydrogen atom, a C1-C6 alkoxy, or a C1-C6 alkyl, 2cd A carboxylic acid compound according to any one of the above [1] to [4], wherein (i) represents a hydrogen atom or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

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

[0044] [ka]

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

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

[0047] [8] The carboxylic acid compound described in [1] above, or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (1) is any of the following: trans-2-[2-methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]o Xy}pyridazine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-4-yl)pyridine-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridine-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5'-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3'-bipyridine-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)piperidine-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-methyl-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-chloro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S,6R)-6-methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]cyclopropanecarboxylic acid, or (1S,2S)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid.

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

[0049]

[10] The pharmaceutical composition described in [9] above, used as an autotaxin inhibitor.

[0050]

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

[0051]

[12] The pharmaceutical composition according to

[11] , wherein the disease in which the 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] , wherein the cancer or tumor is malignant melanoma, brain tumor, neuroblastoma, glioblastoma pleomorphic, EBV-positive Hodgkin 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] , wherein the fibrotic disease is pulmonary fibrosis, scleroderma, hepatic fibrosis, renal fibrosis, diabetic nephropathy, or atherosclerosis.

[0054]

[15] The pharmaceutical composition according to

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

[0055]

[16] The pharmaceutical composition according to

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

[0056]

[17] The pharmaceutical composition according to

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

[0057]

[18] The pharmaceutical composition according to

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

[0058]

[19] The pharmaceutical composition according to

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

[0059]

[20] The pharmaceutical composition according to

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

[0060]

[21] The pharmaceutical composition according to

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

[0061]

[22] The pharmaceutical composition according to

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

[0062]

[23] The pharmaceutical composition according to

[12] , wherein the eye disease is glaucoma.

[0063]

[24] The pharmaceutical composition according to

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

[25] A method for treating or preventing an autotaxin-related disease in a subject, characterized by administering an effective amount of a carboxylic acid compound or a pharmacoposly acceptable salt thereof described in any of [1] to [8] above to the subject.

[26] The method according to

[25] , wherein the disease involving autotaxin is cancer or tumor, fibrotic disease, inflammatory disease, eye disease, urinary tract disease, obesity associated with type 2 diabetes, or acute coronary syndrome.

[27] Use of any of the carboxylic acid compounds described in [1] to [8] above or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prophylaxis of a disease in which autotaxin is involved.

[28] 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 provides compounds that exhibit excellent ATX inhibitory activity and are effective as preventive or therapeutic agents for diseases involving ATX, such as cancer, tumors, fibrotic diseases, inflammatory diseases, eye diseases, urinary tract diseases, obesity associated with type II diabetes, or acute coronary syndrome. [Brief explanation of the drawing]

[0065] [Figure 1] This graph shows the amount of SP-D in Plasma as a result of Experiment Example 3. [Figure 2] This graph shows the amount of Col1a1 mRNA in lung tissue as a result of Experiment Example 3. [Figure 3] This graph shows the amount of CTGFmRNA in lung tissue as a result of Experiment Example 3. [Figure 4] This graph shows the amount of IL-6 mRNA in lung tissue as a result of Experiment Example 3. [Figure 5] This graph shows the ATX activity in Plasma as a result of Experiment Example 3. [Figure 6] This graph shows the amount of LPA (18:2) in BALF as a result of Experiment Example 3. [Figure 7] This graph shows the effect of oral administration of an ATX inhibitor on intraocular pressure in cynomolgus monkeys, as a result of Experiment Example 4. [Figure 8] This graph shows the effect of eye drop administration of an ATX inhibitor on intraocular pressure in cynomolgus monkeys, as a result of Experiment Example 4. [Modes for carrying out the invention]

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

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

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

[0069] R 1a 、R 1c 、R 1d 、R 2a 、R 2b and R 1da refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Particularly preferred are groups having 1 to 4 (C1-C4) carbon atoms. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. can be mentioned. Particularly, methyl, ethyl, isopropyl or tert-butyl is preferred.

[0070] R 1a 、R 1b 、R 1c 、R 1e 、R2d and R 3d and R 3e and R 1aa and R 1ba and R 1ca The C1-C2 perfluoroalkyl in R

[0071] R 1a and R 1c and R 1e and R 1ca The C1-C2 perfluoroalkoxy in R

[0072] R 1a and R 1aa The 1,1-C3-C6 cycloalkylene in R

[0073] R 1c and R 1ca The C1-C2 perfluoroalkylthio in R

[0074] R ?<000?0106>and R2b , R 3d , R 3e , R 2ab , R 2bb , R 2ac , R 2bc , R 2ad and R 2bd In this context, C1-C6 alkoxys are R 1a The C1-C6 alkyl group shown in the diagram is a monovalent group bonded to oxygen, and examples include linear or branched alkyl-O- groups with 1-6 carbon atoms (C1-C6). C1-C4 alkyl-O- groups are particularly preferred, and C1-C2 alkyl-O- groups are especially preferred. Specifically, examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy. Methoxy or ethoxy are particularly preferred.

[0075] In L, C2-C3 alkenylene refers to a linear hydrocarbon divalent group having 2-3 carbon atoms (C2-C3) and at least one double bond. Specifically, vinylene or propenylene are examples.

[0076] Diseases involving autotaxins include, for example, cancer or tumors, fibrotic diseases, inflammatory diseases, eye diseases, urinary tract diseases, obesity associated with type 2 diabetes, or acute coronary syndrome. Tumors include malignant melanoma, brain tumors, neuroblastoma, glioblastoma pleomorphism, EBV-positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumors, breast tumors, ovarian tumors, pancreatic tumors, prostatic intraepithelial neoplasia, prostate tumors, thyroid tumors, follicular lymphoma, liver tumors, and renal cell carcinoma. Fibrotic diseases include pulmonary fibrosis, scleroderma, hepatic fibrosis, renal fibrosis, diabetic nephropathy, and atherosclerosis. Inflammatory diseases include asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, and pruritus. Eye diseases include glaucoma, and urinary tract diseases include benign prostatic hyperplasia, but these are not limited to these. Preferably, the diseases involving autotaxin are selected from the group consisting of fibrotic diseases such as pulmonary fibrosis, scleroderma, hepatic fibrosis, and renal fibrosis; inflammatory diseases such as asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, neuropathic pain or pruritus; and eye diseases such as glaucoma. More preferably, the diseases involving autotaxin are selected from the group consisting of fibrotic diseases such as pulmonary fibrosis, scleroderma, hepatic fibrosis, and renal fibrosis.

[0077] R shown in general formula (1) 1 Preferably, it is one of the groups represented by the following general formulas.

[0078] [ka]

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

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

[0081] [Chemical formula]

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

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

[0084] [Chemical formula]

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

[0086]

[0086] [Chemical formula]

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

[0088] It is any of the groups represented by the following general formulas, which is more preferable.

[0089] [ka]

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

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

[0092] [ka]

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

[0094] [ka]

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

[0096] [Chemical formula]

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

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

[0099] L shown in the general formula (1) is preferably -(CH2) n -(where n represents 1 or 2) or

[0100] [Chemical formula]

[0101] (In the formula, R 3ab and R 3bb may be the same or different and each represents a hydrogen atom or C1-C6 alkyl) ​​​​​​​​​​​​​​​​​​​​​​​​​1 but,

[0105] [ka]

[0106] [In the formula, X 1a -C(R 1a )2-(wherein, R 1a These may be the same or different, and each may be a hydrogen atom, a halogen atom (e.g., a fluorine atom), a C1-C2 perfluoroalkyl group (e.g., trifluoromethyl), or a C1-C6 alkyl group (e.g., methyl), or R 1a (These combine to form 1,1-C3~C6 cycloalkylenes (e.g., 1,1-cyclopropylene, 1,1-cyclobutylene) or -NR 1b -(In the formula, R 1b (These are C1-C2 perfluoroalkyl compounds (e.g., trifluoroethyl), X 1b and X 1c These are identical or different, and are -O- or -CH2- respectively (however, X 1b and X 1c (There is no case where both simultaneously indicate -O-), R 1c These are hydrogen atoms, halogen atoms (e.g., fluorine atoms, chlorine atoms), C1-C2 perfluoroalkyls (e.g., trifluoromethyl), C1-C2 perfluoroalkoxys (e.g., trifluoromethoxy), or C1-C2 perfluoroalkylthios (e.g., trifluoromethylthio). R 1d These are hydrogen atoms, halogen atoms (e.g., fluorine atoms, chlorine atoms), or C1-C6 alkyl groups (e.g., methyl). R 1e [These are C1-C2 perfluoroalkoxys (e.g., trifluoromethoxy); X is either -N= or -CH=; Ring A is

[0107] [ka]

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

[0109] [ka]

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

[0111] Specific examples of compound (1) include, for example, the compounds of Examples 1 to 101 described later, preferably, trans-2-[2-methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, trans-2-[3-methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-4-yl)pyridine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, trans-2-(5-methoxy-5'-{2-[4-(trifluoromethoxy)phenyl]ethyl}-2,3'-bipyridine-6-yl)cyclopropanecarboxylic acid, trans-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, trans-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-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'-bipyridine-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)piperidine-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 1-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)-2,3-dihydro-1H-indole-5-carboxylic acid, 1-(5-{[1-(2,2,2-trifluoroethyl)piperidine-4-yl]methoxy}pyridine-3-yl)-2,3-dihydro-1H-indole-5-carboxylic acid, 4-[4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]benzoic acid, 3-[4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]benzoic acid, 2-Methoxy-4-[4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]benzoic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[4-(trifluoromethyl)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-methyl-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-chloro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S,6R)-6-methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[1-(2,2,2-trifluoroethyl)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)piperazine-2-yl]propanoic acid, [1-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)piperidine-3-yl]acetic acid, 4-[1-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)pyrrolidine-2-yl]butanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclo Ropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]cyclopropanecarboxylic acid, or, (1S,2S)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid And, moreover, trans-2-[2-methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-4-yl)pyridine-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridine-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5'-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3'-bipyridine-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)piperidine-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid, 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[2-methyl-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S)-4-(5-{[3-chloro-4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, 3-[(2S,6R)-6-methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-2-yl]propanoic acid, (1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, (1R,2R)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid, or (1S,2S)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid And more preferably, trans-2-[2-methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)phenyl]cyclopropanecarboxylic acid, trans-2-[2-methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazine-4-yl)pyridine-2-yl]cyclopropanecarboxylic acid, (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazine-4-yl)pyridin-2-yl]cyclo Lopropanecarboxylic acid, (1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-2'-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4'-bipyridine-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'-bipyridine-6-yl)cyclopropanecarboxylic acid, (1R,2R)-2-(5'-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3'-bipyridine-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 It is (1S,2S)-2-[2-ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidine-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 it to an individual who has not yet developed a disease, disorder, or symptoms. Treatment refers to the act of administering the compound of the present invention or a pharmaceutical composition containing it to an individual who has already developed a disease, disorder, or symptoms. Therefore, administering the compound to an individual who has already developed a disease, disorder, or symptoms to prevent the worsening of symptoms, prevent seizures, or prevent recurrence is a form of treatment.

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

[0114] Examples of formulations suitable for oral administration include tablets, capsules, powders, granules, liquids, or syrups. Examples of formulations suitable for parenteral administration include injections, intravenous infusions, or suppositories. For formulations suitable for oral administration, excipients, disintegrants, binders, lubricants, coatings, or bases may be used as additives. Furthermore, when administering the compound of the present invention to a patient who is the target of treatment, the compound of the present invention may be used in combination with other appropriate agents for the treatment of the target disease.

[0115] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intravenous drip infusion, or local administration (such as percutaneous administration, ophthalmic administration, transpulmonary / bronchial administration, transnasal administration, or transrectal administration).

[0116] The compound of the present invention may, in some cases, be used in combination with other pharmaceuticals. The timing of administration of the compound of the present invention, its pharmaceutically acceptable salt, or their solvates, and the concomitant drug is not limited; they may be administered simultaneously to the target patient or with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two separate formulations containing their respective active ingredients, or as a single formulation containing both active ingredients.

[0117] The dosage of the compound of the present invention is determined by considering age, weight, general health status, sex, administration time, administration method, excretion rate, and the severity of the patient's current medical condition, as well as other factors. The daily dosage of the compound of the present invention varies depending on the patient's condition, weight, type of compound, and route of administration, but for example, parenterally it is administered subcutaneously, intravenously, intramuscularly, percutaneously, transocularly, transpulmonaryly / bronchally, transnasally, or rectally at a dose of approximately 0.0001 to 500 mg / person / day, and orally at a dose of approximately 0.001 to 5000 mg / person / day.

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

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

[0120] [ka]

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

[0122] Examples of transition metal complexes include tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), and bis(dibenzylideneacetone). 0-valent palladium complexes such as ceton)palladium(0), bis(tri-tert-butylphosphine)palladium(0), and bis(tricyclohexylphosphine)palladium(0), and divalent palladium complexes such as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) are used.

[0123] Furthermore, appropriate ligands 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-(diph Examples include [(ferrocerylphosphino)ferroceryl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl.

[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 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 base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (A1). In particular, it can be suitably produced by a method using reaction conditions as described in J. Org. Chem., 1995, 60, 7508-7510.

[0125] [Step 1b] Compound (A4) can be produced by reacting compound (A2) and compound (A3) in a solvent in the presence of a transition metal complex and a base. Suitable solvents include, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, 2-propanol, tert-butyl alcohol, water, or a mixed solvent. Examples of transition metal complexes include 0-valent palladium complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-O-tolylphosphine)palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and bis(di-ter A divalent palladium complex such as t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) is used.

[0126] Furthermore, appropriate ligands 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-(diph Examples include [(ferrocerylphosphino)ferroceryl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl.

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

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

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

[0130]

Chemical formula

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

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

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

[0134]

Chemical formula

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

[0136] [Step 3b] Compound (C4) can be produced by reacting compound (C2) and compound (C3) in a solvent in the presence of Mitsunobu's reagent and phosphine reagent. Examples of Mitsunobu's reagents 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-tetrazosin-2,5-dione, N,N,N',N'-tetramethyl azodicarboxamide, 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 Tsunoda reagents such as cyanomethylenetributylphosphoran and cyanomethylenetrimethylphosphoran, this reaction proceeds suitably 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 suitably at -40°C to 100°C, preferably 0°C to 70°C.

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

[0138] Manufacturing 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, X A and X B Q is a halogen atom, 1 (This is a borate ester, and the other symbols are as described above.) [Step 4a] Compound (D2) can be produced by reacting compound (D1) and compound (B1) using the same method as in [Step 1b].

[0141] [Step 4b] Compound (D3) can be prepared 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 solvents include alcoholic 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 palladium complexes with a valency of 0, 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), as well as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tril Divalent palladium complexes such as phosphine)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) are used.

[0142] Furthermore, appropriate ligands 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-(diph Examples include [(ferrocerylphosphino)ferroceryl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl. 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 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 base used can be 1 to 10 equivalents, preferably 2 to 7 equivalents, relative to compound (D2). In particular, it can be suitably produced by a method using reaction conditions as described in Organometallics, 2008, 27, 5402-5422.

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

[0144] [Process 4d] Compound (D6) can be produced by reacting compound (D4) and compound (D5) in a solvent, in the presence of a base, in the presence or absence of a phase transfer catalyst. Examples of solvents 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 bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and sodium Examples include tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, and butyllithium. Examples of phase transfer catalysts include quaternary ammonium halides or crown ethers. This reaction proceeds suitably at 0°C to 200°C, preferably at room temperature to 100°C.

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

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

[0147] [ka]

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

[0149] [Step 5a] Compound (E2) can be produced by reacting compound (E1) and 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, and under a hydrogen atmosphere. Any solvent that does not interfere with this reaction can be used, such as methanol, ethanol, ethyl acetate, and tetrahydrofuran. Palladium-carbon (Pd / C) and palladium-carbon hydroxide (Pd(OH)2 / C) can be used as transition metal catalysts. This reaction proceeds suitably at 0°C to 100°C, preferably at room temperature.

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

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

[0153] [ka]

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

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

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

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

[0158] [ka]

[0159] (In the formula, R 4 is alkyl, X B (This represents a halogen atom, and the other symbols are as described above.) [Step 7a] Compound (G2) can be prepared by reacting compounds (G1) and (A1) in a suitable solvent in the presence of a transition metal complex and a base. Suitable solvents include, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N -Methylpyrrolidone and other substances can be used as appropriate. Examples of transition metal complexes include 0-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), as well as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tolyl Divalent palladium complexes such as phosphine)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) are used.Furthermore, appropriate ligands 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-(diph Examples include [(ferrocerylphosphino)ferroceryl]ethyldicyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl.

[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]deca-5-ene. The amount of 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 base used can be 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 a suitable ligand, as 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] Manufacturing method 8 (when A is a heterocyclic group such as morpholinyl, pyrrolidinyl, or indolinyl)

[0163] [ka]

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

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

[0166] Manufacturing method 9 (when A is a heterocyclic group such as piperidinyl, piperazinyl, or morpholinyl)

[0167] [ka]

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

[0169] [Step 9b] Compound (I3) can be prepared by reacting compound (I2) in a suitable solvent in the presence of 2 equivalents of a base. Alcoholic solvents such as methanol and ethanol can be used as the solvent. This reaction can be carried out. Lithium hydroxide, potassium hydroxide, sodium hydroxide, etc., can be used as the base. The 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] Manufacturing method 10 (when A is a heterocyclic group such as piperidinyl, piperazinyl, or morpholinyl)

[0172] [ka]

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

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

[0175] [Step 10c] Compound (J4) is the PG of compound (J3). 1 It can be manufactured by removing it using conventional methods.

[0176] [Step 10d] Compound (J5) is obtained by using the same method as in [Step 3b] with Compound (J4) and Compound (C3). It can be manufactured by reacting with it.

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

[0178] Manufacturing method 11 (when A is a heterocyclic group such as piperidinyl, piperazinyl, or morpholinyl)

[0179] [ka]

[0180] (In the formula, R 4 is alkyl, R 5 (The symbols are alkyl or aryl, and the other symbols are as described above.) [Step 11a] Compound (K3) can be produced by reacting compound (K1) and compound (K2) in a solvent in the presence of a base. Examples of 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 suitably at -40°C to 100°C, preferably 0°C to room temperature.

[0181] [Step 11b] Compound (K4) can be produced by reacting compound (K3) and compound (J4) in a solvent, in the presence of a base, and in the presence or absence of a phase transfer catalyst. Examples of solvents 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 bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and sodium Examples include 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 halides or crown ethers. This reaction proceeds suitably at -40°C to 120°C, preferably 0°C to room temperature.

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

[0183] Manufacturing method 12 (when A is a heterocyclic group such as piperidinyl, piperazinyl, or morpholinyl)

[0184] [ka]

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

[0186] [Step 12b] Compound (L3) can be produced by reacting compound (L2) in a suitable solvent in the presence of a base, followed by heating in the presence of an acid. Suitable solvents include alcoholic solvents such as methanol and ethanol. Suitable bases include lithium hydroxide, potassium hydroxide, and sodium hydroxide. Suitable acids include acetic acid, hydrochloric acid, and sulfuric acid. This reaction proceeds preferably by proceeding at 0°C to room temperature in the presence of a base, followed by raising the temperature to 100°C in the presence of an acid.

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

[0188] [ka]

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

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

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

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

[0193] [ka]

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

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

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

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

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

[0199] [ka]

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

[0201] [Step 15b] Compound (O3) is the PG of compound (O2) 1 It can be manufactured by removing it using conventional methods.

[0202] [Step 15c] Compound (O5) can be produced by reacting compound (O3) and compound (O4) in a solvent, in the presence of a base, and in 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 halides or crown ethers. This reaction proceeds suitably at -40°C to 120°C, preferably 0°C to room temperature.

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

[0204] Manufacturing 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, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 16a] Compound (P2) can be produced by reacting compound (P1) and compound (A1) using the same method as in [Step 7a].

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

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

[0209] Manufacturing 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, X B It is a halogen atom, PG 1 (This symbol represents a protecting group for hydroxyl groups, and the other symbols are as described above.) [Step 17a] Compound (Q2) can be produced by reacting compound (Q1) and compound (A1) using the same method as in [Step 7a].

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

[0213] [Step 17d] Compound (Q6) can be prepared by reacting compound (Q4) 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, and sodium bis(trimethylsilyl)amide. Examples include potassium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. This reaction proceeds preferably between -20°C and 100°C, and especially between 0°C and 60°C.

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

[0215] Manufacturing 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, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 18a] Compound (R2) can be produced by reacting compound (R1) and Wittig-Horner reagent (Q5) using the same method as in [step 17d].

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

[0219] Manufacturing 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, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 19a] Compound (S3) can be produced by reacting compound (S1) and compound (S2) in a solvent in the presence of a base. An ether-based solvent such as tetrahydrofuran can be used as the solvent. As the base, an alkyl metal such as butyllithium or isopropylmagnesium chloride can be used. This reaction proceeds suitably at -78°C to 100°C, preferably 0°C to room temperature.

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

[0223] [Step 19c] Compound (S5) can be produced by reacting compound (S4) in a solvent, in the presence of a base, and in the presence or absence of 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 halides or crown ethers. This reaction proceeds suitably at -40°C to 120°C, preferably 0°C to room temperature.

[0224] [Step 19d] Compound (R4) can be prepared 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 suitably at 0°C to 120°C, preferably at room temperature to 60°C.

[0225] Manufacturing 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, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 20a] Compound (T2) can be prepared by the Corey-Chaykovsky reaction between compound (T1) and compound (R3). It can be preferably prepared using the reaction conditions described in J.Am.Chem.Soc.,1965,87,1353-1364.

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

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

[0230] [ka]

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

[0232] [Step 21b] Compound (T4) can be produced by reacting compound (T2) and compound (T3) in a solvent in the presence of a base. Examples of solvents include toluene, benzene, and xylamine. Examples of bases include lene, 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, and potassium Examples include tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide. In addition, sodium iodide, potassium iodide, cesium iodide, etc. may be added to accelerate the reaction. This reaction proceeds suitably at 0°C to 120°C, preferably at room temperature to 100°C.

[0233] [Step 21c] Compound (T5) is the PG of compound (T4). 2 It can be manufactured by removing it using conventional methods.

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

[0235] [ka]

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

[0237] [Step 22b] Compound (U3) is formed by using a conventional method to remove the hydroxyl group of compound (U2) from PG. 1 It can be manufactured by protecting it with [a certain method].

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

[0239] [Step 22d] Compound (U5) is the PG of compound (U4). 1 It can be manufactured by removing it using conventional methods.

[0240] [Step 22e] Compound (U6) can be produced by conventional methods of oxidizing the primary alcohol of compound (U5) to a carboxylic acid. In particular, it can be preferably produced under oxidation reaction conditions using 2,2,6,6-tetramethyl-1-piperidinyloxy free radicals, 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 conventional methods for converting carboxylic acids to esters, 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 the PG of compound (U7). 2 It can be manufactured by removing it using conventional methods.

[0243] Manufacturing 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, X A It is a halogen atom, PG 2 (This is a protecting group for the amino group, and the other symbols are as described above.) [Step 23a] Compound (V2) can be produced by reacting compound (V1) with a vinylboronic acid ester using the same method as in [Step 1b].

[0246] [Step 23b] Compound (V3) can be produced by reacting compound (V2) with a halogenating reagent in a solvent, followed by treatment with a base. Suitable solvents include aqueous solutions of tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, and tert-butyl alcohol. Examples of halogenating reagents include N-iodosuccinimide and N-bromosuccinimide. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, tripotassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. 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) and compound (V4) in a solvent, in or without 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 suitably at 0°C to 180°C, preferably room temperature to 100°C.

[0248] [Step 23d] Compound (V6) can be prepared by reacting compound (V5) in a solvent in the presence of Mitsunobu's reagent and a phosphine reagent. Examples of Mitsunobu's reagents 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-tetrazosin-2,5-dione, N,N,N',N'-tetramethyl azodicarboxamide, 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 Tsunoda reagents such as cyanomethylenetributylphosphoran and cyanomethylenetrimethylphosphoran, this reaction proceeds suitably 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 suitably at -40°C to 100°C, preferably 0°C to 70°C.

[0249] [Step 23e] Compound (V7) is the PG of compound (V6). 2 It can be manufactured by removing it using conventional methods.

[0250] Manufacturing method 24 (when A is a heterocyclic group such as morpholinyl)

[0251] [ka]

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

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

[0254] [Step 24c] Compound (W4) is the PG of compound (W3). 2 It can be manufactured by removing it using conventional methods.

[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] The other symbols are as described above. [Step 25a] Compound (X3) can be produced by reacting compound (X1) and compound (X2) in a solvent, in the presence of a base, and in 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 and butyllithium. Examples of phase transfer catalysts include quaternary ammonium halides or 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] The other symbols are as described above. [Step 26a] Compound (Y1) is prepared by using the same method as in [Step 3b] with Compound (X1) and Compound (C1). It can be manufactured by reacting with it.

[0265] Manufacturing method 27

[0266] [ka]

[0267] (In the formula, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 27a] Compound (E1) can be produced by reacting compound (Z1) and compound (D1) in a solvent, in or without a catalytic amount of copper iodide, in the presence of a transition metal complex and a base. Suitable solvents include, for example, toluene, benzene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Suitable transition metal complexes include, for example, 0-valent palladium complexes such as tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), bis(dibenzylideneacetone)palladium(O), bis(tri-tert-butylphosphine)palladium(O), and bis(tricyclohexylphosphine)palladium(O), as well as palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-O-tolyl Divalent palladium complexes such as phosphine)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) are used.

[0268] Furthermore, appropriate ligands 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-(diph Examples of bases include [(ferroceryl)(ferroceryl)ethyldicyclohexylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl, and 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl. Examples of bases include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and triethylamine. Examples include diisopropylethylamine and diisopropylamine. The amount of 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 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 as described in J. Organomet. Chem., 2002, 653, 46-49.

[0269] Manufacturing method 28

[0270] [ka]

[0271] (In the formula, X A and X B (This represents a halogen atom, and the other symbols are as described above.) [Step 28a] Compound (F1) can be produced by reacting compound (AA1) and compound (AA2) in a solvent in the presence of a base. Suitable solvents include ether-based solvents such as tetrahydrofuran and amide-based solvents such as N,N-dimethylformamide. Examples of bases include sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and butyllithium. This reaction proceeds suitably at -78°C to 60°C, preferably -10°C to room temperature.

[0272] Manufacturing method 29

[0273] [ka]

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

[0275] The compound obtained in this way can be separated by known separation methods, such as concentration, vacuum concentration, and dissolution. The compound can be isolated and purified by extraction, crystallization, recrystallization, chromatography, etc. If the compound of the present invention is obtained as a free form, it can be converted to the target salt by a method known or equivalent, and conversely, if it is obtained as a salt, it can be converted to a free form or another target salt by a method known or equivalent.

[0276] Since the compounds of the present invention have basic and acidic groups within their molecules, examples of pharmacoposly acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, and salts with acidic amino acids.

[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, and N,N'-dibenzylethylenediamine. 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, and the like. 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 not only the above compound (1) and its pharmaceutically acceptable salts, but also their hydrates and solvates.

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

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

[0281] The compounds of the present invention may be crystalline, and the compounds of the present invention are encompassed whether they are a single crystalline form or a mixture of crystalline forms. Crystals can be produced by crystallization using known crystallization methods. Furthermore, the compounds of the present invention may be pharmaceutically acceptable cocrystals or cocrystalline salts. Here, cocrystals or cocrystalline salts are two or more unique cocrystals or cocrystalline salts, each possessing different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, stability) at room temperature. This refers to crystalline materials composed of solids. Cocrystals or cocrystal salts can be produced according to known cocrystallization methods.

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

[0283] The present invention will be described in detail below with reference to examples and experimental examples, but the present invention is not limited thereto. 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] 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 were dissolved in 1,4-dioxane (10 mL). To this solution, potassium carbonate (188 mg, 1.36 mmol) was dissolved in water (1.0 mL), tris(dibenzylideneacetone)dipalladium (0) (62 mg, 68 μmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (129 mg, 271 μmol) were added, and the mixture was heated under reflux in a nitrogen atmosphere and stirred overnight. After the reaction mixture cooled to room temperature, it was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 3 (207 mg, 60.2%) was obtained by purifying the residue by NH silica gel chromatography and silica gel chromatography. MS(ESI)m / z:507(M+1) + .

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

[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 the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4a (54.3 mg, 74.1%). This enantiomer is designated as Example 1-1. MS(ESI)m / z:451(M+1) + .

[0289] [Step d] To a solution of compound 3b (81.1 mg, 160 μmol) in dichloromethane (2.0 mL), trifluoroacetic acid (245 μL) was added and the mixture was stirred at room temperature for 4 hours. Further trifluoroacetic acid (122 μL) was added to the reaction solution and the mixture was stirred at room temperature for another 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 designated as Example 1-2. MS(ESI)m / z:451(M+1) + .

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

[0291] [ka]

[0292] [Step a] To a solution of compound 1 (2.37 g, 6.33 mmol) and compound 2 (1.00 g, 5.75 mmol) obtained in step c of Reference Example 1 in 1,4-dioxane (20 mL), 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 the mixture was heated at 80°C under a nitrogen atmosphere and stirred overnight. 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. Compound 3 (894 mg, 45.6%) was obtained by purifying the residue by silica gel chromatography. 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 the mixture was 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 obtain 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 the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. , residue cation exchange resin column (Waters, PoraPak TM After solid-phase extraction and purification using 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) and compound 2 (500 mg, 3.36 mmol) obtained in step c of Reference Example 1, 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 heating at 70°C in a nitrogen atmosphere. After the reaction mixture cooled to room temperature, it was filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (398 mg, 32.9%). MS(ESI) m / z: 361, 363 (M+1) + .

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

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

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

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

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

[0303] [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, and 1,4-dioxane ( To a 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 heated under reflux in a nitrogen atmosphere and stirred overnight. After the reaction mixture cooled to room temperature, compound 3 (52.2 mg, 38.2%) was obtained by purification by NH silica gel chromatography. MS(ESI)m / z:511(M+1) + . [Step b] Compound 3 (50 mg, 98 μmol) was dissolved in methanol (3.0 mL), to which 10% palladium / carbon (10 mg) was added and stirred overnight at room temperature under 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), 10% palladium / carbon (10 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was diluted with chloroform and filtered through Celite. Compound 4 (44 mg, 88%) was obtained by concentrating the filtrate under reduced pressure. 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 the mixture was stirred at room temperature for 3 days. The reaction solution was purified by silica gel chromatography to obtain compound 5 (36 mg). MS(ESI) m / z: 459 (M+1) + .

[0306] Example 5 (1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridine-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(pinacolate)diborane (2.49 g, 9.82 mmol) in 1,4-dioxane (61 mL), potassium acetate (1.81 g, 18.4 mmol) and tris(dibenzylidene) were added. Acetone) dipalladium(0) (337 mg, 368 μmol), 2-dicyclohexyl Phosphino-2',4',6'-triisopropylbiphenyl (351 mg, 736 μm The mixture was heated at 100°C under a nitrogen atmosphere and stirred for 3 hours. The reaction mixture was cooled with ice, the resulting solid was diluted with water, filtered, and washed with water. The obtained solid was washed with hexane to obtain compound 2 (1.78 g, 75.2%). MS(APCI)m / z:387(M+1) + .

[0309] [Step b] Compound 3 (384 mg, 1.50 mmol) obtained in step d of Reference Example 2 and Compound 2 (645 mg, 1.67 mmol) are dissolved in tetrahydrofuran (15 mL), and tripotassium phosphate (1.95 g, 9.19 mmol) is dissolved in water (3.0 mL), and X-Phos A Minobiphenyl palladium chloride pre-catalyst (66 mg, 84 μmol) was added and the mixture was stirred for 4 hours under heating at 80°C in a nitrogen atmosphere. X-Phos aminobiphenyl palladium chloride pre-catalyst (65.7 mg, 83.5 μmol) was then added to the reaction mixture and stirred under a nitrogen atmosphere. The mixture was stirred at 80°C for 2.5 hours. After the reaction mixture cooled 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. Compound 4 (380 mg, 38.0%) was obtained by NH silica gel chromatography of the residue. 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 sodium hydroxide aqueous solution (0.50 mL, 2.0 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (4 mL) and 1M sodium hydroxide solution was added. The mixture was neutralized with hydrochloric acid (2 mL), the resulting solid was filtered, 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'-bipyridine-6-yl)cyclopropanecarboxylic acid

[0312] [ka]

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

[0314] [Step b] In a 1,4-dioxane (5.4 mL) solution of compound 3 (196 mg, 767 μmol) and compound 2 (300 mg, 767 μmol) obtained in step d of Reference Example 2, triphosphate of phosphoric acid was added. A solution of 488 mg, 2.30 mmol of chloropalladium (488 mg, 2.30 mmol) in 0.60 mL of water and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (27 mg, 37 μmol) were added, and the mixture was heated at 100°C under a nitrogen atmosphere and stirred for 4 hours. After the reaction mixture cooled 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 using a 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 RxnCX. MS(ESI)m / z:485(M+1) + 485 (M+1) + .

[0315] [Process c] Compound 4 (120 mg, 248 μmol) was dissolved in methanol (2.4 mL), to which 10% palladium / carbon (24 mg) was added and the mixture was 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 obtain compound 6 (87.5 mg, 72.6%). MS(APCI) m / z: 487(M+1) + .

[0316] [Step d] Compound 6 (85.0 mg, 175 μmol) was mixed with tetrahydrofuran (1.7 mL) and methanol (1.7 mL). 4M sodium hydroxide aqueous solution (218 μL, 0.87 mmol) was added, and the mixture was 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 filtered and washed with water (15 mL). The obtained solid was washed with ethyl acetate (5.0 mL) to obtain compound 7 (42.5 mg, 53.1%). MS(ESI)m / z:459(M+1) + .

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

[0318] [ka]

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

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

[0321] [Process c] A mixed solution of compound 3a (13 mg, 26 μmol) in tetrahydrofuran (1.0 mL) and methanol (0.50 mL) is prepared by adding 2 M sodium hydroxide aqueous solution (0.50 mL, 1 (0.0 mmol) was added and the mixture was 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 mixture under reduced pressure, the resulting solid was filtered, and the mixture was washed with water to obtain compound 4a (11 mg, 90%). The enantiomer is designated as Example 7-1. MS(ESI)m / z:466(M+1) + .

[0322] [Step d] Compound 3b (13 mg, 26 μmol) was mixed with tetrahydrofuran (1.0 mL) and methanol (0.50 mL) and then 2M sodium hydroxide aqueous solution (0.50 mL, 1 (0.0 mmol) was added and the mixture was 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 mixture under reduced pressure, the resulting solid was filtered, and washed with water to obtain compound 4b (9.0 mg, 73%). This enantiomer is designated as Example 7-2. MS(ESI)m / z:466(M+1) + .

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

[0324] [ka]

[0325] [Step a] Compound 1 (380 mg, 1.12 mmol) obtained in step b of Reference Example 42 was dissolved in dimethyl sulfoxide (2.7 mL) of bis(pinacolate)diborane (342 mg, 1.35 mmol). 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 heated at 80°C under a nitrogen atmosphere and stirred overnight. After the reaction mixture cooled to room temperature, it was diluted with ethyl acetate and filtered by Celite. The filtrate was washed with water and saturated saline solution, 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] Compound 3 (180 mg, 666 μmol) obtained in step b of Reference Example 3 and Compound 2 (1.44 g, 2.02 mmol) were dissolved in 1,4-dioxane (6.0 mL). To this solution, tripotassium phosphate (424 mg, 2.00 mmol) was dissolved in water (1.2 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (42 mg, 67 μmol) was added. The mixture was heated at 105 °C under a nitrogen atmosphere and stirred for 3 hours. After the reaction mixture cooled 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. Compound 4 (400 mg, 100%) was obtained by purifying the residue by silica gel chromatography and NH silica gel chromatography. MS(ESI)m / z:449(M+1) + .

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

[0328] [Step d] Compound 4a (119 mg, 265 μmol) was mixed with tetrahydrofuran (3.0 mL) and methanol (1.5 mL) and then 2M sodium hydroxide aqueous solution (1.5 mL, 3 (0.0 mmol) was added and the mixture was 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 as Example 8-1. MS(ESI)m / z:421(M+1) + .

[0329] [Step e] Compound 4b (128 mg, 285 μmol) was mixed with tetrahydrofuran (3.0 mL) and methanol (1.5 mL) and then 2M sodium hydroxide aqueous solution (1.5 mL, 3 (0.0 mmol) was added and the mixture was 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 as Example 8-2. MS(ESI)m / z:421(M+1) + .

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

[0331] [ka]

[0332] [Step a] Compound 1 (719 mg, 1.11 mmol) obtained in step a of Example 8 and Compound 2 (200 mg, 740 μmol, Reference Example 6) were dissolved in 1,4-dioxane (3.6 mL). 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 heated under reflux in a nitrogen atmosphere and stirred for 3 hours. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by NH silica gel chromatography and silica gel chromatography to obtain Compound 3 (115 mg, 34.5%). MS(ESI)m / z:449(M+1) + .

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

[0334] [Process c] To a mixed solution of compound 3a (54 mg, 122 μmol) in tetrahydrofuran (2.0 mL) and methanol (1.0 mL), add 2M sodium hydroxide aqueous solution (1.0 mL, 2. (0 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1 M hydrochloric acid (2.2 mL), diluted with saturated brine (10 mL), and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was washed with diethyl ether to obtain compound 4a (28 mg, 54%). This enantiomer was designated as Example 9-1. MS(ESI)m / z:421(M+1) + .

[0335] [Step d] A mixed solution of compound 3b (54 mg, 122 μmol) in tetrahydrofuran (2.0 mL) and methanol (1.0 mL) is prepared by adding 2M sodium hydroxide aqueous solution (1.0 mL, 2. (0 mmol) was added and the mixture was 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 mixture under reduced pressure, the resulting solid was filtered, 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 recycling) to obtain compound 3a (9.0 mg, 99.9% ee, peak at retention time 38 minutes) and compound 3b (9.0 mg, 99.9% ee, peak at retention time 58 minutes).

[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'-bipyridine-2'-yl)cyclopropanecarboxylic acid (1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4'-bipyridine-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(pinacolate)diborane (2.85 g, 11.2 mmol) in 1,4-dioxane (30 mL), potassium acetate (2.11 g, 21.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (352 mg, 431 μmol) were added. The reaction mixture was heated at 110°C under a nitrogen atmosphere and stirred for 3 hours. After the reaction mixture cooled to room temperature, it was diluted with ethyl acetate and filtered by Celite. The filtrate was washed with water and saturated saline solution, 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 by the same method as in step a of Example 9. MS(ESI)m / z:459(M+1) + .

[0345] [Process c] Compound 5 was obtained from compound 4 by the same method as in step c of Example 7. MS(ESI)m / z:431(M+1) + .

[0346] [Step d] Compound 5 (60 mg) was subjected to chiral resolution using chiral HPLC (CHIRAL PAK IA, 30 × 250, ethanol:acetic acid = 100:0.1, 10 mL / min) to obtain compound 5a (25 mg, 99.9% ee, peak at retention time 38 min) and compound 5b (25 mg, 99.9% ee, peak at retention time 23 min). Compound 5a was designated as Example 11-1, and compound 5b 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}pyridine-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) and compound 2 (78.6 mg, 444 μmol) obtained in step b of Reference Example 42 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 heated under reflux in a nitrogen atmosphere and stirred for 5 hours. After the reaction mixture cooled to room temperature, it was filtered through Celite, and the filtrate was concentrated. The residue was then chromatographed using silica gel chromatography. By purification using a ionizer, compound 3 (109 mg, 84.9%) was obtained. MS(ESI)m / z:435(M+1) + .

[0350] [Step b] Compound 3 (109 mg, 251 μmol) was mixed with tetrahydrofuran (3 mL) and methanol (1.0 mL). 4M sodium hydroxide aqueous solution (0.20 mL, 0.80 mmol) was added, and the mixture was stirred at room temperature for 15 hours, followed by stirring at 60°C for 4 hours. After the reaction mixture cooled to room temperature, 1M hydrochloric acid (0.8 mL) was added for neutralization. Water was added, and the resulting solid was filtered and washed with 50% methanol aqueous solution to obtain compound 4 (85.0 mg, 80.6%). MS(ESI)m / z:421(M+1) + .

[0351] Example 13 3-[4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]benzoic acid

[0352] [ka]

[0353] [Step a] To the hydrochloride salt of compound 2 (133 mg, 591 μmol, Reference Example 15), saturated sodium bicarbonate solution 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 heated at 100 °C under a nitrogen atmosphere and stirred for 3 hours. After the reaction mixture cooled to room temperature, it was filtered through Celite, and the filtrate was concentrated. Compound 3 (100 mg, 75.9%) was obtained by purifying the residue by silica gel chromatography. 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 at 150°C for 3.5 hours. After the reaction solution cooled 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 obtain compound 4 (80 mg, 76.7%). MS(ESI)m / z:465(M+1) + .

[0355] Example 14 3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-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 heated under reflux in a nitrogen atmosphere and stirred for 4 hours. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (1.93 g, 76.4%). MS(ESI)m / z:599(M+1) + .

[0358] [Step b] To a solution of compound 3 (1.93 g, 3.15 mmol) in ethanol (39 mL), potassium hydroxide (85 wt%, 415 mg, 6.29 mmol) was added and the mixture was 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 mixed solution of compound 4 (1.34 g, 2.83 mmol) in tetrahydrofuran (8.0 mL) and methanol (2.7 mL) is prepared by adding 4M sodium hydroxide aqueous solution (2.83 mL). (11.3 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 25 mL of 10% citric acid aqueous solution, and the organic solvent was removed by vacuum distillation. The residue was allowed to stand, and the resulting solid was filtered 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}pyridine-3-yl)morpholine-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 heated under reflux in a nitrogen atmosphere and stirred for 3 hours. After the reaction mixture cooled to room temperature, it was filtered through Celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (5.46 g, 86.5%). MS(ESI)m / z:545(M+1) + .

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

[0364] [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 overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 5 (1.33 g, A score of 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 the mixture was stirred overnight at room temperature. The reaction suspension was diluted with tetrahydrofuran (6.0 mL) and hexane (12 mL), insoluble matter was filtered off, and the mixture was concentrated. The residue was purified by silica gel chromatography and then filtered through a cation exchange resin column (Waters, PoraPak). TM Compound 7 (66.9 mg, 53.5%) was obtained by solid-phase extraction and purification using RxnCX. MS(ESI)m / z:439(M+1) + .

[0366] [Step e] A mixed solution of compound 7 (60.0 mg, 137 μmol) in tetrahydrofuran (1.8 mL) and methanol (1.8 mL) is prepared by adding 0.17 mL of 4 M sodium hydroxide aqueous solution. (0.68 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1M hydrochloric acid (0.78 mL) and diluted with water (12 mL). The resulting solid was filtered 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}pyridine-3-yl)morpholine-2-yl]propanoic acid

[0368] [ka]

[0369] [Step a] 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 were dissolved in N,N-dimethylformamide (1.8 mL). Potassium carbonate (59.2 mg, 428 μmol) was added, and the mixture was stirred at 80°C for 5 hours. After the reaction mixture cooled to room temperature, it was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 3 (63.0 g, 66.2%) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:445(M+1) + .

[0370] [Step b] A mixed solution of compound 3 (60.0 mg, 135 μmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) is prepared by adding 0.17 mL of 4 M sodium hydroxide aqueous solution. (0.68 mmol) was added and the mixture was 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 filtered 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}pyridine-3-yl)morpholine-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 at 105 °C under a nitrogen atmosphere for 7 hours. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (300 mg, 87.2%). MS(ESI) m / z: 541(M+1) + .

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

[0375] Example 18 3-[(2S)-4-(5-{2-[4-(trifluoromethoxy)phenyl]ethyl} Pyridine-3-yl)morpholine-2-yl]propanoic acid

[0376] [ka]

[0377] [Step a] To a solution of compound 1 (190 mg, 552 μmol) and compound 2 (50.0 mg, 267 μmol, Reference Example 39) obtained in step b of Reference Example 45 in 1,4-dioxane (5.0 mL), cesium carbonate (220 mg, 675 μmol), palladium(II) acetate (7.0 mg, 31 μmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2' ,4',6'-triisopropyl-1,1'-biphenyl (25 mg, 54 μmol) was added, and the mixture was heated at 160°C under microwave irradiation and stirred for 30 minutes. After the reaction mixture cooled 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. Compound 3 (155 mg) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:451(M+1) + .

[0378] [Step b] Compound 3 (150 mg, 267 μmol) was dissolved in ethanol (6.0 mL), to which 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. Compound 4 (135 mg) was obtained by concentrating the filtrate under reduced pressure. MS(ESI) m / z: 453 (M+1) + .

[0379] [Process c] A mixed solution of compound 4 (135 mg, 267 μmol) in tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was mixed with 2 M sodium hydroxide aqueous solution (1.5 mL, 3.0 mmol) 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 filtered through a cation exchange resin column (Waters, PoraPak). TM Compound 5 (70 mg, 61%) was obtained by solid-phase extraction and purification using RxnCX. MS(ESI)m / z:425(M+1) + .

[0380] [Step d] Compound 5 (170 mg) was subjected to chiral HPLC (CHIRAL PAK IA, 30 × 25). Compound 5a (28 mg, 99.8% ee, peak at retention time 17 minutes) and compound 5b (27 mg, 99.9% ee, peak at retention time 13 minutes) were obtained by chiral resolution using 0, hexane:methanol:tetrahydrofuran:acetic acid = 70:15:15:0.5, 20 mL / min). Compound 5a was designated as Example 18-1 and compound 5b 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}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1R,2R)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1R,2R)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid (1S,2S)-2-[(2R)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholin-2-yl]cyclopropanecarboxylic acid

[0382] [ka]

[0383] [ka]

[0384] [Step a] 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 were dissolved in 1,4-dioxane (3.5 mL). 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 the mixture was heated at 110 °C under a nitrogen atmosphere and stirred for 5 hours. After the reaction mixture cooled 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. Compound 3 (220 mg, 65.5%) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:457(M+1)+ .

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

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

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

[0388] [Step e] 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 were dissolved in 1,4-dioxane (3.5 mL). 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 the mixture was heated at 110 °C under a nitrogen atmosphere and stirred for 5 hours. After the reaction mixture cooled to room temperature, 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 to obtain Compound 5 (26 mg, 64.5%). MS(ESI)m / z:457(M+1) + .

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

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

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

[0392] Example 20 trans-1-methyl-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridine-3-yl)morpholine-2-yl]cyclopropanecarboxylic acid

[0393] [ka]

[0394] [Step a] 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 were dissolved in 1,4-dioxane (4.0 mL). Cesium carbonate (348 mg, 1.07 mmol), palladium(II) acetate (14 mg, 64 μmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (59.9 mg, 128 μmol) were added, and the mixture was stirred for 8 hours under heating at 110 °C in a nitrogen atmosphere. After the reaction mixture cooled 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. Compound 3 (130 mg, 60.7%) was obtained by purification of the residue by NH silica gel chromatography and silica gel chromatography. MS(ESI)m / z:471(M+1) + .

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

[0396] Example 21 {[(3S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholine-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 heating at 105°C in a nitrogen atmosphere. Further addition of palladium(II) acetate (17 mg, 76 μmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (70.5 mg, 151 μmol) was added to the reaction mixture, and the mixture was stirred for 3 hours under heating at 105°C in a nitrogen atmosphere. 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, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (160 mg, 49.4%). MS(ESI)m / z:429(M+1) + .

[0399] [Step b] To a solution of compound 3 (155 mg, 362 μmol) in tetrahydrofuran (2.0 mL), 6 M hydrochloric acid (2.0 mL, 12 mmol) was added and the mixture was stirred at room temperature for 10 hours. The reaction solution was neutralized with 2 M sodium hydroxide aqueous solution (5.0 mL), and then the reaction was performed using a cation exchange resin column (Waters, PoraPak). TM Compound 4 (70 mg, 50%) was obtained by solid-phase extraction and purification using 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), sodium hydride (60 wt%, 9.4 mg, 0.23 mmol) was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes. To the reaction solution, a solution of tert-butyl bromoacetate (33 mg, 0.17 mmol) in N,N-dimethylformamide (0.50 mL) was added dropwise, and the mixture was stirred at room temperature for 4 hours. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, and ethyl acetate was added. The compound was extracted using a solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 5 (35 mg, 45%). MS(ESI)m / z:499(M+1) + .

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

[0402] Example 22 (2E)-4-[(3R)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridine-3-yl)morpholin-3-yl]-2-butenic acid

[0403] [ka]

[0404] [Step a] To a solution of compound 2 (594 mg, 3.39 mmol) obtained in step c of Reference Example 12 and compound 1 (1.42 g, 4.07 mmol, Reference Example 49) in 1,4-dioxane (30 mL), cesium carbonate (2.76 g, 8.48 mmol), palladium(II) acetate (114 mg, 508 μmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (475 mg, 1.02 mmol) were added, and the mixture was heated under reflux in a nitrogen atmosphere. The mixture was stirred for a specified time. After allowing the reaction mixture 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 saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (731 mg, 48.7%). MS(ESI)m / z:443(M+1) + .

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

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

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

[0408] [Step e] Compound 6 (50.0 mg, 107 μmol) was mixed with tetrahydrofuran (1.0 mL) and methanol (0.5 mL) and then 4M sodium hydroxide aqueous solution (0.5 mL, 2 (0.0 mmol) was added and the mixture was stirred at room temperature for 60 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (2 mL), and neutralized with 1 M hydrochloric acid (2.0 mL). The resulting solid was filtered 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, fractionated after 0.5 recycling cycles) to obtain compound 7a (4.1 mg, 99.8% ee, peak at retention time 27 minutes) and compound 7b (5.2 mg, 99.1% ee, peak at retention time 17 minutes). Compound 7a was designated as Example 22-1 and compound 7b 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}pyridine-3-yl)pyrrolidine-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 the mixture was stirred for 15 hours under heating at 100 °C in a nitrogen atmosphere. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (138 mg, 42.7%). MS(ESI)m / z:451(M+1) + .

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

[0414] [Process c] A mixed solution of compound 4 (97.0 mg, 214 μmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) is prepared by adding 0.11 mL of 4M sodium hydroxide aqueous solution. (0.44 mmol) was added and the mixture was 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}pyridine-3-yl)pyrrolidine-2-yl]methoxy}acetic acid

[0416] [ka]

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

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

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

[0420] [Step d] To a solution of compound 4 (115 mg, 238 μmol) in dichloromethane (3.0 mL), 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 analyzed using a cation exchange resin column (Waters, PoraPak). TM The residue was purified by solid-phase extraction using RxnCX. The residue was dissolved in tetrahydrofuran (2.0 mL) and methanol (1.0 mL), and 2M sodium hydroxide aqueous 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 obtain compound 5 (95.0 mg, 93.5%). MS(ESI)m / z:427(M+1) + .

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

[0422] [Table 1]

[0423] [Table 2]

[0424] The following compounds were prepared according to production methods 7-8 and examples 12-13.

[0425] [Table 3]

[0426] [Table 4]

[0427] [Table 5]

[0428] [Table 6]

[0429] [Table 7]

[0430] [Table 8]

[0431] The following compounds were prepared according to manufacturing methods 7, 9-11 and examples 14-16.

[0432] [Table 9]

[0433] [Table 10]

[0434] [Table 11]

[0435] The following compounds were prepared according to manufacturing methods 7, 14-17 and examples 19-24.

[0436] [Table 12]

[0437] [Table 13]

[0438] Reference example 1

[0439] [ka]

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

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

[0442] [Process c] Compound 3 (2.72 g, 8.31 mmol) and bis(pinacolate)diborane (3.16 g, 12.5 mmol) were dissolved 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 the mixture was heated at 80°C under a nitrogen atmosphere and stirred overnight. After the reaction mixture cooled to room temperature, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 4 (3.38 g, 109%). MS(APCI) m / z: 319 (M-tBu+1) + .

[0443] Reference example 2

[0444] [ka]

[0445] [Step a] To a 30 mL solution of tetrahydrofuran (24.5 mL, 49.0 mmol) of 2M isopropylmagnesium chloride, a 30 mL solution of tetrahydrofuran (12.0 g, 44.5 mmol) of compound 1 was added dropwise under a nitrogen atmosphere at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, a 4.45 mL, 8.91 mmol solution of 2M isopropylmagnesium chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, a 30 mL solution of tetrahydrofuran (6.43 g, 46.8 mmol) of compound 2 was added under ice cooling, and the mixture was stirred for 2 hours. After stirring overnight while gradually increasing the temperature to room temperature, water (40 mL) and saturated ammonium chloride aqueous solution (160 mL) were 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. Compound 3 (5.84 g, 59.6%) was obtained by washing the residue with chloroform (50 mL)-hexane (100 mL). MS(ESI)m / z:220,222(M+1) + .

[0446] [Step b] 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) were mixed with 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 under ice cooling for 7 hours. Water (700 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (700 mL). The organic layer was washed with saturated sodium bicarbonate solution (390 mL), water (520 mL), and saturated brine (260 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4 (14.5 g, 95.3% ee) was obtained by purifying the residue by silica gel chromatography. 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. After extracting the reaction suspension with ethyl acetate (280 mL), the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 ( 11.78g, 99.2%, 90.1% ee) was obtained. 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 solution of 1 M potassium tert-butoxide in tetrahydrofuran (127 mL, 127 mmol) was added dropwise. Then, a solution of compound 5 (11.8 g, 63.3 mmol) in tetrahydrofuran (19 mL) was added, and the mixture was heated under reflux in a nitrogen atmosphere and stirred for 1 day. After the reaction mixture cooled to room temperature, water (740 mL) was added, and the resulting solid was filtered and washed with water (185 mL). The obtained solid was recrystallized with ethanol (150 mL) to obtain compound 7 (11.8 g, 73.2%, 99.7% ee). MS(ESI) m / z: 256, 258 (M+1) + .

[0449] Reference example 3

[0450] [ka]

[0451] [Step a] A suspension of sodium hydride (60 wt%, 421 mg, 10.5 mmol) in dimethyl sulfoxide (35 mL) was heated at 60°C under a nitrogen atmosphere and stirred for 30 minutes. After the reaction solution cooled to room temperature, trimethylsulfoxonium iodide (2.70 g, 12.3 mmol) was added and stirred for 30 minutes. 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 extracted with tert-butyl methyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2 (910 mg, 45.7%) was obtained by purifying the residue by silica gel chromatography. 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), a solution of 1 M potassium tert-butoxide in tetrahydrofuran (7.92 mL, 7.92 mmol) was added dropwise under ice cooling. Compound 2 (900 mg, 3.96 mmol) was then added to the reaction solution, and the mixture was heated under reflux in a nitrogen atmosphere and stirred for 1 day. After the reaction mixture cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 4 (735 mg, 68.7%). MS(ESI) m / z: 270, 272 (M+1) + .

[0453] The following compounds were prepared according to manufacturing methods 18-20 and reference examples 1-3.

[0454] [Table 14]

[0455] Reference example 7

[0456] [ka]

[0457] [Step a] A mixed 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) is prepared by adding potassium carbonate (3.38 g, 24.5 mmol) and tetrakis(tri Phenylphosphine) palladium (0) (354 mg, 306 μmol) was added under a nitrogen atmosphere. The reaction mixture was heated under reflux in an air-filled environment and stirred for 2 hours. After the reaction mixture cooled to room temperature, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 2 (2.35 g, 99.9%). MS(ESI) m / z: 193 (M+1) + .

[0458] [Step b] A mixed solution of compound 2 (2.35 g, 12.2 mmol) in tert-butyl alcohol (30 mL) and water (40 mL) is prepared by adding N-bromosuccinimide (2.39 g, 13.4 mL). Add (mol) and stir at 45°C for 2.5 hours. After the reaction solution has cooled to room temperature, add 4M sodium hydroxide aqueous solution (23.06 mL, 12.2 mL) and stir at room temperature for 10 minutes. Add another 4M sodium hydroxide aqueous solution (3.06 mL, 12.2 mL) to the reaction solution and stir at room temperature overnight. Add water to the reaction solution and extract with ethyl acetate. The organic layer was diluted with water and saturated food. After washing with brine, the compound was dried over anhydrous magnesium sulfate. By filtration and concentration, compound 3 (2.48 g, 97.4%) was obtained. 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 heated at 110 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 5 (2.17 g, 50.7%). MS (APCI) m / z: 360 (M+1) + .

[0460] [Step d] To a solution of compound 5 (2.17 g, 6.04 mmol) in tetrahydrofuran (60 mL), add tributylphosphine (2.23 mL, 9.06 mmol) and 1,1'-(azodical Bonyl dipiperidine (2.29 g, 9.06 mmol) was added and the mixture was stirred overnight at room temperature. After filtering off insoluble matter from the reaction suspension, 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] [Step e] Compound 6 (307 mg, 899 μmol) was dissolved in methanol (45 mL), to which 10% palladium / carbon (92 mg) was added and 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 obtain compound 7 (187 mg, 82.8%). MS (APCI) m / z: 252 (M+1) + .

[0462] Reference example 8

[0463] [ka]

[0464] [Step a] A mixed solution of compound 1 (400 mg, 1.77 mmol) in tetrahydrofuran (18 mL) and methanol (3.0 mL) is prepared by adding di-tert-butyldicarbonate (425 mg). Add (1.95 mmol) and triethylamine (377 μL, 2.65 mmol) and then... The mixture was stirred at temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate the phases. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2 (400 mg, 69.3%) was obtained by purifying the residue by silica gel chromatography. 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 mixed solution of compound 2 (400 mg, 1.23 mmol) in N,N-dimethylformamide (5.0 mL) and ethanol (15 mL), sodium acetate (168 mg, 2.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (289 mg, 354 μmol), and diisopropylethylamine (918 μL, 5.31 mmol) were added. The mixture was heated at 70°C in a carbon monoxide atmosphere and stirred for 2 days. After the reaction mixture cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered through Celite. The filtrate was separated into phases, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (224 mg, 41.5%). MS(ESI)m / z:250(M-tBu+1) + .

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

[0467] Reference example 9

[0468] [ka]

[0469] [Step a] Compound 1 (20.0 g, 92.1 mmol) and triethylamine (16.6 mL, 120 mol) in dichloromethane (180 mL) were mixed with mesylchloride (7.84 mL, 101 mmol) in dichloromethane (8.0 mL) by dropwise addition under ice cooling, and the mixture was stirred under ice cooling for 2 hours. Water (60 mL) was added to the reaction solution under ice cooling, and phase separation was performed. The organic layer was washed with saturated sodium bicarbonate solution (40 mL) and saturated saline solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 2 (30.3 g). MS(ESI)m / z:296(M+1) + .

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

[0471] [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 the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (100 mL) was added dropwise to the reaction solution, and the mixture was extracted three times with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (1.40 g). MS(ESI)m / z:332(M+1) + .

[0472] Reference example 10

[0473] [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 it was extracted with chloroform (40 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL) and saturated saline solution (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (30 mL), and diethylphosphonoethyl acetate (7.73 g, 34.5 mmol) and sodium hydride were added. Compound 2 (2.92 g, 38.3%) was obtained by adding it dropwise to a 30 mL solution of tetrahydrofuran (60 wt%, 1.20 g, 34.5 mmol) under ice cooling, and then stirring overnight while increasing the temperature to room temperature. Water (60 mL) was added to the reaction solution, and it was extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 2 (2.92 g, 38.3%). MS(ESI) m / z: 286 (M+1) + .

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

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

[0477] [Step d] To a mixed solution of compound 4 (280 mg, 1.01 mmol) in acetonitrile (6.0 mL) and carbon tetrachloride (6.0 mL), 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 the mixture was stirred at room temperature for 1 hour. 2-propanol (3.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, after which it was filtered through Celite. Saturated ammonium chloride aqueous solution (9.0 mL) was added to the filtrate, and it 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, and 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. Compound 6 (290 mg, 64.1%) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:300(M+1) +.

[0478] [Step e] A mixed solution of compound 5 (260 mg, 900 μmol) in acetonitrile (5.0 mL) and carbon tetrachloride (5.0 mL) was mixed with sodium periodate (578 mg, 2.70 mmol) in water (7.5 mL) and ruthenium(IV) oxide hydrate (4.1 mg, 27 μmol), and the mixture was stirred at room temperature for 1 hour. 2-propanol (2.5 mL) was added to the reaction mixture and stirred at room temperature for 1 hour, after which it was filtered through Celite. The filtrate was then saturated with ammonium chloride aqueous solution (7 0.5 mL was added and extracted three times with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (3.5 mL), potassium carbonate (377 mg, 2.73 mmol) and iodoethane (218 μL, 2.73 mmol) were added, and the mixture was stirred at room temperature for 4 days. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 7 (210 mg, 77.2%) was obtained by purifying the residue by silica gel chromatography. 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 the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 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 the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 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] Compound 1 (2.50 g, 11.5 mmol) and a solution of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (36.0 mg, 230 μmol) in dichloromethane (35 mL) were mixed with a solution of sodium bromide (118 mg, 1.15 mmol) in water (2.0 mL), saturated sodium bicarbonate solution (5.5 mL), and 5% sodium hypochlorite aqueous solution (17.1 mL, 11.5 mmol), added dropwise over 45 minutes under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Saturated saline solution (30 mL) was added to the reaction mixture, and it was extracted three times with chloroform (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL) and saturated saline solution (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (20 mL), and then added dropwise to a tetrahydrofuran (20 mL) solution of ethyl diethylphosphonopropionate (3.47 g, 14.6 mmol) and sodium hydride (60 wt%, 499 mg, 12.5 mmol) under ice cooling. The mixture was then stirred overnight while gradually increasing the temperature to room temperature. Water (40 mL) was added to the reaction solution, and it 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. Compound 2 (1.74 g, 53.6%) was obtained by purifying the residue by silica gel chromatography. 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 solution of 1 M diisobutylaluminum hydride in dichloromethane (20.3 mL, 20.3 mmol) was added dropwise over 40 minutes at -50°C, and the mixture was stirred for 2 hours while increasing the temperature to -30°C. A mixture of methanol (1.0 mL) and tetrahydrofuran (10 mL) was added dropwise at -30°C, and the mixture was stirred for 1 hour while increasing the temperature to -10°C. A saturated Rochelle salt aqueous solution (10 mL) was added to the reaction solution at -10°C, and the mixture was stirred overnight at room temperature. The mixture was then extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 3 (950 mg, 58.4%). MS(ESI)m / z:258(M+1) + .

[0485] [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 the mixture was stirred at room temperature for 9 hours. Water was added to the reaction solution, and it was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 4 (2.20 g) was obtained by purifying the residue by silica gel chromatography. 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), 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 under ice cooling for 4 hours. 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 stirred overnight at room temperature, then extracted twice with chloroform (30 mL). The organic layer was then extracted using saturated Rochelle salt aqueous solution ( After washing with saturated saline solution (10 mL), the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 5 (1.35 g, 70.9%). 1 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] [Step e] To a solution of compound 5 (1.35 g, 2.41 mmol) in tetrahydrofuran (8.0 mL), a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (4.82 mL, 4.82 mmol) was added and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride (10 mL) was 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 under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 6 (720 mg, 94.7%). MS(ESI)m / z:272(M+1) + .

[0488] [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 the mixture was stirred at room temperature for 1.5 hours. 2-propanol (4.0 mL) was added to the reaction mixture, and after stirring at room temperature for 1 hour, the mixture was filtered through Celite. Saturated ammonium chloride aqueous solution (10 mL) and 10% citric acid aqueous solution (10 mL) were added to the filtrate, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (5.0 mL), and potassium carbonate (564 mg, 3.95 mmol) and iodoethane (316 μL, 3.95 mmol) were added. The mixture was stirred at room temperature for 3 days. Water (30 mL) was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 7 (270 mg, 62.8%) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:314(M+1) + .

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

[0490] Reference example 12

[0491] [ka]

[0492] [Step a] Compound 1 (1.00 g, 4.08 mmol) of 1,2-dimethoxyethane (6.0 mL) To the solution, 4-methylmorpholine (493 μL, 4.48 mmol) and isobutyl chloroformate (586 μL, 4.48 mmol) were added under ice cooling, and the mixture was stirred under ice cooling for 2 hours. 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 under ice cooling for 2 hours. Water was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2 (836 mg, 88.7%) was obtained by purifying the residue by silica gel chromatography. 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), diisopropylethylamine (1.88 mL, 10.8 mmol) and chloromethyl methyl ether (851 μL, 11.21 mmol) were added dropwise under ice cooling, and the mixture was stirred overnight while gradually increasing the temperature to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (926 mg, 93.1%). MS(ESI)m / z:276(M+1) + .

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

[0495] Reference example 13

[0496] [ka]

[0497] [Step a] Compound 1 (400 mg, 1.73 mmol) was dissolved in dichloromethane (12 mL) and Dess-Martin periodinane (1.10 g, 2.59 mmol) was added under ice cooling. The mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution and saturated sodium sulfite solution 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. Compound 2 (399 mg) was obtained by purifying the residue by silica gel chromatography. MS(ESI) m / z: 174 (M-tBu+1) + .

[0498] [Step b] A solution of compound 2 (399 mg, 1.74 mmol) and diethylphosphonoethyl acetate (587 mg, 2.62 mmol) in tetrahydrofuran (12.0 mL) was cooled on ice, and sodium hydride (60 wt%, 90.7 mg, 2.27 mmol) was added and the mixture was stirred for 15 minutes. The mixture was stirred overnight while gradually increasing the temperature to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was then mixed. The compound was extracted with Loloform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain compound 3 (325 mg, 2.1%). MS(ESI)m / z:244(M-tBu+1) + .

[0499] [Process c] Compound 3 (320 mg, 1.07 mmol) was dissolved in methanol (13 mL), to which 10% palladium / carbon (64 mg) was added and the mixture was 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 obtain compound 4 (321 mg, 99.7%). MS(ESI)m / z:302(M+1) + .

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

[0501] Reference example 14

[0502] [ka]

[0503] [Step a] Compound 1 (450 mg, 2.09 mmol) was dissolved in dichloromethane (21 mL) and Dess-Martin periodinane (1.33 g, 3.14 mmol) was added under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate solution and saturated sodium sulfite solution 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, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 2 (295 mg, 66.2%). MS(ESI)m / z:214(M+1) + .

[0504] [Step b] To a solution of diethylphosphonoethyl acetate (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 under ice cooling for 1.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3 (612 mg). MS(ESI)m / z:228(M-tBu+1) + .

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

[0506] The following compounds were prepared according to manufacturing methods 21-24 and reference examples 7-14.

[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. Water (3.0 mL) in a solution of tetrahydrofuran (150 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 45 minutes. 4M sodium hydroxide aqueous solution (3.0 mL) was added to the reaction suspension, and the mixture was stirred at room temperature for 30 minutes, after which water (3.0 mL) was added and the mixture was stirred overnight at room temperature. The reaction suspension was filtered through Celite and washed with tetrahydrofuran (50 mL). Compound 2 (8.70 g, 93.7%) was obtained by concentrating the filtrate under reduced pressure. 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 tetrahydrofuran (20 mL) solution of compound 2 (678 mg, 3.72 mmol) and compound 3 (540 mg, 3.10 mmol), triphenylphosphine (1.22 g, 4.66 mmol) and diisopropyl azodicarboxylate (941 mg, 4.66 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to a 50% N,N-dimethylformamide aqueous solution and extracted with heptane. The organic phase was washed with a 50% N,N-dimethylformamide aqueous solution and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then reduced in volume. Compound 4 (972 mg, 92.6%) was obtained by pressure concentration and purification of the residue by silica gel chromatography. MS(ESI)m / z:338,340(M+1) + .

[0514] Reference example 43

[0515] [ka]

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

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

[0518] [Process c] Compound 5 (1.37 mL, 9.52 mmol) was added to a mixed solution of compound 4 (1.29 g, 4.76 mmol) in N,N-dimethylformamide (15 mL) and diisopropylethylamine (1.65 mL, 9.52 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 6 (1.61 g, 95.5%) was obtained by purifying the residue by silica gel chromatography. 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 in small amounts under ice cooling, and the mixture was stirred for 30 minutes. To the reaction solution, 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 the temperature was raised to room temperature. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (250 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 3 (4.95 g, 30.0%). MS(ESI) m / z: 295, 297 (M+1) + .

[0522] Reference example 45

[0523] [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 the mixture was stirred under reflux for 1 hour. The reaction mixture was diluted with toluene (50 mL) and stirred again under reflux for 1 hour. After the reaction mixture cooled to room temperature, it was diluted with hexane (150 mL), the resulting solid was filtered, and the mixture was washed with hexane (100 mL) to obtain compound 2 (8.78 g, 86.6%). MS(E SI)m / z:437

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

[0526] Reference example 46

[0527] [ka]

[0528] [Step a] A mixed solution 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) was mixed with bistriphenylphosphine palladium(II) dichloride (94.2 mg, 134 μmol), triphenylphosphine (70.4 mg, 268 μmol), and copper iodide (25.6 mg, 134 μmol). The mixture was heated at 50°C under a nitrogen atmosphere and stirred for 6 hours. After the reaction mixture cooled to room temperature, water (30 mL) was added and 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. Compound 3 (160 mg, 40.0%) was obtained by purifying the residue by silica gel chromatography. 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 amounts, and the mixture was stirred overnight at room temperature. The reaction suspension was diluted with hexane (6.0 mL), insoluble matter was filtered off, and the mixture was concentrated. Compound 3 (324 mg, 91.8%) was obtained by purifying the residue by silica gel chromatography. MS(ESI)m / z:332,334(M+1) + .

[0532] Reference example 48

[0533] [ka]

[0534] [Step a] To a solution of compound 1 (100 mg, 549 μmol) obtained in step a of Reference Example 42 in dichloromethane (2.0 mL), pyridine (133 μL, 1.65 mmol) and p-toluenesulfonyl chloride (126 mg, 659 μmol) were added and the mixture was stirred at room temperature for 6 hours. Further p-toluenesulfonyl chloride (62.8 mg, 329 μmol) was added to the reaction solution and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (20 mL), washed with 1 M hydrochloric acid (10 mL) and saturated sodium bicarbonate solution (10 mL), and then concentrated under reduced pressure to obtain 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 prepared according to manufacturing methods 25-29 and reference examples 42-48.

[0536] [Table 18]

[0537] Experimental Example 1: [Enzyme Inhibition Test Method] A mixture of substrate and choline quantification reagent prepared with Assay buffer (50mM Tris (pH 8.0), 140mM NaCl, 5mM KCl, 1mM CaCl2, 1mM MgCl2, 0.1% BSA (Albumin from bovine serum, SIGMA), 0.0025% Triton X-100) and a choline quantification reagent (200μM LPC (1-Oleoyl-sn-glycero-3-phosphocholine Sigma #L1881), 25μM Amplex UltraRed re 10 μL each of agent (Invitrogen), 0.1 U / mL peroxidase (TOYOBO), and 1 U / mL choline oxidase (TOYOBO), along with 10 μL of enzyme (0.4 ng / μL human recombinant ATX) and 100 nL of 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 then measured. Choline chloride was used as the standard. The blank sample (without enzyme) was defined as having a 100% inhibition rate, and the control sample (without inhibitor) was defined as having a 0% inhibition rate. The inhibition rate was calculated, and the IC50 value was calculated from the percentage of inhibitory activity at each concentration.

[0538] Experimental Example 2: [Measurement of ATX activity in plasma (ex vivo)] The compound was wet-milled for 10 minutes using a mixer mill (model: MM400) and then prepared by diluting it with a 0.5% carboxymethylcellulose aqueous solution to the desired concentration. This compound solution was orally administered to male Wistar rats (5 weeks old at the time of administration) at a rate of 5 mL / kg. Blood was collected sequentially from the jugular vein 8 to 24 hours after administration. The blood was heparinized using a small blood collection container (CJ-AL, Terumo), and the plasma was separated by centrifugation (4°C, 12,000 rpm, 2 minutes), after which it was stored at -80°C. The rats were treated with isoflavones after blood collection. The animals were euthanized by draining blood from the posterior vena cava under inhalation anesthesia. ATX activity in plasma was evaluated by measuring the plasma choline concentration released from lysophosphatidylcholine (a substrate of ATX) by the lysophospholipase D activity of ATX. Equal volumes of 2×assay buffer (200mM Tris-HCl pH9.0, 10mM MgCl2, 1M NaCl, 0.1% Triton X-100) were added to 12 μL of plasma and reacted at 37°C for 6 hours. 10 μL of the reaction mixture and 45 μL of reagent R1 (100mM Tris-HCl pH8.0, 0.5mM TOOS, 10U / mL peroxidase, 0.01% Triton X-100) were added and mixed, and the absorbance at 550-700 nm was measured and used as the pre-value. Choline chloride was used as the standard. 1 mM choline chloride was diluted in 2x assay buffer in 7 steps by 2-fold serial dilution, and the absorbance of solution R1 was measured after similar treatment. Furthermore, 15 μL of reagent R2 (100 mM Tris-HCl pH 8.0, 1 mM) was added. 4-aminoantipyrine, 10 U / mL and choline oxidase, 0.01% (Triton X-100) were added and reacted at room temperature for 10 minutes. The absorbance at 550-700 nm was measured. The choline concentration per unit reaction time was calculated from the difference between the absorbance after adding R2 solution and the pre-addition value measured before adding R2, and this was used as the ATX activity value. <Calculation formula> Inhibitory activity (%) = 100 × {1 - [choline concentration in the test substance administration group (μM) / choline concentration in the solvent control group (μM)]} The results obtained in Experimental Examples 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: [Evaluation of the effects of ATX inhibitors on a mouse bleomycin-induced pulmonary fibrosis model] ATX inhibitor (Example 5, hereafter referred to as example 5 in the figure) bleomycin ( Efficacy for BLM-induced pulmonary fibrosis models, and each fibrosis index in plasma or BALF The effects were evaluated using markers or changes in fibrosis-related genes in the lungs as indicators. As a result, it suppressed SP-D in plasma (Figure 1), and in terms of lung genes, it showed inhibitory effects on the expression of Col1a1 (Figure 2), CTGF (Figure 3), and IL-6 (Figure 4). Furthermore, it completely suppressed ATX activity in plasma (Figure 5) and also showed an inhibitory effect on LPA(C18:2) production in BALF (Figure 6). <Creation of a bleomycin-induced pulmonary fibrosis model> Eight-week-old mice were divided into groups using a simulation method to ensure uniform body weight by the day before bleomycin administration, according to the group composition shown in Table 24 (SOP / STA / RA-0003). The mice were anesthetized with isoflurane, and a bleomycin-induced pulmonary fibrosis model was created by intratracheal administration of 0.5 mg / mL bleomycin solution at a rate of 50 μL / head (1.25 U / kg). The Saline group received physiological saline instead of bleomycin. An ATX inhibitor (Example 5) was administered orally twice daily starting from the day of bleomycin administration. Body weight was measured once daily starting from the day of group division.

[0545] [Table 24]

[0546] <Preparation Method of ATX Inhibitor> A mixed solution of 1 equivalent of 1N NaOH and 0.5% CMC solution (total 100 μL) was added to the ATX inhibitor (Example 5), and 10 zirconia beads with a diameter of 3 mm were added, followed by grinding using a Mixer Mill MM400 (frequency 28.01 / min, grinding time 10 min). 0.5% CMC was added to make a suspension with 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. It was administered twice a day, and the first administration was performed 30 minutes before the BLM administration.

[0547] <Reagents> Bleomycin Hydrochloride for Injection (BLM, product name: Bleo (5 mg / ampoule), manufacturer: Nippon Kayaku Co., Ltd., production 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 purified water (Otsuka Pharmaceutical Factory Co., Ltd., storage condition: stored at room temperature). Sircol Soluble / Insoluble Collagen Assay kit (Biocolor, S1111). Rat / Mouse SP-D kit "Yamasa" EIA (Yamasa Soy Sauce, 80072).

[0548] <Test Animals> Animal species: Female C57BL / 6J mice, 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 tissue 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 centrifuged for recovery. Then, the ATX activity (Figure 5) and SP-D (Figure 1) in plasma were measured. Furthermore, the chest was opened to recover whole lung tissue, and gene expression analysis of Col1a1 (Figure 2), CTGF (Figure 3), and IL-6 (Figure 4) in the lung was performed. For gene expression analysis, mRNA in lung tissue 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> To 200 μL of the collected BALF, an organic solvent and LPA(17:0) solution as an internal standard substance were added, and vacuum drying was performed at 35°C. After drying, 50 μL of 50% ethanol aqueous solution was added to the residue, and the redissolved solution was used as an analytical sample. The analytical sample was separated using a reverse-phase column, and LPA(18:2) was detected using a QTRAP6500 system (ABSciex). 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 it with a calibration sample that had undergone the same pretreatment (Figure 6).

[0552] <Measurement of ATX activity in plasma> It was measured and calculated 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% two-sided. 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 a cynomolgus 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-reducing effect in both single oral administration (Figure 7) and single topical administration (Figure 8) of the test drug. <Creation of a cynomolgus 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) and transferred it to an agate mortar and gently triturated it. A few drops of an oral vehicle (0.5% w / v CMC-Na) were added dropwise and mixed with the ATX inhibitor (Example 5). The addition and mixing of the oral vehicle to the mixture were repeated to make a paste. The paste was transferred to a graduated cylinder, and the oral vehicle was added up to 60% of the final preparation volume. While stirring with a stirrer, a vehicle (0.5% w / v CMC-Na containing 0.5 mol / L NaOH) was added (so that NaOH was 0.75 mol per 1 mol of Example 5). The oral vehicle was added to make up the volume, and it was confirmed that the pH did not exceed 11.0 (measured value: pH 10.55 - 10.88).

[0558] <Method for preparing a topical administration solution of an ATX inhibitor> Britton-Robinson buffer (pH 8.5) was prepared by mixing 307 mL of 0.04 mol / L boric acid / phosphoric acid / acetic acid mixture with 193 mL of 0.2 mol / L sodium hydroxide aqueous solution (pH approximately 8.4), and then adjusting the pH to 8.5 with 1 mol / L hydrochloric acid. A solution of 5% kolliphor EL dissolved in the above solution was used as an ophthalmic administration medium (5% w / v kolliphor EL solution (pH 8.5)). Four portions were dispensed into a 10 mL volumetric flask. 0.5 mg of ATX inhibitor (Example 5) was weighed out, 9.6 mL of ophthalmic administration medium was added, and the mixture was ultrasonically treated for 30 minutes in an ultrasonic cleaner set to approximately 40°C. After confirming that the mixture was uniformly suspended, the mark on the volumetric flask was cut with the ophthalmic administration medium, and the mixture was ultrasonically treated for 40 minutes in the same manner as above, and complete dissolution was confirmed visually. If the mixture remained suspended at this point, ultrasonic treatment was continued until complete dissolution was achieved.

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

[0560] <Test animals> Animal species: Male crab-eating macaque Supplier: Shin Nippon Biomedical Laboratories, Ltd. Number of animals used: 10 (age 7-8 years old at the start of acclimatization)

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

[0562] <Measurement of intraocular pressure> Intraocular pressure was measured three times using a rebound tonometer (TonoVet Tonometer TV01, Tiolat Oy) while the animals were restrained without anesthesia. The median of the three measurements was used as the value to adopt. Surface anesthetics were not used due to concerns about corneal irritation from frequent administration.

[0563] <Points to check for intraocular pressure> Before compound administration, and approximately 1, 2, 4, 8, and 24 hours after administration (6 points each day of administration).

[0564] <Statistical analysis> For the left eye (high-tension eye), the mean and standard error of the adopted values, the mean and standard error of the percentage change from before each administration, and the mean and standard error of the amount of change from before each administration were calculated for each measurement point. [Regarding eye drop administration] 1) To examine the effect of lowering intraocular pressure after administration at each time point, an analysis of covariance was performed at each time point after administration, with the individual as the variable, the administration group as the fixed factor, and pre-administration intraocular pressure as the covariate. A comparative test was then performed between the eye drop media (administered as eye drops) group, the test substance (administered as eye drops) group, and the positive control substance group (multiple selections were not adjusted for). 2) The percentage change and amount of change in intraocular pressure from before each administration were measured for each individual at each time point after administration. An analysis of variance was performed with the administration group and administration date as fixed factors, and comparative tests were conducted between the ophthalmic media (administered as eye drops) group, the test substance (administered as eye drops) group, and the positive control substance group. [Regarding oral administration] 1) To examine the effect of lowering intraocular pressure after administration at each time point, an analysis of covariance was performed at each time point after administration, with the individual as the variable, the administration group as the fixed factor, and the pre-administration intraocular pressure as the covariate, and a comparative test was performed between the oral media (oral administration) group and the test substance (oral administration) group. 2) For the percentage change and amount of change in intraocular pressure from before each administration, an analysis of variance was performed for each time point after administration, with the individual as the variable and the administration group and administration day as fixed factors, and a comparative test was performed between the oral media (oral administration) group and the test substance (oral administration) group. These tests include SAS System for Windows, Release We used version 9.3 (SAS Institute Inc.). The significance level for the test was set at a two-tailed 5%. [Industrial applicability]

[0565] The compounds of the present invention have excellent autotaxin inhibitory activity and are useful as preventive or therapeutic agents for various diseases caused by autotaxin, such as cancer or tumors (e.g., malignant melanoma, brain tumor, neuroblastoma, glioblastoma pleomorphic, EBV-positive Hodgkin 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.), fibrous diseases (e.g., pulmonary fibrosis, scleroderma, hepatic fibrosis, renal fibrosis, diabetic nephropathy, atherosclerosis, etc.), inflammatory diseases (e.g., asthma, COPD, rheumatoid arthritis, osteoarthritis, NASH, NAFLD, obesity associated with type II diabetes, acute coronary syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain, pruritus, etc.), eye diseases (e.g., glaucoma, etc.), and urinary tract diseases (e.g., benign prostatic hyperplasia, etc.). This application is based on Japanese Patent Application No. 2018-141254, the same as which is fully incorporated herein.

Claims

1. The following general formula (A5): 【Chemistry 1】 {In the formula, R １ teeth, 【Chemistry 2】 [wherein, X １ａ is -C(R １ａ )(wherein, R ２ may be the same or different and each represents a hydrogen atom, a halogen atom, C １ａ to C １ to C ２ perfluoroalkyl, C １ to C ２ perfluoroalkoxy or C １ to C ６ alkyl, or R １ａ is bonded to form 1,1-C ３ to C ６ cycloalkylene), or -NR １ｂ -(wherein, R １ｂ represents a hydrogen atom or C １ to C ２ perfluoroalkyl), and X １ｂ and X １ｃ These are the same or different, respectively, -O- or -CH ２ - indicates (however, X １ｂ and X １ｃ (There are no cases where both simultaneously indicate -O-). R １ｃ is a hydrogen atom, a halogen atom, C １ ~C ２ Perfluoroalkyl, C １ ~C ２ Perfluoroalkoxy, C １ ~C ６ Alkyl or C １ ~C ２ It exhibits perfluoroalkylthio, R １ｄ is a hydrogen atom, a halogen atom, or C １ ~C ６ It shows alkyl, R １ｅ C is a hydrogen atom. １ ~C ２ Perfluoroalkyl or C １ ~C ２ [Indicates perfluoroalkoxy] X indicates -N= or -CH=, Ring A is, 【Transformation 3】 [In the formula, X ２ａ is -N = or -CR ２ａ = (in the formula, R ２ａ is a hydrogen atom, a halogen atom, C １ ~C ６ Alkyl or C １ ~C ６ (Indicates an alkoxy) R ２ｂ is a hydrogen atom, a halogen atom, C １ ~C ６ Alkyl or C １ ~C ６ It shows an alkoxy, L is -(CHR ３ａ ) ｎ - (wherein n represents 0, 1, 2 or 3, R ３ａ They may be the same or different, and each may be a hydrogen atom or C １ ~C ６ (Indicates alkyl), - (CH ２ ) ｍ -O-(CH ２ ) ｍ’ - (In the formula, m and m' are the same or different, representing 0, 1, or 2, respectively), C ２ ~C ３ Alkenylene, 【Chemistry 4】 (In the formula, R ３ｂ and R ３ｃ These may be the same or different, and each may be a hydrogen atom or C １ ~C ６ It indicates alkyl, R ３ｄ C is a hydrogen atom. １ ~C ６ Alkoxy, C １ ~C ６ Alkyl or C １ ~C ２ R indicates a perfluoroalkyl group. ３ｅ C is a hydrogen atom. １ ~C ６ Alkoxy, C １ ~C ６ Alkyl or C １ ~C ２ (Indicates perfluoroalkyl.) A method for producing a carboxylic acid compound represented by or a pharmaceutically acceptable salt thereof, The following general formula (A4): 【Transformation 5】 (In the formula, R ４ (This symbol is an alkyl group, and the other symbols are defined as above.) A step of hydrolyzing the compound represented by the above in a mixed aqueous solution in the presence of a base, A manufacturing method that includes this.

2. The following general formula (A2): 【Transformation 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): 【Transformation 7】 (In the formula, X Ａ (wherein is a halogen atom, and the other symbols are as defined in claim 1.) The manufacturing method according to claim 1, further comprising the step of reacting a compound represented by 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): 【Transformation 8】 (In the formula, X Ｂ (wherein is a halogen atom, and the other symbols are as defined in claim 1.) The manufacturing method according to claim 2, further comprising the step of reacting a compound represented by with bis(pinacolate)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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