Novel anthranilic acid-based compounds, pin 1 inhibitor, therapeutic agent, and preventive agent for infectious diseases, etc. using same

Abstract

[Problem] The purpose of this invention is to develop novel compounds having an activity that inhibits the function of Pin1 and use these compounds as candidate compounds for pharmaceuticals. [Solution] This invention provides compounds represented by formula (I) and salts thereof. (In the formula: R1 and R2 are each a phenyl group or a thienyl group, at least one of R1 and R2 is substituted with at least one R4 substituent and is not substituted with a substituent other than R4, R4 being a halogen, a hydroxyl group, a C1-C6 alkyl group, which may have a substituent, or a methylenedioxy group, which may have a substituent; R3 is a hydrogen atom, a hydrocarbon group, which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent; and X is a single bond, a -CH2- group, or a -CH2-O- group. However, compounds in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond are excluded).

Description

Novel anthranilic acid compounds, Pin1 inhibitors using the same, and therapeutic or preventive agents for infectious diseases, etc.

[0001] The present invention relates to novel anthranilic acid-based low-molecular-weight organic compounds, and further relates to Pin1 inhibitors, pharmaceutical compositions, therapeutic or preventive agents for coronavirus infections, infectious diseases including herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, and Theileria parasite infections, therapeutic or preventive agents for inflammatory diseases including non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, and pulmonary fibrosis, therapeutic or preventive agents for cancer, and therapeutic or preventive agents for obesity, all of which use the compounds.

[0002] Pin1 is a type of peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the cis / trans conformational change of proline in proteins. It specifically acts on the proline located next to phosphorylated serine or threonine to change the conformation. Therefore, Pin1 is a molecule that links protein phosphorylation to protein conformational changes and is thought to play an important role in intracellular signal transduction. It has been reported that Pin1 expression levels are significantly increased in several tissues, such as the liver, muscle, adipose tissue, and kidney, of obese and diabetic mice (Non-Patent Documents 1-3). It has also been reported that Pin1 promotes the proliferation of several viruses, including cytomegalovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and feline coronavirus (Non-Patent Documents 4-10). However, it is presumed that the molecular mechanisms underlying the promotion of Pin1 induction by viral proliferation differ between these viruses. It has also been reported that Pin1 knockout mice exhibit Alzheimer's disease-like symptoms (Non-Patent Document 11). Furthermore, the present inventors have previously reported that Pin1, a type of cis-trans isomerase, binds to IRS-1, which plays a central role in insulin signaling, and enhances its signal transduction (Non-Patent Document 3).

[0003] Compounds that inhibit Pin1 have been reported, including phenylalaninol phosphate derivatives, indole or benzimidazole alanine derivatives, fredericamycin A compounds, phenylimidazole derivatives, naphthyl-substituted amino acid derivatives, and glutamic or aspartic acid derivatives (Patent Documents 1 to 4 and Non-Patent Documents 12 to 15). Furthermore, it is known that Pin1 inhibitors having specific structures can be used as therapeutic or preventive agents for fatty liver disease, obesity, inflammatory diseases, and cancer (Patent Documents 5 to 8 and Non-Patent Documents 12, 13, and 16). It has also been reported that the Pin1 inhibitor dipentamethylenethiuram monosulfide inhibits the replication of feline coronavirus (FCoV) (Non-Patent Document 10), and that Pin1 inhibitors can suppress the proliferation of SARS-CoV-2, potentially making them useful as therapeutic or preventive agents for coronavirus infection (COVID-19) caused by SARS-CoV-2 (Patent Documents 8 and 9).

[0004] Coronaviruses are viruses that infect not only humans but also animals, causing a variety of diseases. In addition to domestic animals such as dogs, cats, cows, pigs, chickens, horses, alpacas, and camels, coronaviruses specific to each animal (animal coronaviruses) have been detected in beluga whales, giraffes, ferrets, suncus, bats, and sparrows. Coronaviruses are highly species-specific and rarely cross species barriers to infect other animals. Coronaviruses that infect humans include four commonly occurring human coronaviruses (HCoVs): HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. Two severe pneumonia viruses transmitted from animals are known: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).

[0005] Around December 2019, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) was confirmed as a novel coronavirus. It quickly spread around the world, becoming a global pandemic with no end in sight. COVID-19, an infectious disease caused by SARS-CoV-2, is primarily transmitted person-to-person through airborne droplets dispersed by infected individuals when they cough or sneeze. Symptoms of COVID-19 include fever, respiratory symptoms, headache, and fatigue, and may also cause loss of smell and taste. The mortality rate of COVID-19 is particularly high among the elderly and patients with underlying conditions (cardiovascular disease, diabetes, chronic respiratory disease, chronic kidney disease, hypertension, and obesity). Under these circumstances, there is a strong need for effective therapeutic and preventive drugs for COVID-19. Coronaviruses are a type of RNA virus (single-stranded RNA virus) that carries RNA as its genetic information. They have a double membrane made of lipids called an "envelope" on the outermost surface of the particle. They are spherical, approximately 100 nm in diameter, with protrusions on their surface, giving them a crown-like shape. Coronaviruses cannot replicate on their own, but they attach to and penetrate human mucous membranes and other cells to multiply. Virologically, they are classified into the Nidovirales order, Orthocoronavirinae subfamily, and Coronaviridae family. Based on genetic characteristics, they are divided into four groups: alpha, beta, gamma, and delta. HCoV-229E and HCoV-NL63 are classified as alpha coronaviruses, while MERS-CoV, SARS-CoV, SARS-CoV-2, HCoV-OC43, and HCoV-HKU1 are classified as beta coronaviruses.

[0006] Other known viral infections include herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, gamak virus, vaccinia virus, poliovirus, and cocksackievirus. Herpes simplex virus (HSV) is classified into type 1 (HSV-1) and type 2 (HSV-2) based on its serotype and genotype. It has a 150-kbp genome and encodes more than 80 genes. It uses the host cell membrane as its envelope, with tegument proteins inside and a capsid inside, within which viral DNA is packaged. Mature particles are large, measuring 100–150 nm (1 nanometer = 1 / 1,000,000 of a millimeter). After infecting humans through the skin or mucous membranes, HSV invades cells by fusing its envelope with the host cell membrane. Teguments and nucleocapsids are released into the cell. Viral protein and DNA synthesis continues in the nucleus, producing progeny viruses that eventually escape the cell. They may then infect neighboring cells.

[0007] Zika virus is a spherical virus with a diameter of 40-50 nm belonging to the Flavivirus genus of the Flaviviridae family. Its core particle, 25-35 nm in diameter, is composed of a basic core protein of approximately 12 kDa, containing viral RNA. The core particle is surrounded by an envelope composed of two proteins: an approximately 8 kDa membrane protein (M protein) and an approximately 53 kDa glycoprotein (E protein). The E protein is involved in host affinity and cell adsorption, and is the primary protein responsible for inducing protective immunity against Zika virus. The viral RNA is a single-stranded RNA of 10,794 bases, a positive-strand RNA that functions as mRNA upon release into host cells following viral infection. Zika virus infection is primarily transmitted via mosquitoes in a human-mosquito-human cycle. Symptoms include generalized discomfort and fatigue, followed by fever, headache, and generalized muscle pain.

[0008] Respiratory syncytial virus (RSV) belongs to the Orthopneumovirus genus of the Pneumoviridae family and is a type of enveloped, spherical, or filamentous negative-single-stranded RNA virus with a diameter of 80-350 nm. The viral RNA is approximately 15.2 kb long and encodes 11 proteins. The viral surface contains the G (large glycoprotein) protein (which adheres to the host), the F (fusion) protein (which causes membrane fusion), and the SH (small hydrophobic) protein. Two serotypes, A and B, are known. RSV can become severe in immunocompromised adults and in infants, causing bronchitis and pneumonia.

[0009] Hantaviruses (orthohantaviruses) are a collective term for viruses belonging to the genus Hantavirus (Hantaviridae) in the family Bunyavirales. Their natural hosts are small mammals such as rodents and shrews, and they are not pathogenic to these animals. However, human infection can cause severe diseases such as hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantaviruses contain three negative-strand RNA segments within their particles, designated S, M, and L segments. The S segment encodes the nucleoprotein (N), the M segment encodes the glycoprotein precursor (GPC) for two envelope glycoproteins (Gn and Gc), and the L segment encodes the RNA-dependent RNA polymerase (RdRp). The base sequences at both ends of each genome are complementary to each other, allowing them to combine to form a circular structure. Hantavirus particles are spherical or ovoid, with diameters ranging from 80 to 120 nm. Hantaviruses infect vascular endothelial cells, epithelial cells, macrophages, follicular dendritic cells, lymphocytes, and other cells through binding of their envelope glycoproteins to receptors on the host cell surface. β3 integrin, DAF / CD55, and gC1qR / p32 have been reported as receptors for hantaviruses. Nonpathogenic hantaviruses have also been reported to use β1 integrin as a receptor. Hantaviruses migrate to early endosomes via clathrin-coated pits and are then transported to late endosomes or lysosomes. When the pH drops below 6.4 in the endolysosomal compartment, they fuse with the plasma membrane and undergo uncoating. Hantavirus replication occurs entirely in the cytoplasm. RdRp synthesizes positive-strand mRNA from genomic S, M, and L segments (vRNA) using the N cap-snatching mechanism. The replicated viral genome binds to nucleoproteins to form nucleocapsids, which then bind to envelope glycoproteins on the cytoplasmic side of the Golgi apparatus and bud off into the Golgi apparatus. The budding virions are then released outside the cell.

[0010] Rhinovirus is a general term for viruses of the Rhinovirus family (types A to C) belonging to the Enterovirus genus of the Picornaviridae family, and generally refers to human rhinovirus (HRV). Human rhinovirus is one of the viruses that causes acute respiratory disease, and while most symptoms are mild, similar to the common cold, it has also been suggested that it may be closely related to other respiratory diseases such as asthma. Human rhinovirus is a single-stranded RNA virus.

[0011] Gamak virus (GAKV) is a recently discovered virus belonging to the genus Henipavirus in the family Paramyxoviridae. It has a single-stranded RNA genome of approximately 18,460 nucleotides and contains six genes. The virus was originally discovered in shrews, which are the natural host for human pathogens. The Henipavirus genus, to which Gamak virus belongs, is an important zoonotic pathogen that causes severe acute respiratory distress and neurological disorders in humans. Although Gamak virus infection has not yet been reported in humans, Gamak virus infects human lung epithelial cells in culture and induces the upregulation of several human innate antiviral genes in vitro.

[0012] Vaccinia virus (VACV or VV) is an enveloped DNA virus belonging to the Poxviridae family. It has a linear double-stranded DNA genome of approximately 190,000 base pairs, encoding approximately 250 genes. Vaccinia virus is used as a live vaccine against smallpox. Vaccinia virus is highly attenuated, and healthy individuals generally show no symptoms even after infection, or may develop a mild rash and fever, which resolves spontaneously. However, immunocompromised individuals and those with poor general health (homeostatic stability) may become seriously ill.

[0013] Poliovirus is a type C enterovirus belonging to the genus Enterovirus (an enteric virus) of the family Picornaviridae. It is antigenically classified into three types: type 1, type 2, and type 3. Poliovirus is an RNA virus composed of a positive-sense genome of single-stranded RNA (ssRNA) consisting of approximately 7,500 base pairs and a protein capsid. The virus particle has an icosahedral structure with a diameter of approximately 30 nm. Poliovirus is a human host. It enters the human body orally, replicates in the mucous membranes of the pharynx and small intestine, and enters the bloodstream via lymph nodes. It then reaches the central nervous system, centered on the spinal cord, infecting anterior horn cells of the spinal cord and motor neurons in the brainstem, destroying them and resulting in the typical symptoms of acute poliomyelitis (commonly known as poliomyelitis). There is no specific treatment; symptomatic treatment is the primary focus. In cases where respiratory compromise or inability to expectorate secretions is present, tracheotomy, intubation, or assisted ventilation may be required.

[0014] Coxsackievirus (CV) is a non-enveloped, linear, single-stranded, positive-sense RNA virus belonging to the genus Enterovirus in the family Picornaviridae. Coxsackieviruses are classified as "Enterovirus A" and "Enterovirus B" by the International Committee on Taxonomy of Viruses. Coxsackieviruses are divided into two groups, Group A and Group B, and are the causative agents of herpangina and hand, foot, and mouth disease. Group A causes flaccid paralysis due to systemic myositis, while Group B causes spastic paralysis (caused by localized muscle damage and degeneration of nervous tissue). Both Groups A and B commonly present with nonspecific fever, rash, and upper respiratory tract infections. They are the causative agents of summer colds and can also cause viral meningitis (aseptic meningitis) and encephalitis.

[0015] Influenza A virus (IAV) is a single-stranded, negative-sense RNA virus belonging to the Orthomyxoviridae family that is known to infect humans, birds, pigs, and other animals. Influenza A viruses are classified into subtypes based on mutations in the hemagglutinin (HA) and neuraminase (NA) proteins, and are designated as H3N2 (the virus that caused the 1968 "Hong Kong flu" pandemic, resulting in significant morbidity and mortality worldwide) and H5N3 (the virus that causes highly pathogenic avian influenza, occasionally infects humans, and is thought to have the potential to cause a pandemic if successfully adapted to human infection). Transmission occurs primarily through respiratory droplets from infected individuals, but can also occur by touching a virus-contaminated surface followed by contact with the mouth, nose, or eyes. IAV infection causes mild to severe influenza characterized by high fever, chills, generalized aches, and inflammation of the respiratory tract mucosa. Complications from infection can be particularly severe in high-risk groups, leading to hospitalization and even death. Vaccination against influenza viruses can prevent infection and reduce symptoms, but it only vaccinates against the subtypes that are most prevalent each season and cannot completely prevent large-scale epidemics. Antiviral drugs such as oseltamivir and zanamivir can reduce the severity and duration of illness, but are only effective if taken early in the course of the illness. Influenza A viruses are a major public health concern because of their potential to cause large-scale outbreaks and pandemics.

[0016] Feline calicivirus (FCV) is a single-stranded, positive-sense RNA virus belonging to the Caliciviridae family that infects and causes disease in cats. The virus is transmitted between cats through contact with saliva, nasal discharge, eye discharge, or respiratory droplets from an infected cat. Infection causes respiratory symptoms such as sneezing, nasal congestion, and stomatitis, as well as systemic symptoms such as fever, loss of appetite, and lethargy. While a vaccine is available to prevent infection, there is no specific treatment for infected cats.

[0017] Feline infectious peritonitis virus (FIPV) is a variant of feline coronavirus (FCoV) and is closely related to human coronaviruses. It is an enveloped, single-stranded, positive-sense RNA virus belonging to the Coronaviridae family. Infection occurs primarily via fecal-oral ingestion of FCoV, which can mutate into FIVP after intestinal infection. Infected cats develop either exudative peritonitis, characterized by fluid accumulation in the abdomen and chest, leading to respiratory distress, loss of appetite, fever, weight loss, jaundice, and diarrhea, or nonexudative peritonitis, characterized by granulomatous lesions in various organs, leading to jaundice, neurological signs, ocular changes, and gastrointestinal distress. There is no available vaccine to prevent FIPV, and no specific treatment is available to treat infection.

[0018] Severe fever with thrombocytopenia syndrome virus (SFTSV, also known as Daby-Banda virus) is a single-stranded, negative-sense RNA virus belonging to the family Fenuiviridae. The virus is transmitted by ticks and infects many mammalian hosts, including cats, mice, hedgehogs, weasels, brush-tailed possums, yaks, and humans. In addition to infection via tick bites, SFTSV can also be transmitted person-to-person via contact with the blood or mucus of infected individuals. The main clinical symptoms of SFTS infection are fever, vomiting, diarrhea, multiple organ failure, thrombocytopenia, leukopenia, and elevated liver enzymes. The mortality rate among infected individuals with severe fever with thrombocytopenia syndrome is estimated to range from 6% to 27%, with the difference in mortality likely related to the genotype of the virus prevalent in affected areas. As of 2024, the virus has been found primarily in East Asia, namely China, South Korea, and Japan, but due to the increasing incidence of SFTS and the rapid global spread of the SFTSV vector, the virus is considered to have pandemic potential and poses an imminent threat to global public health.

[0019] Infectious bronchitis virus (IBV) is an enveloped, single-stranded, positive-sense RNA virus belonging to the coronavirus family that infects and causes disease in chickens. The virus is primarily transmitted by direct and indirect contact between birds, aerosol transmission, and occasionally vertical transmission from chicken to egg. Infection causes avian infectious bronchitis, a disease affecting the respiratory, intestinal, renal, and reproductive systems. IBV impacts productivity in both meat and layer chickens, causing significant economic losses in the poultry industry. Currently, there is no specific antiviral treatment for IBV, so vaccination is widely used to prevent outbreaks.

[0020] Adenoviruses (AdV) are non-enveloped, double-stranded DNA viruses of the Adenoviridae family. Adenoviruses of the Mastadenovirus genus infect humans, causing respiratory illnesses (including the common cold), conjunctivitis, and gastroenteritis, and are associated with human obesity. Adenoviral type 8 is reported to be the most common cause of adenoviral keratoconjunctivitis, followed by types 19 and 37. The virus is primarily transmitted via respiratory droplets, but also via the fecal-oral route. Currently, most adenovirus infections are treated with nonspecific supportive care. Vaccines have been produced against a few serotypes, but are generally only used by the military to reduce infection outbreaks on military bases. Pool chlorination is also used to prevent adenoviral conjunctivitis acquired from swimming in public pools.

[0021] Murine norovirus (MNV) is a non-enveloped, positive-sense, single-stranded RNA virus belonging to the Calciviridae family of the Norovirus genus. It is a highly prevalent and contagious virus that infects mice. The primary route of infection is through the ingestion of virus-contaminated feces. In most cases, infection is asymptomatic in immunocompetent mice. However, immunocompromised mice can develop a variety of symptoms similar to those of human norovirus infection, including diarrhea, weight loss, and dehydration. MNV is widespread in laboratory mouse colonies worldwide and poses a significant concern for researchers. MNV infection can potentially impact research outcomes, particularly in studies of the immune system, digestive system, and other related fields. Meanwhile, MNV has become a useful animal model for studying the pathogenesis and genetics of human norovirus infection.

[0022] Rotavirus (RoV) is a non-enveloped, double-stranded RNA virus belonging to the Cedreoviridae family. The primary mode of infection is ingestion of the virus via the fecal-oral route from contaminated hands, surfaces, food, or water. RoV infection causes severe diarrhea and gastroenteritis, accompanied by fever and severe, sometimes life-threatening, dehydration, especially in young children. Vaccines to prevent rotavirus infection are available for infant vaccination and are recommended in immunization programs worldwide. However, individuals with rotavirus infection can only receive supportive care, such as oral rehydration therapy and intravenous fluid therapy to prevent dehydration, and medications to relieve fever and pain.

[0023] Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is an enveloped, double-stranded DNA virus belonging to the Orthoherpesviridae family and is one of the most common viruses in humans. It is primarily transmitted through the exchange of saliva, such as kissing or the sharing of drinks, eating utensils, or other personal items. Less commonly, EBV can be transmitted through blood or semen, or vertically from mother to child in the womb or at birth. EBV infection can cause infectious mononucleosis, characterized by fever, sore throat, swollen lymph nodes, and fatigue. In some cases, EBV infection can remain chronically active, resulting in prolonged illness. EBV infection is associated with certain cancers, including Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. It is also associated with multiple sclerosis (MS) and other autoimmune diseases. There is no specific antiviral treatment for EBV, and no approved EBV vaccine. Supportive care is available, including rest, fluids, and painkillers as needed depending on symptoms.

[0024] Japanese encephalitis virus (JEV) is an enveloped, positive-sense, single-stranded RNA virus belonging to the Flaviviridae family. It is transmitted to humans by mosquitoes and is usually asymptomatic, although a small percentage of infected individuals develop severe encephalitis. Symptoms of severe encephalitis include high fever, headache, neck stiffness, loss of consciousness, coma, spastic paralysis, and death. Infected individuals who develop encephalitis may experience long-term neurological or psychiatric complications. While a vaccine is available to prevent JEV infection, no specific antiviral treatment for JEV is available. Supportive care is available to alleviate symptoms and manage complications.

[0025] Theileria parasites are obligate intracellular protozoan parasites belonging to the Apicomplexa phylum. They infect a variety of wild and domestic animals, especially cattle, and are transmitted by ticks. Theileria parasites are responsible for several important veterinary diseases, primarily in tropical and subtropical regions. Among the species of Theileria that infect livestock, Theileria parva causes East Coast fever in cattle, characterized by high fever, swollen lymph nodes, respiratory distress, anemia, and high mortality if left untreated. Theileria annulata causes tropical theileriosis in cattle, characterized by fever, anemia, jaundice, swollen lymph nodes, weakness, and decreased milk production. Theileria orientalis causes theileriosis in cattle, characterized by fever, anemia, jaundice, and lethargy. Theileria equi causes piroplasmosis in horses, characterized by fever, anemia, jaundice, abdominal swelling, and weight loss. Antiprotozoal drugs such as buparvaquone are available to treat infection, but resistance to these drugs has recently begun to develop, making them less effective. Supportive care is typically used to alleviate the symptoms of the disease. Acaricides can also be used to reduce tick populations and prevent infection, and a vaccine against Theileria parva is also available. Despite the availability of treatments and preventative measures, infections caused by Theileria parasites have a significant economic impact due to the high costs of treatment and tick control (hundreds of millions of dollars), the deaths of over one million cattle annually, and reduced cattle production.

[0026] Incidentally, it is known that certain anthranilic acid compounds have the activity of inhibiting the proliferation of T cells and can be used as therapeutic agents for autoimmune diseases and the like (Patent Document 10), that they regulate the activity of peroxisome proliferator-activated receptors (PPAR) α and / or γ and are useful in the treatment of metabolic diseases, such as type 2 diabetes (Patent Document 11), and that they are useful as agricultural and horticultural fungicides (Patent Document 12).

[0027] International Publication No. WO 2004 / 087720 International Publication No. WO 2006 / 040646 International Publication No. WO 2005 / 007123 International Publication No. WO 2002 / 060436 International Publication No. WO 2019 / 031471 International Publication No. WO 2019 / 031472 International Publication No. WO 2019 / 031470 International Publication No. WO 2021 / 182457 International Publication No. WO 2022 / 107745 Special Publication No. 2010-520857 International Publication No. WO 03 / 004458 International Publication No. 2016 / 182021

[0028] Yusuke Nakatsu and other 10 books, International Journal of Molecular Sciences, September 7, 2016, Vol. 17(9), E1495Yusuke Nakatsu and other 20 books, Journal of Biological Chemistry, December 2012, Vol. 287(53), p. 44526-35Yusuke Nakatsu and other 22 books, Journal of Biological Chemistry, June 2011, Vol. 286(23), p. 20812-22Martin Schutz and other 9 books, Virus Research, August 2020, Vol. 285, 198023Yohei Narita and other 7 books, Journal of Virology, February 2013, Vol. 87, No. 4, p. 2120-2127Mayuko Nishi (9 other books), Frontiers in Cell and Developmental Biology, January 2020, Vol. 8, Article 26; Yun-Sook Lim (4 other books), Journal of Virology, September 2011, Vol. 85, No. 17, pp. 8777-8788; Hai Hou (3 other books), Gene, June 2015, Vol. 565, Issue 1, pp. 9-14; Shogo Misumi (6 other books), Journal of Biological Chemistry, August 13, 2010, Vol. 285, No. 33, pp. 25185-25195; Yoshikazu Tanaka (4 other books), Antiviral Research Journal, February 2016, Vol. 126, pp. 1-7; Yih-Cherng (1 other books). Liou and other 11 famous books, Nature, published July 31, 2003, Vol. 424, pp. 556-561 Andrew Potter and other 16 famous books, Bioorganic & Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.), November 15, 2010 (Online edition published September 17, 2010), Vol. 20, No. 22, pp.6483-6488 Andrew Potter and 14 other authors, Bioorganic & Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.), January 15, 2010 (online edition published November 22, 2009), Vol. 20, No. 2, pp. 586-590 Liming Dong and 11 other authors, Bioorganic & Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.), April 1, 2010 (online edition published February 14, 2010), Vol. 20, No. 7, pp. 2210-2214 Hidehiko Nakagawa and 6 other authors, Bioorganic & Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.) Lett.), December 1, 2015 (online edition published October 22, 2015), Vol. 25, pp. 5619-5624. Tomoichiro Asano, "New Treatment for Inflammatory Bowel Disease with Pin1 Inhibitors," materials for the DSANJ Disease-Specific Business Meeting (Gastrointestinal Diseases) hosted by the Osaka Chamber of Commerce and Industry, published January 30, 2015.

[0029] In view of the above-mentioned conventional situation, an object of the present invention is to develop a group of novel compounds having activity to inhibit the function of Pin1, and to use them as candidate compounds for pharmaceuticals.

[0030] To achieve the above object, the present inventors conducted extensive research and developed a group of novel compounds by synthesizing numerous anthranilic acid derivatives containing a phenyl or thienyl group substituted with a halogen, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted methylenedioxy group. The present inventors discovered that these novel compounds have activity that inhibits the function of Pin1 and can be used as therapeutic or preventive agents for infectious diseases including coronavirus infections, herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, and Theileria parasite infections, as well as therapeutic or preventive agents for non-alcoholic steatohepatitis, cancer, and the like, thereby completing the present invention.

[0031] Specifically, the present invention provides novel compounds or salts thereof that are candidate compounds for pharmaceuticals, Pin1 inhibitors, pharmaceutical compositions, therapeutic or preventive agents for coronavirus infections, herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infections, therapeutic or preventive agents for inflammatory diseases including non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, and pulmonary fibrosis, therapeutic or preventive agents for cancer, and therapeutic or preventive agents for obesity.

[0032] The compound of the present invention or a salt thereof is represented by formula (I): (wherein R1 and R2 each represent a phenyl group or a thienyl group, at least one of R1 and R2 is substituted with at least one R4 substituent, and R1 and R2 are not substituted with any substituent other than R4, wherein R4 represents a halogen, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted methylenedioxy group, R3 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group, X represents a single bond, -CH ２ - group, or -CH ２ -O- group, provided that compounds in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond are excluded.) or a salt thereof.

[0033] Furthermore, in the above compound, R4 may be a halogen atom, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group. Furthermore, in the above compound, the total number of halogen atoms contained in R1 and R2 may be 3 or more. Furthermore, in the above compound, R3 may be a hydrogen atom or a methyl group.

[0034] Furthermore, the Pin1 inhibitor of the present invention includes any of the above compounds or a salt thereof. Furthermore, the pharmaceutical composition of the present invention includes any of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0035] The therapeutic or preventive agent for coronavirus infection of the present invention contains any of the above compounds or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, in the therapeutic or preventive agent for coronavirus infection, the coronavirus infection may be an infection caused by a β-coronavirus or SARS-CoV-2. Furthermore, the therapeutic or preventive agent for coronavirus infection may further contain the active ingredient of at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for coronavirus infection. Furthermore, the therapeutic or preventive agent for coronavirus infection may be used in combination with at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for coronavirus infection for treating or preventing coronavirus infection. The present invention also provides use of the therapeutic or preventive agent for coronavirus infection for the manufacture of a medicament for treating or preventing coronavirus infection. The present invention also provides a method for treating or preventing coronavirus infection, comprising administering an effective amount of the therapeutic or preventive agent for coronavirus infection to a subject in need thereof.

[0036] The therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention is a compound represented by the formula (I'): (wherein R1 and R2 are each a phenyl group or a thienyl group, (1) R1 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, or (2) R2 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, or (3) R1 and R2 are substituted with at least one R4 substituent and are not substituted with any other substituent than R4, wherein R4 is a halogen, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted methylenedioxy group, R3 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group, X is a single bond, -CH ２ - group, or -CH ２-O- group.) or a salt thereof as an active ingredient. Furthermore, in the above-mentioned therapeutic or prophylactic agent, R4 may be a halogen atom, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group. Furthermore, in the above-mentioned therapeutic or prophylactic agent, the total number of halogen atoms contained in R1 and R2 may be 3 or more. Furthermore, in the above-mentioned therapeutic or prophylactic agent, R3 may be a hydrogen atom or a methyl group. Furthermore, the above-mentioned therapeutic or preventive agent may further contain at least one or more active ingredients selected from herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or other agents classified as therapeutic or preventive agents for Theileria parasitic infections.Furthermore, the above-mentioned therapeutic or preventive agent may be used in combination with at least one or more drugs selected from herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or other drugs classified as therapeutic or preventive agents for Theileria parasitic infections. The present invention may be for treating or preventing infection with a herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, Cocksackie virus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite. The present invention also provides use of any of the above therapeutic or prophylactic agents for the manufacture of a medicament for treating or preventing infection with a herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, Cocksackie virus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite.The present invention also provides a method for treating or preventing herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection, which comprises administering an effective amount of any of the above therapeutic or preventive agents to a subject in need thereof.

[0037] The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention contains any of the above compounds or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, in the therapeutic or preventive agent, the inflammatory disease accompanied by fibrosis may be non-alcoholic steatohepatitis, inflammatory bowel disease, or pulmonary fibrosis. Furthermore, the therapeutic or preventive agent may further contain the active ingredient of at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis. Furthermore, the therapeutic or preventive agent may be used in combination with at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis to treat or prevent inflammatory diseases accompanied by fibrosis. The present invention also provides use of any of the therapeutic or preventive agents described above for the manufacture of a medicament for treating or preventing inflammatory diseases accompanied by fibrosis. The present invention also provides a method for treating or preventing inflammatory diseases accompanied by fibrosis, comprising administering an effective amount of any of the therapeutic or preventive agents described above to a subject in need thereof.

[0038] The cancer therapeutic or preventive agent of the present invention contains any of the above compounds or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, in the above therapeutic or preventive agent, the cancer may be colon cancer or prostate cancer. Furthermore, the above therapeutic or preventive agent may further contain the active ingredient of at least one or more drugs selected from other drugs classified as cancer therapeutic or preventive agents. Furthermore, the above therapeutic or preventive agent may be used in combination with at least one or more drugs selected from other drugs classified as cancer therapeutic or preventive agents for the treatment or prevention of cancer. The present invention also provides use of any of the above therapeutic or preventive agents for the manufacture of a medicament for treating or preventing cancer. The present invention also provides a method for treating or preventing cancer, comprising administering an effective amount of any of the above therapeutic or preventive agents to a subject in need thereof.

[0039] The therapeutic or preventive agent for obesity of the present invention contains any of the above compounds or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the therapeutic or preventive agent may further contain the active ingredient of at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for obesity. Furthermore, the therapeutic or preventive agent may be used in combination with at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for obesity to treat or prevent obesity. The present invention also provides use of any of the above therapeutic or preventive agents for the manufacture of a medicament for treating or preventing obesity. The present invention also provides a method for treating or preventing obesity, comprising administering an effective amount of any of the above therapeutic or preventive agents to a subject in need thereof.

[0040] The novel compound or a salt thereof of the present invention can be a compound or a precursor thereof having activity of inhibiting the function of Pin1, or can be a therapeutic agent, a preventive agent, or a prodrug thereof for viral infections, parasitic infections, inflammatory diseases, cancer, obesity, etc., and therefore has the effect of being usable in the development of Pin1 inhibitors or pharmaceuticals for use in the treatment of viral infections, parasitic infections, inflammatory diseases, cancer, obesity, etc.

[0041] A shows the quantitative values ​​of the Zika virus NS1 gene by real-time quantitative PCR after treatment with various concentrations of H-958, B shows the results of nonlinear regression analysis, and C shows the results of plaque assay and calculated plaque-forming units per mL (PFU / ml). A shows the quantitative values ​​of the RS virus N gene by real-time quantitative PCR after treatment with various concentrations of H-958, B shows the results of nonlinear regression analysis. A shows the quantitative values ​​of the Seoul-type hantavirus S segment by real-time quantitative PCR after treatment with various concentrations of H-958, B shows the results of nonlinear regression analysis. A shows the quantitative values ​​of the Gamak virus N9 gene by real-time quantitative PCR after treatment with various concentrations of H-958. Figure 1 shows the quantitative values ​​of the hRV-A virus VP1 gene by real-time quantitative PCR after treatment with various concentrations of H-958, B shows the results of nonlinear regression analysis thereof, and C shows the results of plaque assay and calculated plaque-forming units per mL (PFU / ml). Figure 1 shows the quantitative values ​​of the vaccinia virus E9L gene by real-time quantitative PCR after treatment with various concentrations of H-958, B shows the results of nonlinear regression analysis thereof, and C shows the results of plaque assay and calculated plaque-forming units per mL (PFU / ml). Figure 1 shows the quantitative values ​​of the HSV-1 UL30 gene by real-time quantitative PCR after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days. Quantitative real-time quantitative PCR results for IAV (H3N2) HA gene after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days are shown. Quantitative real-time quantitative PCR results for IAV (H5N3) HA gene after treatment with 10 μM H-1134 for 3 days are shown. Quantitative real-time quantitative PCR results for PoV genome after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days are shown. Quantitative real-time quantitative PCR results for FCV VP1 gene after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days are shown. Quantitative real-time PCR of the FIPV ORF1ab gene after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days is shown.Figure 1 shows the quantitative values ​​of real-time quantitative PCR for the SFTSV genome S segment after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days. Figure 2 shows the quantitative values ​​of real-time quantitative PCR for the CV genome after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days. Figure 3 shows the quantitative values ​​of real-time quantitative PCR for the MNV nsp gene after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 1 day. Figure 4 shows the quantitative values ​​of real-time quantitative PCR for the RoV VP1 gene after treatment with 10 μM H-958, H-1134, H-1209, or H-1211 for 3 days.

[0042] 1. Chemical Structure of the Compound 1-1. General Formula of the Compound The anthranilic acid compound of the present invention has a chemical structure represented by the following formula (I): In the formula, R1 and R2 each represent a phenyl group or a thienyl group, at least one of R1 and R2 is substituted with at least one R4 substituent, and R1 and R2 are not substituted with any substituent other than R4, wherein R4 represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted methylenedioxy group, R3 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group, X represents a single bond, -CH ２ - group, or -CH ２ -O- group, except for compounds in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond.

[0043] 1-2. Regarding R1 and R2 In formula (I), R1 is a phenyl group or a thienyl group, which may be substituted with at least one R4 substituent and is unsubstituted with any other substituents. When R1 is a phenyl group, it may be substituted with 1 to 5 R4 substituents. When R1 is a thienyl group, it may be substituted with 1 to 3 R4 substituents, and hydrogen is bonded to the carbon atom not substituted with an R4 substituent. When R1 is a thienyl group, it may be connected to the -O-CH2- of the skeletal structure at the 2-position or the 3-position. In formula (I), R2 is a phenyl group or a thienyl group, which may be substituted with at least one R4 substituent and is unsubstituted with any other substituents. When R2 is a phenyl group, it may be substituted with 1 to 5 R4 substituents. When R2 is a thienyl group, it may be substituted with 1 to 3 R4 substituents, and hydrogen is bonded to the carbon atom not substituted with an R4 substituent. When R2 is a thienyl group, it may be linked to the —O—CH2— of the skeleton structure at the 2-position or the 3-position.

[0044] R1 and R2, which are not substituted with an R4 substituent, are as follows:

[0045] 1-3. Regarding R4 At least one of R1 and R2 is substituted with at least one R4 substituent, and R1 and R2 are not substituted with any substituent other than R4. That is, any of the following applies: R1 is substituted with at least one R4 substituent and not with any substituent other than R4, and R2 is not substituted with any substituent; R1 is not substituted with any substituent, and R2 is substituted with at least one R4 substituent and not with any substituent other than R4; or both R1 and R2 are substituted with R4 substituents and not with any substituent other than R4. When both R1 and R2 are substituted with R4 substituents, the R4 substituent of R1 and the R4 substituent of R2 may be the same group or different groups. When each of R1 and R2 is substituted with multiple R4 substituents, they may be the same group or different groups.

[0046] R1 and R2 substituted with one R4 substituent are as follows:

[0047] R1 and R2 substituted with two R4 substituents are as follows: The two R4 substituents may be the same or different.

[0048] R1 and R2 substituted with three R4 substituents are as follows: The three R4 substituents may be the same or different.

[0049] R1 and R2 substituted with four and five R4 substituents are phenyl groups only, as follows: The four R4 substituents may be the same or different.

[0050] R4 is a halogen, a hydroxyl group (-OH), an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a methylenedioxy group which may have a substituent. Halogen is fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At). Examples of R1 and R2 when R4 is a halogen are shown below.

[0051] An example of R1 and R2 when R4 is a hydroxyl group is shown below.

[0052] The alkyl group having 1 to 6 carbon atoms is a chain alkyl group, and examples thereof include C groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group. 1-6 Examples of the alkyl group and cycloalkyl group include C groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. 3-6Examples of the "substituent" of the alkyl group having 1 to 6 carbon atoms which may have a substituent include a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), an amino group, a cyclic amino group (a 3- to 6-membered cyclic amino group which, in addition to carbon atoms and one nitrogen atom, may contain 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an imidazolidinyl group, a piperidyl group, a morpholinyl group, a dihydropyridyl group, a pyridyl group, an N-methylpiperazinyl group, an N-ethylpiperazinyl group, etc.), a cyano group, an amido group, a carbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group (e.g., a C group such as a methoxycarbonylamino group, an isoproxycarbonylamino group, or a tert-butoxycarbonylamino group). 1-6 alkoxycarbonylamino group), acylamino group (for example, formylamino group, acetylamino group, propionylamino group, etc. 1-6 acylamino group), thiol group, thioether group, and thioester group. Examples of the substituted alkyl group include halogenoalkyl groups (e.g., fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, chloroethyl group, dichloroethyl group, trichloroethyl group, bromoethyl group, dibromoethyl group, and tribromoethyl group), aminoalkyl groups (e.g., aminomethyl group, aminoethyl group, and morpholinylmethyl group), alkoxycarbonylaminoalkyl groups (e.g., tert-butoxycarbonylaminomethyl group), and acylaminoalkyl groups (e.g., acetylaminomethyl group). The following are examples of R1 and R2 when R4 is an alkyl group having 1 to 6 carbon atoms that may have a substituent: Here, Boc is a t-butoxycarbonyl group (-COOC(CH3)3), and Ac is an acetyl group (-COCH3).

[0053] The methylenedioxy group is a group containing -O-CH2-O-, and may be an alkoxymethoxy group in which an alkyl group is bonded to oxygen (for example, a methoxymethoxy group (-O-CH2-O-CH3) or an ethoxymethoxy group (-O-CH2-O-C2H5)), or a cyclic 1,3-dioxolane group. Furthermore, it may be a 1,3-dioxolane ring in which one side of the phenyl or thienyl groups in R1 and R2 is shared. The "substituent" of the optionally substituted methylenedioxy group can be bonded to oxygen or carbon, and includes an alkyl group (methyl group) or a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.). Examples of R1 and R2 when R4 is an optionally substituted methylenedioxy group are shown below.

[0054] The total number of halogen atoms contained in R1 and R2, i.e., the total number of halogen atoms contained in the R4 substituent, is preferably 2 or more, and more preferably 3 or more. R4 may be 3 or more halogen atoms, or R4 may be an alkyl group having 1 to 6 carbon atoms containing 2 or 3 or more halogen atoms as a substituent, or a methylenedioxy group containing 2 or 3 or more halogen atoms as a substituent. One of R1 or R2 may contain 2 or 3 or more halogen atoms, or both R1 and R2 may contain halogen atoms, resulting in a total of 2 or 3 or more halogen atoms. For example, R1 or R2 may be a di-, tri-, tetra-, or penta-halogenophenyl group, or a di-, tri-, or tetra-halogenothienyl group. Furthermore, the substituent R4 may contain 2 or 3 or more halogenoalkyl groups containing one halogen atom, 1 or 2 or more halogenoalkyl groups containing two halogen atoms, or 1 or 3 or more halogenoalkyl groups containing 2 or 3 or more halogen atoms. For example, R4 may be a halogen, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.

[0055] 1-4. Regarding R3 R3 is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent. From the viewpoint of the activity of the compound, R ３ is a hydrogen atom or a methyl group, and it is particularly preferred to use a compound where R is a hydrogen atom and the -COR group is a carboxyl group (-COH). However, even if R is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group and has low activity, it can easily be hydrolyzed to a hydrogen atom to form a carboxyl group, thereby increasing activity. Therefore, such compounds can also be used as prodrugs.

[0056] The term "hydrocarbon group" refers to a group of a compound composed of carbon atoms and hydrogen atoms, and includes, but is not limited to, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, or an aromatic hydrocarbon group, preferably one having 1 to 16 carbon atoms. Specific examples include, but are not limited to, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group. Here, examples of the "alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group. Examples of the "alkenyl group" include a vinyl group, a 1-propenyl group, an allyl group, an isopropenyl group, a butenyl group, and an isobutenyl group. Examples of the "alkynyl group" include an ethynyl group, a propargyl group, and a 1-propynyl group. Examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the "aryl group" include a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, an anthryl group, a biphenylenyl group, a phenanthrenyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenalenyl group, a fluorancenyl group, a pyrenyl group, a naphthacenyl group, and a hexacenyl group. Examples of the "substituent" of the hydrocarbon group which may have a substituent include a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), an amino group, a cyclic amino group (a 3- to 6-membered cyclic amino group which, in addition to carbon atoms and one nitrogen atom, may contain 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an imidazolidinyl group, a piperidyl group, a morpholinyl group, a dihydropyridyl group, a pyridyl group, an N-methylpiperazinyl group, an N-ethylpiperazinyl group, etc.), a cyano group, an amido group, a carbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group (e.g., a C group such as a methoxycarbonylamino group, an isoproxycarbonylamino group, or a tert-butoxycarbonylamino group, etc. 1-6alkoxycarbonylamino group), acylamino group (for example, formylamino group, acetylamino group, propionylamino group, etc. 1-6 acylamino group), thiol group, thioether group, and thioester group.

[0057] The term "heterocyclic group" refers to a group of a cyclic compound consisting of carbon atoms and atoms other than carbon. It is preferable to use an aromatic heterocyclic group as the "heterocyclic group." The "heterocyclic group" is not limited to these, but may be, for example, a 5- to 14-membered, monocyclic or pentacyclic heterocyclic group containing, in addition to carbon atoms, one to four heteroatoms, one or two of which are selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Specific examples include, but are not limited to, 5-membered ring groups containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon atoms, such as a 2- or 3-thienyl group, a 2- or 3-furyl group, a 1-, 2-, or 3-pyrrolyl group, a 1-, 2-, or 3-pyrrolidinyl group, a 2-, 4-, or 5-oxazolyl group, a 3-, 4-, or 5-isoxazolyl group, a 2-, 4-, or 5-thiazolyl group, a 3-, 4-, or 5-isothiazolyl group, a 3-, 4-, or 5-pyrazolyl group, a 2-, 3-, or 4-pyrazolidinyl group, a 2-, 4-, or 5-imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, and a 1H- or 2H-tetrazolyl group. Furthermore, it can be a 6-membered ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as a 2-, 3-, or 4-pyridyl group, N-oxide-2-, 3-, or 4-pyridyl group, N-oxide-2-, 4-, or 5-pyrimidinyl group, N-oxide-2-, 4-, or 5-pyrimidinyl group, thiomorpholinyl group, morpholinyl group, piperidino group, 2-, 3-, or 4-piperidyl group, thiopyranyl group, 1,4-oxazinyl group, 1,4-thiazinyl group, 1,3-thiazinyl group, piperazinyl group, triazinyl group, 3- or 4-pyridazinyl group, pyrazinyl group, or N-oxide-3- or 4-pyridazinyl group.Furthermore, it can be a bicyclic to tetracyclic fused ring group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as, for example, an indolyl group, a benzofuryl group, a benzothiazolyl group, a benzoxazolyl group, a xanthenyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, an indolizinyl group, a quinolidinyl group, a 1,8-naphthyridinyl group, a dibenzofuranyl group, a carbazolyl group, an acridinyl group, a phenanthridinyl group, a perimidinyl group, a phenazinyl group, a chromanyl group, a phenothiazinyl group, a phenoxazinyl group, or a 7H-pyrazino[2,3-c]carbazolyl group. Examples of the "substituent" of the optionally substituted heterocyclic group include a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), an amino group, a cyclic amino group (a 3- to 6-membered cyclic amino group which, in addition to carbon atoms and one nitrogen atom, may contain 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an imidazolidinyl group, a piperidyl group, a morpholinyl group, a dihydropyridyl group, a pyridyl group, an N-methylpiperazinyl group, an N-ethylpiperazinyl group, etc.), a cyano group, an amido group, a carbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group (e.g., a C-substituted alkoxycarbonylamino group such as a methoxycarbonylamino group, an isoproxycarbonylamino group, or a tert-butoxycarbonylamino group). 1-6 alkoxycarbonylamino group), acylamino group (for example, formylamino group, acetylamino group, propionylamino group, etc. 1-6 acylamino group), thiol group, thioether group, and thioester group.

[0058] The amino group which may have a substituent is a primary amino group, a secondary amino group, or a tertiary amino group. The secondary amino group may be an amino group having one substituent, and may be, for example, an alkylamino group, an arylamino group, an alkoxycarbonylamino group, or the like, but is not limited thereto. The tertiary amino group may be an amino group having two identical or different substituents, and may be, for example, a dialkylamino group, a diarylamino group, or the like, but is not limited thereto.

[0059] 1-5. About X X is a single bond, -CH ２ - group, or -CH ２ From the viewpoint of the activity of the compound, X is a single bond or a —CH ２ It is preferable to use a compound in which X is a - group, and more preferably, a compound in which X is a single bond. When X is a single bond, the chemical structure is represented by the following formula (I-I), and X is -CH ２ In the case of a - group, the chemical structure is represented by the following formula (I-II), and X is -CH ２ In the case of an —O— group, the chemical structure is represented by the following formula (I-III):

[0060] 1-6. Salts of Compounds Salts of the compounds of the present invention may be salts with inorganic bases, organic bases, inorganic acids, organic acids, acidic or basic amino acids, etc. When the compound of the present invention represented by formula (I) has an acidic functional group, it may be a salt with an inorganic base, organic base, or basic amino acid. Furthermore, when the compound of the present invention represented by formula (I) has a basic functional group, it may be a salt with an inorganic acid, organic acid, or acidic amino acid.

[0061] Salts with inorganic bases include, but are not limited to, sodium salts, potassium salts, ammonium salts, etc. Salts with organic bases include, but are not limited to, salts with trimethylamine, ethanolamine, cyclohexylamine, etc. Salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, phosphoric acid, etc. Salts with organic acids include, but are not limited to, salts with acetic acid, phthalic acid, fumaric acid, oxalic acid, etc. Salts with acidic amino acids include, but are not limited to, salts with aspartic acid and glutamic acid, and salts with basic amino acids include, but are not limited to, salts with arginine and lysine.

[0062] 1-7. Specific Examples of Compounds Table 1 shows specific examples of compounds having the chemical structure represented by formula (I).

[0063] 2. Method for Producing Compounds The anthranilic acid compounds of the present invention can be synthesized, for example, as shown in Scheme I below, by dehydration and hydrolysis using an anthranilic acid derivative (intermediate) having an alkoxy group containing an appropriate R1 at the 5-position and a carboxylic acid derivative containing an appropriate R2 and X. Alternatively, as shown in Scheme II below, the intermediate can be synthesized using the known methyl 2-acetamido-5-hydroxybenzoate (H-122) and a halogenated methyl group containing R1 (e.g., a bromomethyl group). In Schemes I and II, R1, R2, and X are the same as those in Formula (I). Specific synthesis conditions, etc., are described in detail in the Examples. The following schemes and Examples are merely examples of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art will be able to synthesize the compounds of the present invention by appropriately modifying the schemes based on the disclosures herein, existing commercially available chemicals, and known synthesis examples.

[0064] In Scheme I, first, the amino group of methyl anthranilate having an alkoxy group containing R at the 5-position and the carboxylic acid of a carboxylic acid derivative containing R and X were subjected to dehydration condensation to form an amide bond, thereby synthesizing the compound of the present invention in which R is a methyl group. Then, the ester of methyl anthranilate was hydrolyzed to synthesize the compound of the present invention in which R is a hydrogen atom.

[0065] Scheme II shows an example of a procedure for synthesizing an anthranilic acid derivative (intermediate) having an alkoxy group containing an appropriate R at the 5-position. First, methyl 2-acetamido-5-hydroxybenzoate (H-122), the starting compound for Scheme II, was synthesized in two steps using anthranilic acid as a starting material according to the method described in J. Org. Chem., 2001, vol. 66, pp. 2784-2788. Furthermore, as shown in Scheme II, an anthranilic acid derivative (intermediate) was synthesized in two steps using R bonded to a methyl halide group (e.g., a bromomethyl group) for H-122 according to the method described in J. Org. Chem., 2001, vol. 66, pp. 2784-2788.

[0066] In addition, in the compound of the present invention in which R3 in Scheme I is a hydrogen atom, by substituting the hydrogen atom with a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent, it is possible to synthesize a compound of the present invention containing any R3.

[0067] 3. Pin1 Inhibitors and Activity of Inhibiting Pin1 Function The Pin1 inhibitor of the present invention is a compound that inhibits the function of Pin1, and includes a compound represented by formula (I) or a salt thereof. The compound represented by formula (I) is a compound that has activity of inhibiting the function of Pin1, and the compound or a salt thereof can be used as a Pin1 inhibitor. Pin1 is a type of peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the cis / trans conformational change of proline in proteins, and is an enzyme that acts specifically on proline located next to phosphorylated serine or threonine to change the conformation. In the present invention, "inhibiting Pin1 function" means inhibiting the isomerase activity (isomerase activity) of Pin1 and / or inhibiting the activity of Pin1 to bind to or interact with other proteins such as IRS-1 and / or promoting degradation of the Pin1 enzyme.

[0068] To test whether a compound serving as an active ingredient has the activity of inhibiting Pin1 function, the activity of the compound of the present invention to inhibit Pin1 function can be measured, for example, by using, but not limited to, phosphorylation of AMPK (AMP-activated protein kinase) as an indicator (see Yusuke Nakatsu et al., Journal of Biological Chemistry, 2015, Vol. 290, No. 40, pp. 24255-24266). Alternatively, the activity of the compound of the present invention to inhibit Pin1 function can be measured by detecting the isomerase activity of Pin1 using a peptide as a substrate based on a change in absorbance (see Hailong Zhao et al., Bioorganic & Medicinal Chemistry, 2016, Vol. 24, pp. 5911-5920). Alternatively, the activity of the compounds of the present invention to inhibit the function of Pin1 can be measured by detecting binding to Pin1 in competition with a substrate peptide (see Shuo Wei et al., Nature Medicine, Vol. 21, No. 5, pp. 457-466, online methods).

[0069] The pharmaceutical composition of the present invention is a composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can treat or prevent various diseases by inhibiting the function of Pin1 as one of its mechanisms of action.

[0070] "Pharmaceutically acceptable salts" include, but are not limited to, sodium salts, potassium salts, ammonium salts, etc., when the compound has an acidic functional group. Furthermore, when the compound has a basic functional group, the salts can be salts with hydrochloric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid, oxalic acid, etc.

[0071] The pharmaceutical composition of the present invention can be obtained by mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, and can be in the form of, for example, but not limited to, tablets, granules, capsules, powders, liquids, injections, suppositories, patches, eye drops, or inhalants.

[0072] Various inorganic or organic carrier substances can be used as pharmaceutically acceptable carriers in the pharmaceutical composition of the present invention. When the pharmaceutical composition is prepared as a solid preparation such as a tablet or granule, excipients, lubricants, binders, disintegrants, etc. can be used. When the pharmaceutical composition is prepared as a liquid preparation such as a liquid or injection, solvents, solubilizers, suspending agents, buffers, etc. can be used. Furthermore, additives such as antioxidants, preservatives, colorants, etc. can also be used as needed.

[0073] Examples of excipients that can be used include, but are not limited to, lactose, D-mannitol, starch, etc., lubricants that can be used include magnesium stearate, talc, etc., binders that can be used include crystalline cellulose, gelatin, etc., and disintegrants that can be used include carboxymethyl cellulose, etc. Furthermore, examples of solvents that can be used include distilled water, alcohol, propylene glycol, etc., solubilizers that can be used include polyethylene glycol, ethanol, etc., suspending agents that can be used include stearyl triethanolamine, sodium lauryl sulfate, etc., and buffers that can be used include phosphates, acetates, etc.

[0074] 5. Therapeutic or Preventive Agents for Coronavirus Infections The therapeutic or preventive agent for coronavirus infections of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described above in Section 1-1, and its pharmaceutically acceptable salts are as described above in Section 4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which serves as the active ingredient in the present invention, has a mechanism of action of inhibiting the function of Pin1 and is capable of suppressing coronavirus proliferation, and therefore can be used as a therapeutic or preventive agent for coronavirus infections. The therapeutic or preventive agent for coronavirus infections of the present invention can be administered as a therapeutic or preventive agent not only to patients diagnosed with coronavirus infection, but also to patients who may have coronavirus infection, patients at risk of developing coronavirus infection, patients who have developed coronavirus infection, medical professionals who frequently come into contact with coronaviruses, and service industry workers who interact with large numbers of people.

[0075] The compound represented by formula (I) contained as an active ingredient in the agent for treating or preventing coronavirus infection of the present invention is R １ , R ２ , R ３ , R, and X, etc., can have a wide variety of chemical structures. Therefore, the chemical structure of the therapeutic or preventive agent for coronavirus infection of the present invention can be modified so that the drug's absorbability, distribution, degradability, ease of excretion, etc. are optimized.

[0076] Coronaviruses that infect humans are alphacoronaviruses (HCoV-229E, HCoV-NL63) and betacoronaviruses (MERS-CoV, SARS-CoV, SARS-CoV-2, HCoV-OC43, HCoV-HKU1). HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 cause the common cold, which is usually mild but can also cause high fever. SARS-CoV is thought to be a bat coronavirus that has infected humans and caused severe pneumonia. MERS-CoV is a virus that causes cold symptoms in dromedaries, but is thought to cross the species barrier and cause severe pneumonia when it infects humans. The infection caused by SARS-CoV-2 (COVID-19) is spread primarily by person-to-person transmission via airborne droplets dispersed by coughing or sneezing from an infected individual. COVID-19 symptoms include fever, respiratory symptoms, headache, fatigue, and may also cause olfactory and taste disorders. The therapeutic or preventive agent for coronavirus infection of the present invention is particularly preferably applied to coronavirus infections caused by β-coronaviruses, and is particularly preferably applied to coronavirus infections (COVID-19) caused by SARS-CoV-2. Because the therapeutic or preventive agent for coronavirus infection of the present invention inhibits the proliferation of β-coronavirus (SARS-CoV-2 virus), it can be particularly suitably used for the treatment or prevention of coronavirus infections caused by β-coronavirus (SARS-CoV-2).

[0077] The therapeutic or preventive agent for coronavirus infection of the present invention may further contain the active ingredient of at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for coronavirus infection. In addition, the therapeutic or preventive agent for coronavirus infection of the present invention can be used in combination with at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for coronavirus infection. Examples of such drugs or active ingredients that can be used include, but are not limited to, remdesivir, favipiravir, chloroquine, hydroxychloroquine, nafamostat, interferon, ensitrelvir, nitazoxanide, dexamethasone, nirmatrelvir, ritonavir, lopinavir, molnupiravir, baricitinib, and tocilizumab. The therapeutic or preventive agent for coronavirus infection of the present invention may be used for the manufacture of a medicament for treating or preventing coronavirus infection. The present invention provides a method for treating or preventing coronavirus infection, which comprises administering an effective amount of the therapeutic or preventive agent for coronavirus infection of the present invention to a subject in need thereof, such as a COVID-19 patient, a patient at risk of developing coronavirus infection, a medical professional who frequently comes into contact with COVID-19 patients or coronaviruses, or a customer service worker who serves a large number of people.

[0078] 6. Therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, cocksackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection The herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus of the present invention A therapeutic or preventive agent for an infection with a parasitic worm, such as a virion containing a virion of formula (I'), a virion containing ... (wherein R1 and R2 are each a phenyl group or a thienyl group, (1) R1 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, or (2) R2 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, or (3) R1 and R2 are substituted with at least one R4 substituent and are not substituted with any other substituent than R4, wherein R4 is a halogen, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted methylenedioxy group, R3 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group, X is a single bond, -CH ２ - group, or -CH ２ The present invention relates to a pharmaceutical composition comprising a compound represented by the formula (I) or a salt thereof as an active ingredient.

[0079] As a result of intensive research, the present inventors have found that the use of a Pin1 inhibitor can suppress the proliferation of viruses and parasites in infections with herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite. Therefore, in addition to using the novel compound represented by formula (I) or a pharmaceutically acceptable salt thereof as a therapeutic or preventive agent for such infectious diseases, the inventors have discovered novel uses of a compound of formula (I) in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond, a compound in which R1 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, and R2 is substituted with a substituent other than R4, and a compound in which R2 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4, and R1 is substituted with a substituent other than R4, as a therapeutic or preventive agent for such infectious diseases.The herpes simplex virus, Zika virus, RS virus, Hantavirus, Rhinovirus, and Gamak virus of the present invention The therapeutic or preventive agent for infection with a parasitic worm, such as a cerebrospinal fluid (CW) virus, a vaccinia virus, a poliovirus, a coxsackie virus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite, contains, in addition to the compound of formula (I), as an active ingredient: a compound in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond; a compound in which R1 is substituted with at least one R4 substituent and is not substituted with any other substituent other than R4, and R2 is substituted with a substituent other than R4; a compound in which R2 is substituted with at least one R4 substituent and is not substituted with any other substituent other than R4, and R1 is substituted with a substituent other than R4, or a pharmaceutically acceptable salt thereof. Formula (I') is a compound obtained by adding to formula (I) a compound in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond, a compound in which R1 is substituted with at least one R4 substituent and is not substituted with any other substituent other than R4, and R2 is substituted with any other substituent other than R4, or a compound in which R2 is substituted with at least one R4 substituent and is not substituted with any other substituent other than R4, and R1 is substituted with any other substituent other than R4, and except for these points, R1, R2, and X are the same as those in formula (I). Pharmaceutically acceptable salts thereof are as described in Section 4 above.Examples of the "substituent other than R4" include an amino group, a cyclic amino group (a 3- to 6-membered cyclic amino group which may contain, in addition to carbon atoms and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an imidazolidinyl group, a piperidyl group, a morpholinyl group, a dihydropyridyl group, a pyridyl group, an N-methylpiperazinyl group, an N-ethylpiperazinyl group, etc.), a cyano group, a cycloalkyl ... These include groups, amido groups, carbonyl groups, carboxyl groups, alkoxy groups (e.g., methoxy groups, ethoxy groups, etc.), alkoxycarbonyl groups, alkoxycarbonylamino groups (e.g., C alkoxycarbonylamino groups such as methoxycarbonylamino groups, isoproxycarbonylamino groups, tert-butoxycarbonylamino groups, etc.), acylamino groups (e.g., C acylamino groups such as formylamino groups, acetylamino groups, propionylamino groups, etc.), thiol groups, thioether groups, and thioester groups. There may be one or more "substituents other than R", and when there are more than one, they may be the same or different groups.

[0080] In the therapeutic or preventive agent for herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention, the total number of halogen atoms contained in R1 and R2, i.e., the total number of halogen atoms contained in the R4 substituent, is preferably 3 or more, and R4 may be a halogen, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group. Furthermore, in the therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention, R ３ It is preferable to use a compound in which R3 is a hydrogen atom or a methyl group, and it is particularly preferable to use a compound in which R3 is a hydrogen atom and the -CO2R3 group is a carboxyl group (-CO2H).

[0081] The compound represented by formula (I') or a pharmaceutically acceptable salt thereof, which is an active ingredient in the present invention, has an action mechanism of inhibiting the function of Pin1 and can suppress the proliferation of viruses and parasites. Therefore, the compound can suppress the proliferation of herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection, and can be suitably used for the treatment or prevention of these infections. The therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention can be administered as a therapeutic or preventive agent not only to patients diagnosed with these infections, but also to patients who may have the infection, patients who are at risk of developing the infection, patients who have developed the infection, medical professionals who have frequent contact with viruses and parasites, and service industry workers who interact with many people.

[0082] The compound represented by formula (I') contained as an active ingredient in the agent for treating or preventing infection with herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite of the present invention is R １ , R ２ , R ３ , R, and X, etc., can have a wide variety of chemical structures. Therefore, the chemical structure of the therapeutic or preventive agent for infectious diseases of the present invention can be modified so as to optimize the absorbability, distribution, degradability, ease of excretion, etc. of the drug.

[0083] In the present invention, "herpes simplex virus infection" refers to a disease caused by infection with herpes simplex virus (HSV). Herpes simplex virus infections include mucocutaneous infections in which small blisters appear on the skin or mucous membranes, eye infections such as herpes keratitis, central nervous system infections such as herpes simplex encephalitis, and neonatal herpes that occurs in newborns. In the present invention, "Zika virus infection" refers to a disease caused by infection with Zika virus (ZV). Zika virus infection is transmitted primarily via mosquitoes in a human-to-mosquito-to-human cycle, and begins with generalized discomfort and fatigue, followed by the simultaneous appearance of fever, headache, and generalized muscle pain. In the present invention, "respiratory syncytial virus infection" refers to a disease caused by infection with respiratory syncytial virus (RSV). Respiratory syncytial virus infections typically begin with upper respiratory tract symptoms and fever, and progress to bronchiolitis, pneumonia, and the like, which then progress to dyspnea, cough, and wheezing. In the present invention, "hantavirus infection" refers to a disease caused by infection with a hantavirus. Hantavirus infections include hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In the present invention, "rhinovirus infection" refers to a disease caused by infection with a rhinovirus. Rhinovirus infections infect the upper respiratory tract, such as the nose and throat, and are a common cold (common cold) that causes symptoms such as sore throat, nasal congestion, sneezing, and runny nose. In the present invention, "Gamak virus infection" refers to a disease caused by infection with a Gamak virus. Possible symptoms of Gamak virus infection include severe acute respiratory distress and neurological symptoms. Although Gamak virus infection has not yet been reported in humans, Gamak virus infects human lung epithelial cells in culture. The Henipavirus genus, to which Gamaku virus belongs, is an important zoonotic pathogen that causes severe acute respiratory distress and neurological disorders in humans, and is known to include Hendra virus, Nipah virus, and Langya virus. There are concerns that Gamaku virus may also infect humans in the future.In the present invention, "vaccinia virus infection" refers to a disease caused by infection with vaccinia virus. Vaccinia virus is used as a live vaccine against smallpox and is highly attenuated. Therefore, healthy individuals generally show no symptoms even if infected, or may develop a mild rash and fever. In the present invention, "poliovirus infection" refers to a disease caused by infection with poliovirus. Poliovirus infections include mild abortive polio, which causes symptoms such as slight fever, fatigue, headache, sore throat, and vomiting, and paralytic polio or non-paralytic polio, which causes central nervous system disease. In the present invention, "Cocksackievirus infection" refers to a disease caused by infection with Cocksackievirus. Cocksackievirus infections cause symptoms such as nonspecific fever, rash, and upper respiratory tract infection. They are the causative virus of summer colds and can also cause herpangina, hand, foot, and mouth disease, viral meningitis (aseptic meningitis), encephalitis, and the like.

[0084] In the present invention, "influenza A virus infection" refers to a disease caused by infection with influenza A virus (IAV). Infection with IAV causes mild to severe influenza characterized by high fever, chills, generalized pain, and inflammation of the respiratory mucosa. In the present invention, "feline calicivirus infection" refers to a disease caused by infection of cats with feline calicivirus (FCV). Infection with FCV causes respiratory symptoms such as sneezing, nasal congestion, and stomatitis, as well as systemic symptoms such as fever, loss of appetite, and lethargy. Feline calicivirus infection includes virulent systemic feline calicivirus infection, which is a very serious systemic disease. In the present invention, "feline infectious peritonitis virus infection" refers to a disease caused by infection of cats with feline infectious peritonitis virus (FIPV). Cats infected with FIPV develop exudative peritonitis, in which fluid accumulates in the abdomen and chest, leading to respiratory distress, loss of appetite, fever, weight loss, jaundice, and diarrhea, or non-exudative peritonitis, in which granulomatous lesions appear in various organs, leading to jaundice, neurological signs, ocular changes, and gastrointestinal disorders. In the present invention, "severe fever with thrombocytopenia syndrome virus infection" refers to a disease caused by infection with severe fever with thrombocytopenia syndrome virus (SFTSV). The main clinical symptoms of SFTS infection are fever, vomiting, diarrhea, multiple organ failure, thrombocytopenia, leukopenia, and elevated liver enzyme levels. In the present invention, "infectious bronchitis virus infection" refers to a disease caused by infection of chickens with infectious bronchitis virus (IBV). IBV infection causes avian infectious bronchitis, affecting the respiratory, intestinal, kidney, and reproductive systems. In the present invention, "adenovirus infection" refers to a disease caused by infection with adenovirus (AdV). AdV infects humans and causes diseases such as respiratory diseases (including the common cold), conjunctivitis, and gastroenteritis. In the present invention, "murine norovirus infection" refers to a disease caused by infection of mice with murine norovirus (MNV). MNV infection is asymptomatic in immunocompetent mice, but can cause various symptoms similar to human norovirus infection in immunodeficient mice, such as diarrhea, weight loss, and dehydration.In the present invention, "rotavirus infection" refers to a disease caused by infection with rotavirus (RoV). RoV infection causes severe diarrhea and gastroenteritis, and in young children in particular, it is accompanied by fever and severe, sometimes life-threatening, dehydration. In the present invention, "Epstein-Barr virus infection" refers to a disease caused by infection with Epstein-Barr virus (EBV). EBV infection can cause infectious mononucleosis, which is characterized by fever, sore throat, swollen lymph nodes, and fatigue. In the present invention, "Japanese encephalitis virus infection" refers to a disease caused by infection with Japanese encephalitis virus (JEV). JEV infection is usually asymptomatic, but a small percentage of infected individuals develop severe encephalitis. Symptoms of severe encephalitis include high fever, headache, neck stiffness, loss of consciousness, coma, spastic paralysis, and death. In the present invention, "Theileria parasitic infection" refers to a disease caused by infection with Theileria parasites. Theileria parva causes East Coast fever in cattle, characterized by high fever, swollen lymph nodes, respiratory distress, anemia, and high mortality if left untreated. Theileria annulata causes tropical theileriosis in cattle, characterized by fever, anemia, jaundice, swollen lymph nodes, weakness, and decreased milk production. Theileria orientalis causes theileriosis in cattle, characterized by fever, anemia, jaundice, and lethargy. Theileria equi causes piroplasmosis in horses, characterized by fever, anemia, jaundice, abdominal swelling, and weight loss.

[0085] The therapeutic or preventive agent for herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention may further contain the active ingredient of at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for these infections. Furthermore, the therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention can be used in combination with at least one or more drugs selected from other drugs classified as therapeutic or preventive agents for these infections.Examples of drugs or active ingredients for each of these infectious diseases include, but are not limited to, herpes simplex virus: acyclovir, famciclovir, valacyclovir; Zika virus: polyanion suramin, atovaquone; Respiratory syncytial virus: ribavirin, palivizumab, motavizumab, RSV immune globulin (RSV-IVIG), nirsevimab; Hantavirus: ribavirin, chloroquine, zapnometinib; Rhinovirus: pleconaril, WIN56921, luprintivir, itraconazole, niclosamide; Gamak virus: ribavirin; Poliovirus: pocapavir, V-7404; Coxsackie virus: disoxaril, pleconaril, pirodavir, vapentavir, pocapavir; Influenza A virus: peramivir, zanamivir, oseltamivir phosphate, baloxavir. Marboxil, amantadine, rimantadine; feline calicivirus: famciclovir; feline infectious peritonitis virus: GS-441524, GC376, remdesivir, molnupiravir; severe fever with thrombocytopenia syndrome virus: ribavirin, favipiravir; infectious bronchitis virus: interferon alpha, interferon beta; adenovirus: cidofovir, brincidofovir, ribavirin; murine norovirus: favipiravir, nitazoxanide, ribavirin, remdesivir; rotavirus: nitazoxanide; Theileria parasite: buparvaquone, parvaquone, halofuginone lactate, oxytetracycline, diminazene acetate; and the like can be used.

[0086] The therapeutic or preventive agent for herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, cocksackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention is selected from the group consisting of herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, cocksackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, and Theileria parasite infection. virus), vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection. The present invention can provide a method for treating or preventing viral and parasitic infections, which comprises administering an effective amount of the therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection of the present invention to a subject in need thereof, for example, not only patients diagnosed with such infections, but also patients who may have the infection, patients who are at risk of developing the infection, patients who have developed the infection, medical professionals who have frequent contact with viruses and parasites, and service industry workers who serve many people.

[0087] 7. Therapeutic / Preventive Agent for Inflammatory Diseases Accompanied by Fibrosis The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in 1-1 above, and its pharmaceutically acceptable salts are as described in 4 above. In the present invention, inflammatory diseases accompanied by fibrosis are diseases in which fibrosis is caused by continued inflammation of tissues, and include non-alcoholic steatohepatitis, inflammatory bowel disease, and pulmonary fibrosis.

[0088] In the present invention, "non-alcoholic steatohepatitis," also known as NASH (Non-Alcoholic Steatohepatitis), refers to a severe form of non-alcoholic fatty liver disease in which fatty deposits similar to those of alcoholic hepatitis are observed despite no history of alcohol consumption sufficient to cause liver damage. Non-alcoholic steatohepatitis is known to cause cirrhosis, in which hepatocytes die and are replaced by fibrous tissue. In the present invention, "inflammatory bowel disease" is a general term for diseases that cause chronic inflammation and ulcers in the mucosa of the large and small intestine. Representative examples of inflammatory bowel disease include ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease in which chronic inflammation of the large intestine causes ulcers, while Crohn's disease is a disease in which inflammatory lesions such as ulcers and swelling occur throughout the digestive tract. In cases where inflammatory bowel disease causes intestinal stenosis due to fibrosis, surgery is necessary. In the present invention, "pulmonary fibrosis" refers to a disease in which chronic inflammation occurs in lung tissue, the inflamed tissue becomes fibrotic and hard, and the expansion and contraction of the lungs is hindered.

[0089] The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention contains the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and thereby exerts the effect of alleviating the symptoms of inflammatory diseases accompanied by fibrosis, such as non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, pulmonary fibrosis, etc., or preventing the onset of inflammatory diseases accompanied by fibrosis. Such efficacy is thought to be based on the mechanism of action of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof inhibits the function of Pin1.

[0090] The compound represented by formula (I) contained as an active ingredient in the agent for treating or preventing inflammatory diseases accompanied by fibrosis of the present invention is R １ , R ２ , R ３ , R, and X, etc., can have a wide variety of chemical structures. Therefore, the chemical structure of the therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention can be modified so as to optimize the absorbability, distribution, degradability, ease of excretion, etc. of the drug.

[0091] The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention can be administered as a therapeutic or preventive agent not only to patients diagnosed with inflammatory diseases accompanied by fibrosis such as non-alcoholic steatohepatitis, inflammatory bowel disease, and pulmonary fibrosis, but also to patients who may have these diseases or who are at risk of developing these diseases.

[0092] As described in 4 above, the therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention can be mixed with a pharmaceutically acceptable carrier and formulated into various dosage forms. When used as a therapeutic or preventive agent for non-alcoholic steatohepatitis, the dosage form is not limited to these, but can be orally administered as, for example, tablets, granules, capsules, powders, liquids, etc. Furthermore, from the viewpoint of directly acting on the liver to reduce side effects, it can also be administered directly to the liver as an injection via a tube or the like. When used as a therapeutic or preventive agent for inflammatory bowel disease, the dosage form is not limited to these, but from the viewpoint of directly acting on the intestine, it is preferable to use tablets, granules, capsules, powders, liquids, or suppositories. When used as a therapeutic or preventive agent for pulmonary fibrosis, the dosage form is not limited to these, but it is preferable to use an inhalant or the like from the viewpoint of directly acting on the lungs.

[0093] The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention is administered in an amount of preferably 0.01 to 100 mg, more preferably 0.1 to 10 mg, of the active ingredient per kg of patient body weight per day.

[0094] The therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, at least one active ingredient selected from agents classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis. Examples of such active ingredients include, but are not limited to, corticosteroids, anti-TNFα antibodies, 5-ASA (5-aminosalicylic acid; melasiadine), obeticholic acid (6-ethyl-chenodeoxycholic acid), etc. Furthermore, examples of active ingredients that can be used for the therapeutic agent for non-alcoholic steatohepatitis include vitamin E, obeticholic acid (6-ethyl-chenodeoxycholic acid), elafibranor, selonsertib, saroglitazar, lanifibranor, semaglutide, pemafibrate, etc., which are in clinical trials at the time of filing this application. Furthermore, as an active ingredient of the therapeutic agent for inflammatory bowel disease, in addition to 5-aminoacetyl acid and salazosulfapyridine, an anti-IL-12 / 23 antibody, an anti-α4β7 antibody, a JAK inhibitor, etc. can be used. Furthermore, the therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis of the present invention can be used in combination with other therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis.

[0095] 8. Cancer Therapeutic or Preventive Agent The cancer therapeutic or preventive agent of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in 1-1 above, and its pharmaceutically acceptable salt is as described in 4 above. The cancer therapeutic or preventive agent of the present invention has the effect of suppressing cancer growth or preventing cancer onset. Such efficacy is thought to be based on the mechanism of action in which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof inhibits the function of Pin1.

[0096] The cancer therapeutic or preventive agent of the present invention can be used for colon cancer, prostate cancer, brain tumor, laryngeal cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, ovarian cancer, cervical cancer, bladder cancer, testicular cancer, leukemia, lymphoma, multiple myeloma, etc. The cancer therapeutic or preventive agent of the present invention can be suitably used as a therapeutic or preventive agent for colon cancer or prostate cancer.

[0097] The compound represented by formula (I) contained as an active ingredient in the cancer treatment or prevention agent of the present invention is R １ , R ２ , R ３ , R, and X, etc., can have a wide variety of chemical structures. Therefore, the chemical structure of the cancer treatment or prevention agent of the present invention can be modified so as to optimize the drug's absorbability, distribution, degradability, ease of excretion, etc.

[0098] The cancer therapeutic or preventive agent of the present invention can be administered as a therapeutic or preventive agent not only to patients diagnosed with cancer, but also to patients who may have cancer or who are at risk of developing cancer. It is particularly effective to administer the agent as a preventive agent to patients at risk of developing colorectal cancer. Examples of patients at risk of developing colorectal cancer include, but are not limited to, patients with familial adenomatous polyposis, Lynch syndrome, MUTYH-associated adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, Cowden disease, Crohn's disease, ulcerative colitis, and Cronkhite-Canada syndrome.

[0099] The cancer therapeutic or preventive agent of the present invention can be mixed with a pharmaceutically acceptable carrier and formulated into various dosage forms, as described in 4 above. The cancer therapeutic or preventive agent of the present invention is administered in an amount of preferably 0.01 to 100 mg, more preferably 0.1 to 10 mg, calculated as the active ingredient per kg of patient body weight per day.

[0100] The cancer therapeutic or preventive agent of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, at least one active ingredient selected from drugs classified as cancer therapeutic or preventive agents. Examples of such active ingredients include, but are not limited to, oxaliplatin, cisplatin, cyclophosphamide, fluorouracil, irinotecan, doxorubicin, bevacizumab, cetuximab, gemcitabine, or cancer immunotherapy antibodies such as anti-CTLA-4 antibodies, anti-PD-1 antibodies, and anti-PD-L1 antibodies. Furthermore, the cancer therapeutic or preventive agent of the present invention can be used in combination with other cancer therapeutic or preventive agents.

[0101] 9. Agent for Treating or Preventing Obesity The agent for treating or preventing obesity of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in 1-1 above, and its pharmaceutically acceptable salt is as described in 4 above. The agent for treating or preventing obesity of the present invention suppresses fat accumulation, thereby achieving the effect of treating obesity or preventing the onset of obesity. It is believed that this efficacy is due to the mechanism of action in which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof inhibits the function of Pin1.

[0102] The compound represented by formula (I) contained as an active ingredient in the agent for treating or preventing obesity of the present invention is R １ , R ２ , R ３ , R, and X, etc., can have a wide variety of chemical structures. Therefore, the chemical structure of the therapeutic or preventive agent for obesity of the present invention can be modified so as to optimize the absorbability, distribution, degradability, ease of excretion, etc. of the drug.

[0103] In the present invention, "obesity" refers to a disease in which fat accumulates excessively in the viscera or subcutaneously, and can be diagnosed based on the area of ​​fat in an abdominal CT scan, etc. The therapeutic or preventive agent for obesity of the present invention can be administered as a therapeutic or preventive agent not only to patients diagnosed with obesity, but also to patients who may be obese or who are at risk of developing obesity.

[0104] The therapeutic or preventive agent for obesity of the present invention can be mixed with a pharmaceutically acceptable carrier and formulated into various dosage forms, as described above in Section 3. The therapeutic or preventive agent for obesity of the present invention is preferably administered in an amount of 0.01 to 100 mg, more preferably 0.1 to 10 mg, of the active ingredient per kg of patient body weight per day.

[0105] The therapeutic or preventive agent for obesity of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, at least one active ingredient selected from drugs classified as therapeutic or preventive agents for obesity. Examples of such active ingredients include, but are not limited to, mazindol, cetilistat, sibutramine, orlistat, lorcaserin, Qsymia, glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide analogs, and the like. The therapeutic or preventive agent for obesity of the present invention may also be used in combination with other therapeutic or preventive agents for obesity. The therapeutic or preventive agent for obesity of the present invention may also be used in combination with dietary therapy, exercise therapy, behavioral therapy, and the like used for the treatment or prevention of obesity.

[0106] 10. Examples The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0107] 10-1. Example 1 Synthesis of Compounds (Example 1-1) Synthesis of H-916 and 917 In this example, first, an intermediate (S-1) used to synthesize the compounds of the present invention was produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material and benzyl bromide, the precursor methyl 2-acetamido-5-benzyloxybenzoate (preS-1) was synthesized according to the method described in J. Org. Chem., 2001, vol. 66, pp. 2784-2788, as shown in the following reaction scheme. Then, methyl 2-amino-5-benzyloxybenzoate (S-1) was synthesized.

[0108] EDCI (598 mg, 3.12 mmol) and DMAP (9.5 mg, 0.078 mmol) were added to a dichloromethane (4 mL) solution of S-1 (200 mg, 0.78 mmol) and 4-morpholinomethylbenzoic acid (206 mg, 0.93 mmol), and the mixture was stirred at the same temperature for 2 days. Water was added to the mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 10:1 to 1:1) to obtain H-916 as a white powder (222 mg, 0.48 mmol, 62%). The NMR spectrum and HR-ESI-MS mass spectrometry results for H-916 are as follows: 1 H NMR (400 MHz, CDCl3)d 2.43-2.50 (4H, m), 3.57 (2H, s),3.70-3.74 (4H, m), 3.96 (3H, s), 5.09 (2H, s), 7.23-7.28 (1H, m), 7.32-7.50(7H, m), 7.68 (1H, d, J = 3.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8.86(1H, d, J = 9.1 Hz), 11.79 (1H, s); HRMS(ESI-TOF) calcd for C 27 H28 N2O5Na[M+Na] + 483.1896, found 483.1895.

[0109] To a solution of H-916 (159 mg, 0.35 mmol) in THF (5 mL), an aqueous solution of lithium hydroxide (1 M, 2 mL, 2 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 22 hours. The mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-917 as a white powder (103 mg, 0.23 mmol, 66%). The NMR spectrum and HR-ESI-MS mass spectrometry results for H-917 are as follows: 1 H NMR (400 MHz, DMSOd6)d 2.36 (4H, bs), 3.53 (2H, s), 3.57(4H, bt, J = 4.6 Hz), 5.09 (2H, s), 7.23-7.28 (1H, m), 7.32-7.50 (7H,m), 7.68 (1H, d, J = 3.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8.86 (1H,d, J = 9.1 Hz), 11.79 (1H, s); HRMS(ESI-TOF) calcd for C 26 H 26 N2O5Na[M+Na] + 469.1739, found 469.1740.

[0110] (Example 1-2) Synthesis of other compounds (H-930, 931, 932, 933, 934, 957, 958, 959, 960, 1097, 1098, 1101, 1102, 1151, 1152, 1159, 1160, 1167, 1168, 1190, 1191, 1192, 1193, 1198, 1199) using intermediate (S-1) Methyl 2-amino-5-benzyloxybenzoate (S-1) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-930, 931, 932, 933, 934, 957, 958, 959, 960, 1097, 1098, 1101, 1102, 1151, 1152, 1159, 1160, 1167, 1168, 1190, 1191, 1192, 1193, 1198, and 1199 of the present invention by dehydration and hydrolysis in the same manner as in Example 1-1. The structures of each compound are shown in Table 1.

[0111] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-930 are as follows: H-930 1 H NMR (400 MHz, CDCl3)d 2.07 (3H, s), 3.96 (3H, s), 4.52(2H, d, J = 5.5 Hz), 5.09 (2H, s), 7.08 (1H, dd, J = 9.2, 2.8Hz), 7.29-7.34 (1H, HRMS(ESI-TOF)calcd for C 27 H 28 N2O5Na [M+Na] + 455.1583, found 455.1577.

[0112] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-931 are as follows: H-931 1H NMR (400 MHz, DMSOd6)d 1.88 (3H, s), 4.31 (2H, d, J= 5.9 Hz), 5.10 (2H, s), 7.12 (1H, dd, J = 9.1, 3.2 Hz), 7.28-7.48 (7H, m), 7.66 (1H, d, J = 3.2 Hz), 7.92 (2H,d, J = 8.3 Hz), 8.42 (1H, t, J = 5.9 Hz), 8.60 (1H, d, J =8.7 Hz); HRMS(ESI-TOF) calcd for C 24 H 22 N2O5Na[M+Na] + 441.1426, found 441.1422.

[0113] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-932 are as follows: H-932 1 H NMR (400 MHz, CDCl3)d 1.48 (9H, s), 3.96 (3H, s), 4.40(2H, d, J = 6.0 Hz), 4.91 (1H, bs), 5.09 (2H, s), 7.24-7.27 (1H, m),7.32-7.47 (7H, m), 7.68 (1H, d, J = 3.2 Hz), 7.99 (2H, d, J = 8.2Hz), 8.86 (1H, d, J = 9.2 Hz), 11.80 (1H, s); HRMS(ESI-TOF) calcd for C 28 H 30 N2O6Na[M+Na] + 513.2002, found 513.2004.

[0114] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-933 are as follows: 1H NMR (400 MHz, DMSOd6)d 1.39 (9H, s), 4.19 (2H, d, J= 5.9 Hz), 5.12 (2H, s), 7.29-7.35 (1H, m), 7.36-7.42 (4H, m), 7.43-7.51 (3H,m), 7.62 (1H, d, J = 2.7 Hz), 7.89 (2H, d, J = 8.2 Hz), 8.57 (1H,d, J = 8.6 Hz), 11.80 (1H, s); HRMS(ESI-TOF) calcd for C 27 H 28 N2O6Na[M+Na] + 499.1845, found 499.1839.

[0115] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-934 are as follows: H-934 1 H NMR (400 MHz, CDCl3)d 3.96 (5H, s), 5.09 (2H, s),7.24-7.27 (1H, m), 7.32-7.48 (7H, m), 7.68 (1H, d, J = 3.2 Hz), 8.00(2H, d, J = 8.2 Hz), 8.86 (1H, d, J = 9.2 Hz), 11.79 (1H, s); HRMS(ESI-TOF)calcd for C 23 H 22 N2O4Na [M+Na] + 413.1477, found 413.1471.

[0116] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-957 are as follows: H-957 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.10 (2H, s),7.24-7.28 (1H, m), 7.32-7.47 (5H, m), 7.59 (1H, d, J = 8.2 Hz), 7.68(1H, d, J = 3.2 HRMS(ESI-TOF)calcd for C 22 H 17 Cl2NO4Na [M+Na] + 452.0432, found 452.0427.

[0117] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-958 are as follows: H-958 1 H NMR (400 MHz, DMSOd6)d 5.08 (2H, s), 7.07 (1H, dd, J= 9.1, 1.9 Hz), 7.28-7.34 (1H, m), 7.38 (2H, t, J = 7.7 Hz), 7.45 (2H,d, J = 7.3 Hz), 7.70 (1H, bs), 7.81 (1H, dd, J = 8.2, 1.9 Hz),7.94 (1H, dd, J = 8.3, 1.9 Hz), 8.12 (1H, bs), 8.55 (1H, d, J =8.7 Hz); HRMS(ESI-TOF) calcd for C 21 H 15 Cl2NO4Na[M+Na] + 438.0276, found 438.0271.

[0118] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-959 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.10 (2H, s),7.24-7.47 (7H, m), 7.68 (1H, d, J = 2.8 Hz), 7.76-7.81 (1H, m),7.86-7.92 (1H, m), 8.80 (1H, d, J = 9.2 Hz), 11.85 (1H, s); HRMS(ESI-TOF)calcd for C 22 H 17 F2NO4Na [M+Na] + 420.1023, found 420.1017.

[0119] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-960 are as follows: H-960 1 H NMR (400 MHz, CDCl3)d 5.10 (2H, s), 7.24-7.47 (7H, m),7.72 (1H, d, J = 2.8 Hz), 7.72-7.79 (1H, m), 7.82-7.89 (1H, m), 8.81(1H, d, J = 9.6 Hz), 11.80 (1H, s); HRMS(ESI-TOF) calcd for C 21 H 15 F2NO4Na[M+Na] + 406.0867, found 406.0861.

[0120] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1097 are as follows: H-1097 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.10 (2H, s), 7.26(1H, dd, J = 8.7, 3.2 Hz), 7.32-7.47 (5H, m), 7.54 (1H, t, J =1.9 Hz), 7.69 (1H, d, J = 3.2 Hz), 7.88 (2H, d, J = 1.9 Hz), 8.78 (1H, d, J = 9.1 Hz), 11.83 (1H, s); 22 H17 Cl2NO4Na[M+Na] + 452.0432, found 452.0428.

[0121] The NMR spectrum and mass spectrometry results for H-1098 by HR-ESI-MS are as follows: H-1098 1 H NMR (400 MHz, DMSOd6)d 5.13 (2H, s), 7.21-7.27 (1H, m),7.32 (1H, t, J = 7.4 Hz), 7.39 (2H, t, J = 7.4 Hz), 7.46 (2H, d, J= 7.8 Hz), 7.60 (1H, d, J = 3.2 Hz), 7.89 (1H, t, J = 1.8 Hz),7.91 (2H, d, J = 1.8 Hz), 8.39 (1H, d, J = 8.2 Hz); HRMS(ESI-TOF)calcd for C 21 H 15 Cl2NO4Na [M+Na] + 438.0276, found 438.0271.

[0122] The NMR spectrum and mass spectrometry results for H-1101 by HR-ESI-MS are as follows: H-1101 1 H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 5.10 (2H, s),7.24-7.28 (1H, m), 7.32-7.46 (7H, m), 7.69 (1H, d, J = 2.7 Hz), 8.79(1H, d, J = 9.2 Hz), 11.12 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 16 Cl3NO4Na[M+Na] + 486.0043, found 486.0043.

[0123] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1102 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.07-7.15 (1H, m),7.31 (1H, t, J = 7.3 Hz), 7.38 (2H, t, J = 6.9 Hz), 7.45 (2H, d, J= 6.9 Hz), 7.60 (1H, d, J = 3.2 Hz), 7.81 (2H, s), 8.38 (1H, d, J= 8.7 Hz); HRMS(ESI-TOF) calcd for C 21 H 14 Cl3NO4Na[M+Na] + 471.9886, found 471.9883.

[0124] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1151 are as follows: H-1151 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.10 (2H, s), 7.27(1H, dd, J = 9.7, 3.2 Hz), 7.33-7.47 (5H, m), 7.66 (1H, t, J =7.8 Hz), 7.69 (1H, HRMS(ESI-TOF) calcd for C 23 H 18 F3NO4Na[M+Na] + 452.1086, found 452.1081.

[0125] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1152 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 7.28 (1H, bd, J= 8.2 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.39 (2H, t, J = 7.3 Hz),7.46 (2H, d, J = 7.8 Hz), 7.61 (1H, d, J = 2.7 Hz), 7.82 (1H, t, J= 7.8 Hz), 7.99 (1H, d, J = 7.7 Hz), 8.21-8.27 (2H, m), 8.48 (1H, d, J= 8.7 Hz); HRMS(ESI-TOF) calcd for C 22 H 16 F3NO4Na[M+Na] + 438.0929, found 438.0925.

[0126] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1159 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.10 (2H, s), 7.27(1H, dd, J = 9.7, 3.2 Hz), 7.33-7.47 (5H, m), 7.69 (1H, d, J =3.2 Hz), 7.79 (2H, d, J = 8.2 Hz), 8.14 (2H, d, J = 7.7 Hz), 8.85(1H, d, J = 9.2 Hz), 11.94 (1H, s); 23 H 18 F3NO4Na[M+Na] + 452.1086, found 452.1085.

[0127] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1160 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 7.24-7.49 (6H, m),7.62 (1H, bs), 7.91-7.97 (2H, m), 8.10-8.16 (2H, m), 8.47-8.54 (1H, m); HRMS(ESI-TOF)calcd for C 22 H 16 F3NO4Na [M+Na] + 438.0929, found 438.0926.

[0128] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1167 are as follows: H-1167 1 H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.11 (2H, s), 7.28(1H, dd, J = 9.6, 3.2 Hz), 7.33-7.47 (5H, m), 7.71 (1H, d, J =2.7 Hz), 8.06 (1H, HRMS(ESI-TOF) calcd for C 24 H 17 F6NO4Na[M+Na] + 520.0959, found 520.0960.

[0129] The NMR spectrum and mass spectrometry results for H-1168 by HR-ESI-MS are as follows: H-1168 1 H NMR (400 MHz, DMSOd6)d 5.15 (2H, s), 7.26-7.33 (1H, m),7.33 (1H, t, J = 7.8 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.46 (2H, d, J= 7.8 Hz), 7.61 (1H, d, J = 2.8 Hz), 8.38 (1H, d, J = 9.1 Hz),8.40 (1H, s), 8.54 (2H, s); HRMS(ESI-TOF) calcd for C 23 H 15F6NO4Na[M+Na] + 506.0803, found 506.0803.

[0130] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1190 are as follows: 1 H NMR (400 MHz, DMSOd6)d 3.77 (3H, s), 3.85 (2H, s), 5.11(2H, s), 7.27 (1H, dd, J = 9.2, 3.2 Hz),7.29-7.46 (7H, m), 7.50 (1H, d, J = 8.2 HRMS(ESI-TOF) calcdfor C 23 H 19 Cl2NO4Na [M+Na] + 466.0589, found 466.0589.

[0131] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1191 are as follows: H-1191 1 H NMR (400 MHz, DMSOd6)d 3.83 (2H, s), 5.08 (2H, s), 7.14(1H, dd, J = 9.2, 2.7 Hz), 7.28-7.46 (6H, m), 7.51(1H, d, J = 8.2 Hz), 7.53 (1H, bs), 7.62 (1H, d, J = 1.9 Hz),8.36 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF) calcd for C 22 H 17 Cl2NO4Na[M+Na] + 452.0432, found 452.0428.

[0132] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1192 are as follows: 1H NMR (400 MHz, DMSOd6)d 3.72 (2H, s), 3.74 (3H, s), 5.11(2H, s), 7.26 (1H, dd, J = 9.1, 3.2 Hz),7.29-7.46 (7H, m), 7.60 (1H, d, J = 8.2 HRMS(ESI-TOF) calcdfor C 23 H 19 Cl2NO4Na [M+Na] + 466.0589, found 466.0589.

[0133] The NMR spectrum and mass spectrometry results for H-1193 by HR-ESI-MS are as follows: H-1193 1 H NMR (400 MHz, DMSOd6)d 3.75 (2H, s), 5.09 (2H, s), 7.20(1H, dd, J = 9.1, 2.8 Hz), 7.29-7.45 (6H, m), 7.50(1H, d, J = 2.8 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J= 1.9 Hz), 8.29 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 22 H 17 Cl2NO4Na[M+Na] + 452.0432, found 452.0432.

[0134] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1198 are as follows: H-1198 1H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 4.67 (2H, s), 5.08(2H, s), 6.92 (1H, d, J = 8.6 Hz), 7.18-7.23 (2H,m), 7.32-7.46 (6H, m), 7.63 (1H, d, J = 3.2 Hz), 8.64 (1H, d, J= 9.2 Hz), 11.57 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 19 Cl2NO5Na[M+Na] + 482.0538, found 482.0536.

[0135] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1199 are as follows: 1 H NMR (400 MHz, DMSOd6)d 4.83 (2H, s), 5.11 (2H, s), 7.17(1H, d, J = 8.6 Hz), 7.24-7.46 (7H, m), 7.55(1H, d, J = 3.2 Hz), 7.62 (1H, d, J = 2.3 Hz), 8.52 (1H, d, J= 9.1 Hz); HRMS(ESI-TOF) calcd for C 22 H 16 Cl2NO5[MH] + 444.0406, found 444.0406.

[0136] Example 1-3 Synthesis of Compounds (H-1024, 1025, 1042, 1043) Using Intermediate (S-2) In this example, first, intermediate (S-2) used to synthesize the compounds of the present invention was produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material and 3,5-difluorobenzyl bromide instead of the benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(3,5-difluorobenzyloxy)benzoate (preS-2) was synthesized as shown in the following reaction scheme, and further methyl 2-amino-5-(3,5-difluorobenzyloxy)benzoate (S-2) was synthesized. The NMR spectrum of preS-2 is as follows: Methyl 2-acetamido-5-((3,5-difluorobenzyl)oxy)benzoate (preS-2) 1 H NMR (400 MHz, DMSOd6) 2.05 (3H, s), 3.82 (3H, s), 5.15 (2H, s), 7.15-7.24 (3H, m), 7.27 (1H, dd, J = 9.1, 2.7 Hz), 7.42 (1H, d, J = 2.7 Hz), 7.95 (1H, d, J = 9.1 Hz), 10.20 (1H, s). The NMR spectrum and mass analysis by HR-ESI-MS for S-2 are as follows: Methyl 2-amino-5-((3,5-difluorobenzyl)oxy)benzoate (S-2) 1 H NMR (400 MHz, DMSOd6)d 3.77 (3H, s), 5.01 (2H, s), 6.35(2H, bs), 6.75 (1H, d, J = 9.2 Hz), 7.07 (1H, dd, J = 9.2, 2.7Hz), 7.12-7.22 (3H, m), 7.26 (1H, J = 2.7 Hz); HRMS(ESI-TOF) calcd for C 15 H 13 F2NO3Na[M+Na] +316.0761, found 316.0757.

[0137] Methyl 2-amino-5-(3,5-difluorobenzyloxy)benzoate (S-2) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-1024, 1025, 1042, and 1043 of the present invention by dehydration and hydrolysis in the same manner as in Example 1-1. The structures of each compound are shown in Table 1.

[0138] The NMR spectrum and mass spectrometry results for H-1024 by HR-ESI-MS are as follows: H-1024 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.08 (2H, s),6.74-6.81 (1H, m), 6.95-7.02 (2H, m), 7.24 (1H, dd, J = 9.1, 2.7 Hz),7.49-7.59 (3H, m), 7.65 (1H, d, J = 3.2 Hz), 8.01-8.06 (2H, m), 8.90(1H, d, J = 9.1 Hz), 11.82 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 17 F2NO4Na[M+Na] + 420.1023, found 420.1021.

[0139] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1025 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.19 (2H, s), 7.17-7.25 (3H, m),7.36 (1H, dd, J = 8.7, 2.8 Hz), 7.54-7.65 (4H, m), 7.93 (2H, d, J= 7.7 Hz), 8.59 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF) calcd for C 21 H 15 F2NO4Na[M+Na] + 406.0867, found 406.0862.

[0140] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1042 are as follows: H-1042 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.08 (2H, s),6.74-6.81 (1H, m), 6.94-7.01 (2H, m), 7.21-7.26 (1H, m), 7.60 (1H, d, J= 8.2 Hz), 7.65 (1H, d, J = 2.7 Hz), 7.83 (1H, dd, J = 8.2, 2.0Hz), 8.13 (1H, d, J = 1.8 Hz), 8.82 (1H, d, J = 9.1 Hz), 11.87(1H, s); HRMS(ESI-TOF) calcd for C 22 H 15 Cl2F2NO4Na[M+Na] + 488.0244, found 488.0238.

[0141] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1043 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.19 (2H, s), 7.17-7.24 (3H, m),7.35 (1H, dd, J = 9.2, 2.7 Hz), 7.59 (1H, d, J = 3.2 Hz), 7.87(2H, s), 8.11 (1H, s), 8.41 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF) calcd forC 21 H 12 Cl2F2NO4[MH] + 450.0111, found 450.0111.

[0142] Example 1-4 Synthesis of Compounds (H-1026, 1027, 1036, 1037, 1048, 1049, 1067, 1068, 1069, 1070, 1075, 1076, 1079, 1080, 1113, 1114, 1121, 1122, 1129, 1130, 1206, 1207, 1208, 1209, 1210, 1211) Using Intermediate (S-3) In this example, first, intermediate (S-3) used to synthesize the compound of the present invention was produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material, and using 3,4-difluorobenzyl bromide instead of benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(3,4-difluorobenzyloxy)benzoate (preS-3) was synthesized as shown in the following reaction scheme, and further methyl 2-amino-5-(3,4-difluorobenzyloxy)benzoate (S-3) was synthesized. The NMR spectrum of preS-3 is as follows: Methyl 2-acetamido-5-((3,4-difluorobenzyl)oxy)benzoate (preS-3) 1 H NMR (400 MHz, DMSOd6) 2.05 (3H, s), 3.82 (3H, s), 5.10 (2H, s), 7.27 (1H, dd, J = 9.1, 2.7 Hz), 7.28-7.34 (1H, m), 7.42 (1H, d, J = 3.2 Hz), 7.42-7.49 (1H, m), 7.50-7.57 (1H, m), 7.95 (1H, d, J = 9.1 Hz), 10.19 (1H, s). The NMR spectrum and mass analysis by HR-ESI-MS for S-3 are as follows: Methyl 2-amino-5-((3,4-difluorobenzyl)oxy)benzoate (S-3) 1H NMR (400 MHz, CDCl3)d 3.88 (3H, s), 4.94 (2H, s), 5.48(2H, bs), 6.64 (1H, d, J = 9.1 Hz), 6.99 (1H, dd, J = 9.1, 3.2Hz), 7.10-7.20 (2H, m), 7.23-7.30 (1H, m), 7.41 (1H, d, J = 3.2 Hz);HRMS(ESI-TOF) calcd for C 15 H 13 F2NO3Na[M+Na] + 316.0761, found 316.0757.

[0143] Methyl 2-amino-5-(3,4-difluorobenzyloxy)benzoate (S-3) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-1026, 1027, 1036, 1037, 1048, 1049, 1067, 1068, 1069, 1070, 1075, 1076, 1079, 1080, 1113, 1114, 1121, 1122, 1129, 1130, 1206, 1207, 1208, 1209, 1210, and 1211 of the present invention by dehydration and hydrolysis in the same manner as in Example 1-1. The structures of each compound are shown in Table 1.

[0144] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1026 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.04 (2H, s),7.13-7.33 (4H, m), 7.49-7.59 (3H, m), 7.65 (1H, d, J = 3.2 Hz),8.01-8.06 (2H, m), 8.90 (1H, d, J = 9.1 Hz), 11.82 (1H, s); HRMS(ESI-TOF)calcd for C 22 H 17 F2NO4Na [M+Na] + 420.1023, found 420.1017.

[0145] The NMR spectrum and mass spectrometry results for H-1027 by HR-ESI-MS are as follows: H-1027 1 H NMR (400 MHz, DMSOd6)d 5.13 (2H, s), 7.30-7.36 (2H, m),7.42-7.50 (1H, m), 7.52-7.65 (5H, m), 7.93 (2H, d, J = 6.9 Hz), 8.58(1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 15 F2NO4Na[M+Na] + 406.0867, found 406.0861.

[0146] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1036 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.04 (2H, s),7.13-7.32 (4H, m), 7.60 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 3.2Hz), 7.83 (1H, dd, J = 8.7, 2.1 Hz), 8.13 (1H, d, J = 2.2 Hz), 8.82 (1H, d, J = 9.1 Hz), 11.87 (1H, s); 22 H 14 Cl2F2NO4[MH] + 464.0268, found 464.0268.

[0147] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1037 are as follows: H-1037 1H NMR (400 MHz, DMSOd6)d 5.10 (2H, s), 7.17 (1H, bd, J= 8.7 Hz), 7.29-7.35 (1H, m), 7.41-7.50 (1H, m), 7.51-7.58 (1H, m), 7.63 (1H,d, J = HRMS(ESI-TOF)calcd for C 21 H 13 Cl2F2NO4Na[M+Na] + 474.0087, found 474.0085.

[0148] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1048 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.04 (2H, s),7.13-7.35 (5H, m), 7.65 (1H, d, J = 3.2 Hz), 7.76-7.82 (1H, m),7.85-7.92 (1H, m), 8.82 (1H, d, J = 9.1 Hz), 11.86 (1H, s); HRMS(ESI-TOF)calcd for C 22 H 14 F4NO4[MH] + 432.0859, found 432.0859.

[0149] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1049 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.12 (2H, s), 7.22-7.35 (2H, m),7.42-7.70 (4H, m), 7.78-7.84 (1H, m), 7.89-7.96 (1H, m), 8.45 (1H, d, J= 8.7 Hz); HRMS(ESI-TOF) calcd for C21 H 13 F4NO4Na[M+Na] + 442.0678, found 442.0675.

[0150] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1067 are as follows: H-1067 1 H NMR (400 MHz, CDCl3)d 3.50 (3H, s), 3.97 (3H, s), 5.03(2H, s), 5.25 (2H, s), 7.12-7.32 (6H, m), 7.64 (1H, d, J = 3.2 Hz), 7.99(2H, d, J = 8.7 Hz), 8.87 (1H, d, J = 9.6 Hz), 11.74 (1H, s); HRMS(ESI-TOF)calcd for C 24 H 21 F2NO6Na [M+Na] + 480.1235, found 480.1232.

[0151] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1068 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.50 (3H, s), 5.04 (2H, s), 5.24(2H, s), 7.11-7.32 (6H, m), 7.66 (1H, d, J = 3.2 Hz), 7.96 (2H, d, J= 8.7 Hz), 8.90 (1H, d, J = 9.6 Hz); HRMS(ESI-TOF) calcd for C 23 H 19 F2NO6Na[M+Na] + 466.1078, found 466.1078.

[0152] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1069 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.03 (2H, s), 6.94(2H, d, J = 8.7 Hz), 7.14-7.32 (4H, m), 7.64 (1H, d, J = 3.2 Hz),7.96 (2H, d, J = 8.7 Hz), 8.86 (1H, d, J = 9.2 Hz), 11.71 (1H,s); HRMS(ESI-TOF) calcd for C 22 H 17 F2NO5Na[M+Na] + 436.0972, found 436.0968.

[0153] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1070 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 6.99 (2H, d, J= 8.7 Hz), 7.30-7.51 (4H, m), 7.58 (1H, bs), 7.78 (2H, d, J = 8.7 Hz),8.59 (1H, d, J = 9.2 Hz), 10.22 (1H, s); HRMS(ESI-TOF) calcd for C 21 H 15 F2NO5Na[M+Na] + 422.0816, found 422.0812.

[0154] The NMR spectrum and mass spectrometry results for H-1075 by HR-ESI-MS are as follows: H-1075 1 H NMR (400 MHz, CDCl3) d 4.00 (3H, s), 5.04 (2H,s), 7.13-7.34 (4H, m), 7.54 (1H, t, J = 1.4 Hz), 7.66 (1H, d, J =3.2 Hz), 7.88 (2H, d, J = 1.4 Hz), 8.80 (1H, d, J = 9.1 Hz),11.83 (1H, s); HRMS(ESI-TOF)calcd for C 22 H 14Cl2F2NO4[MH] + 464.0268, found 464.0271.

[0155] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1076 are as follows: 1 H NMR (400 MHz, DMSOd6) d 5.10 (2H, s), 7.13 (1H,bd, J = 8.7 Hz), 7.29-7.34 (1H, m), 7.45 (1H, dt, J = 10.5, 8.2Hz), 7.50-7.57 (1H, m), 7.63 (1H, bs), 7.87 (1H, t, J = 1.8 Hz), 7.92(2H, d, J = 1.8 Hz), 8.46 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd forC 21 H 12 Cl2F2NO4[MH] + 450.0111, found 450.0111.

[0156] The NMR spectrum and mass spectrometry results for H-1079 by HR-ESI-MS are as follows: H-1079 1 H NMR (400 MHz, CDCl3) d 3.90 (3H, s), 5.04 (2H,s), 7.13-7.32 (4H, m), 7.41 (2H, s), 7.64 (1H, d, J = 2.7 Hz), 8.81 (1H,d, J = 9.1 Hz), 11.13 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 14 Cl3F2NO4Na[M+Na] + 521.9854, found 521.9857.

[0157] The NMR spectrum and mass spectrometry results for H-1080 by HR-ESI-MS are as follows: H-1080 1H NMR (400 MHz, CDCl3) d 5.12 (2H, s), 7.18-7.26(1H, m), 7.29-7.35 (1H, m), 7.41-7.59 (3H, m), 7.82 (2H, s), 8.33 (1H, d, J= 9.1 Hz); HRMS(ESI-TOF)calcd for C 21 H 12 Cl3F2NO4Na[M+Na] + 507.9698, found 507.9698.

[0158] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1113 are as follows: 1 H NMR (400 MHz, CDCl3) d 3.98 (3H, s), 5.05 (2H,s), 7.15-7.33 (4H, m), 7.65 (1H, d, J = 6.8 Hz), 7.68 (1H, d, J =6.8 Hz), 7.82 (1H, d, J = HRMS(ESI-TOF)calcd for C 23 H 17 F5NO4 [M+H] + 466.1078, found 466.1074.

[0159] The NMR spectrum and mass spectrometry results for H-1114 by HR-ESI-MS are as follows: H-1114 1H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.18 (1H, d, J= 6.8 Hz), 7.30-7.35 (1H, m), 7.41-7.50 (1H, m), 7.51-7.58 (1H, m), 7.64 (1H,bs), 7.81 (1H, t, J = 8.3 Hz), 7.97 (1H, d, J = 7.8 Hz), 8.26(2H, bs), 8.33 (1H, bs), 8.53 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcdfor C 22 H 14 F5NO4Na [M+Na] + 474.0741, found 474.0741.

[0160] The NMR spectrum and mass spectrometry results for H-1121 by HR-ESI-MS are as follows: H-1121 1 H NMR (400 MHz, CDCl3)d 4.00 (3H, s), 5.05 (2H, s),7.14-7.33 (4H, m), 7.68 (1H, d, J = 3.2 Hz), 8.06 (1H, bs), 8.48 (2H,s), 8.82 (1H, d, J = 9.1 Hz), 12.11 (1H, s); HRMS(ESI-TOF) calcd for C 24 H 15 F8NO4Na[M+Na] + 556.0771, found 556.0771.

[0161] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1122 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.15 (2H, s), 7.31-7.40 (2H, m),7.42-7.51 (1H, m), 7.53-7.60 (1H, m), 7.59 (1H, d, J = 3.2 Hz), 8.33(1H, d, J = 9.1 Hz), 8.43 (1H, bs), 8.53 (2H, s); HRMS(ESI-TOF) calcdfor C 23 H 13 F8NO4Na [M+Na] + 542.0615, found 542.0615.

[0162] The NMR spectrum and mass spectrometry results for H-1129 by HR-ESI-MS are as follows: H-1129 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.05 (2H, s),7.13-7.32 (4H, m), 7.66 (1H, d, J = 2.7 Hz), 7.79 (2H, d, J = 8.2Hz), 8.14 (2H, d, J = 8.2 Hz), 8.87 (1H, d, J = 9.1 Hz), 11.95(1H, s); HRMS(ESI-TOF) calcd for C 23 H 15 F5NO4[MH] + 464.0921, found 464.0924.

[0163] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1130 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.20 (1H, d, J= 9.1 Hz), 7.30-7.35 (1H, m), 7.41-7.50 (1H, m), 7.51-7.58 (1H, m), 7.64 (1H, d, J = HRMS(ESI-TOF) calcd for C 22 H 14 F5NO4Na[M+Na] + 474.0741, found 474.0743.

[0164] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1206 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.86 (2H, s), 3.87 (3H, s), 4.99(2H, s), 7.11-7.30 (5H, m), 7.35 (1H, d, J= 8.2 Hz), 7.44 (1H, d, J = 2.3 Hz), 7.55 (1H, d, J = 3.2 Hz), 8.63 (1H, d, J= 9.2 Hz), 10.83 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 17 Cl2F2NO4[M+Na] + 502.0400, found 502.0400.

[0165] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1207 are as follows: H-1207 1H NMR (400 MHz, DMSOd6)d 3.79 (2H, s), 5.04 (2H, s), 7.01(1H, bd, J = 9.6 Hz), 7.26-7.32 (1H, m),7.36-7.59 (5H, m), 7.60 (1H, d, J = 2.3 Hz), 8.35 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF)calcd for C 22 H 15 Cl2F2NO4[M+Na] + 488.0244, found 488.0244.

[0166] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1208 are as follows: H-1208 1 H NMR (400 MHz, CDCl3)d 3.69 (2H, s), 3.89 (3H, s), 5.00(2H, s), 7.10-7.29 (5H, m), 7.43 (1H, d, J= 8.2 Hz), 7.48 (1H, d, J = 2.3 Hz), 7.56 (1H, d, J = 2.7 Hz), 8.61 (1H, d, J= 9.1 Hz), 10.89 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 16 Cl2F2NO4[MH] + 478.0424, found 478.0421.

[0167] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1209 are as follows: 1H NMR (400 MHz, DMSOd6)d 3.74 (2H, s), 5.07 (2H, s), 7.18(1H, dd, J = 9.2, 3.2 Hz), 7.27-7.34 (1H, m), 7.33(1H, dd, J = 8.3, 1.9 Hz), 7.44 (1H, dt, J = 10.5, 8.7 Hz), 7.48-7.56 (2H, m), 7.59(1H, d, J = 8.3 Hz), 7.63 (1H, d, J= 2.3 Hz), 8.30 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 22 H 15 Cl2F2NO4[M+Na] + 488.0244, found 488.0243.

[0168] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1210 are as follows: H-1210 1 H NMR (400 MHz, CDCl3) d 3.90 (3H, s), 4.67 (2H,s), 5.02 (2H, s), 6.91 (1H, d, J = 8.7 Hz), 7.13-7.30 (5H, m), 7.44 (1H,d, J = 2.8 Hz), 7.60 (1H, d, J = 2.8 Hz), 8.66 (1H, d, J =9.2 Hz), 11.58 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 16 Cl2F2NO5[MH] + 494.0374, found 494.0374.

[0169] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1211 are as follows: H-1211 1H NMR (400 MHz, DMSOd6) d 4.78 (2H, s), 5.06 (2H,s), 7.05-7.10 (1H, m), 7.13 (1H, d, J = 9.2 Hz), 7.27-7.33 (1H, m), 7.35(1H, dd, J = HRMS(ESI-TOF) calcd for C 22 H 14 Cl2F2NO5[MH] + 480.0217, found 480.0217.

[0170] Example 1-5 Synthesis of Compounds (H-1030, 1031, 1034, 1035, 1046, 1047, 1063, 1064, 1065, 1066, 1073, 1074, 1081, 1082, 1117, 1118, 1125, 1126, 1133, 1134, 1212, 1213, 1214, 1215, 1216, 1217) Using Intermediate (S-4) In this example, first, intermediate (S-4) used to synthesize the compound of the present invention was produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material and 4-chlorobenzyl chloride instead of benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(4-chlorobenzyloxy)benzoate (preS-4) was synthesized, as shown in the following reaction scheme. Further, methyl 2-amino-5-(4-chlorobenzyloxy)benzoate (S-4) was synthesized. The NMR spectrum of preS-4 is as follows: Methyl 2-acetamido-5-((4-chlorobenzyl)oxy)benzoate (preS-4) 1H NMR (400 MHz, CDCl3)d 2.22 (3H, s), 3.93 (3H, s), 5.03 (2H, s), 7.17 (1H, dd, J = 9.2, 3.2 Hz), 7.36 (4H, s), 7.58 (1H, d, J = 3.2 Hz), 8.63 (1H, d, J = 9.2 Hz), 10.79 (1H, s). The NMR spectrum and mass analysis results by HR-ESI-MS for S-4 are as follows: Methyl 2-amino-5-((4-chlorobenzyl)oxy)benzoate (S-4) 1 H NMR (400 MHz, CDCl3)d 3.87 (3H, s), 4.96 (2H, s), 5.48(2H, bs), 6.64 (1H, d, J = 9.2 Hz), 6.99 (1H, dd, J = 9.2, 3.2Hz), 7.35 (4H, s), 7.42 (1H, d, J = 3.2 Hz); HRMS(ESI-TOF) calcd for C 15 H 14 ClNO3Na[M+Na] + 314.0560, found 314.0555.

[0171] Methyl 2-amino-5-(4-chlorobenzyloxy)benzoate (S-4) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-1030, 1031, 1034, 1035, 1046, 1047, 1063, 1064, 1065, 1066, 1073, 1074, 1081, 1082, 1117, 1118, 1125, 1126, 1133, 1134, 1212, 1213, 1214, 1215, 1216, and 1217 of the present invention. The structures of each compound are shown in Table 1.

[0172] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1030 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.06 (2H, s), 7.24(1H, dd, J = 9.2, 2.8 Hz), 7.36-7.40 (4H, m), 7.49-7.58 (3H, m), 7.65(1H, d, J = 2.7 Hz), 8.01-8.06 (2H, m), 8.88 (1H, d, J = 9.6 Hz),11.81 (1H, s); 22 H 18 ClNO4Na[M+Na] + 418.0822, found 418.0817.

[0173] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1031 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.15 (2H, s), 7.35 (1H, dd, J= 9.2, 2.8 Hz), 7.44-7.52 (4H, m), 7.54-7.65 (4H, m), 7.90-7.96 (2H, m), 8.57(1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 16 ClNO4Na[M+Na] + 404.0666, found 404.0660.

[0174] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1034 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.06 (2H, s), 7.24(1H, dd, J = 9.6, 3.2 Hz), 7.36-7.40 (4H, m), 7.59 (1H, d, J =8.2 Hz), 7.66 (1H, HRMS(ESI-TOF) calcd for C 22 H 16 Cl3NO4Na[M+Na] + 486.0043, found 486.0043.

[0175] The NMR spectrum and mass spectrometry results for H-1035 by HR-ESI-MS are as follows: H-1035 1 H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 7.28 (1H, bd, J= 8.6 Hz), 7.42-7.50 (4H, m), 7.58 (1H, bs), 7.84-7.91 (2H, m), 8.11 (1H, bs),8.42 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 21 H 13 Cl3NO4[MH] + 447.9910, found 447.9909.

[0176] The NMR spectrum and mass spectrometry results for H-1046 by HR-ESI-MS are as follows: H-1046 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.05 (2H, s), 7.24(1H, dd, J = 9.1, 2.7 Hz), 7.26-7.34 (1H, m), 7.35-7.40 (4H, m), 7.65(1H, d, J = HRMS(ESI-TOF)calcd for C 22 H 15 ClF2NO4[MH] + 430.0658, found 430.0660.

[0177] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1047 are as follows: H-1047 1 H NMR (400 MHz, DMSOd6)d 5.10 (2H, s), 7.12 (1H, dd, J= 9.1, 2.7 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2Hz), 7.59-7.68 (2H, m), 7.80-7.86 (1H, m), 7.89-7.96 (1H, m), 8.50 (1H, d, J= 9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 14 ClF2NO4Na[M+Na] + 440.0477, found 440.0476.

[0178] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1063 are as follows: 1H NMR (400 MHz, CDCl3)d 3.49 (3H, s), 3.96 (3H, s), 5.05(2H, s), 5.24 (2H, s), 7.14 (2H, d, J = 8.2 Hz), 7.23 (1H, dd, J= 9.1, 2.7 Hz), 7.35-7.40 (4H, m), 7.64 (1H, d, J = 2.8 Hz), 7.99 (2H,d, J = 8.2 Hz), 8.86 (1H, d, J = 9.1 Hz), 11.73 (1H, s); HRMS(ESI-TOF)calcd for C 24 H 22 ClNO6Na [M+Na] + 478.1033,found 478.1032.

[0179] The NMR spectrum and mass spectrometry results for H-1064 by HR-ESI-MS are as follows: H-1064 1 H NMR (400 MHz, CDCl3)d 3.50 (3H, s), 5.07 (2H, s), 5.25(2H, s), 7.14 (2H, d, J = 7.8 Hz), 7.23-7.30 (1H, m), 7.35-7.41 (4H, m),7.68 (1H, bs), 7.97 (2H, d, J = 7.8 Hz), 8.88 (1H, d, J = 9.1Hz), 11.59 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 20 ClNO6Na[M+Na] + 464.0877, found 464.0873.

[0180] The NMR spectrum and mass spectrometry results for H-1065 by HR-ESI-MS are as follows: H-1065 1H NMR (400 MHz, CDCl3)d 3.96 (3H, s), 5.05 (2H, s), 6.94(2H, d, J = 8.7 Hz), 7.23 (1H, dd, J = 9.1, 2.7 Hz), 7.35-7.40(4H, m), 7.64 (1H, d, J = 2.7 Hz), 7.96 (2H, d, J = 8.7 Hz), 8.86(1H, d, J = 9.1 Hz), 11.71 (1H, s); 22 H 18 ClNO5Na[M+Na] + 434.0771, found 434.0766.

[0181] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1066 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 6.90 (2H, d, J= 8.7 Hz), 7.32 (1H, dd, J = 9.1, 3.2 Hz), 7.41-7.51 (4H, m), 7.58 (1H,d, J = 2.8 Hz), 7.79 (2H, d, J = 8.7 Hz), 8.59 (1H, d, J =9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 16 ClNO5Na[M+Na] + 420.0615, found 420.0610.

[0182] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1073 are as follows: 1H NMR (400 MHz, CDCl3) d 3.98 (3H, s), 5.06 (2H,s), 7.22-7.28 (2H, m), 7.36-7.40 (3H, m), 7.53-7.56 (1H, m), 7.65-7.68 (1H, m),7.87-7.90 (2H, m), 8.76-8.81 (1H, m), 11.83 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 16 Cl3NO4Na[M+Na] + 486.0043, found 486.0040.

[0183] The NMR spectrum and mass spectrometry results for H-1074 by HR-ESI-MS are as follows: H-1074 1 H NMR (400 MHz, DMSOd6) d 5.15 (2H, s), 7.30 (1H,dd, J = 9.1, 2.3 Hz), 7.42-7.51 (4H, m), 7.58 (1H, d, J = 3.2Hz), 7.90 (3H, s), 8.36 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 13 Cl3NO4[MH] + 447.9910, found 447.9910.

[0184] The NMR spectrum and mass spectrometry results for H-1081 by HR-ESI-MS are as follows: H-1081 1 H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 5.07 (2H, s),7.22-7.28 (1H, m), 7.35-7.43 (6H, m), 7.64 (1H, bs), 8.80 (1H, d, J =9.1 Hz), 11.13 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 15 Cl4NO4Na[M+Na] + 519.9653, found 519.9651.

[0185] The NMR spectrum and mass spectrometry results for H-1082 by HR-ESI-MS are as follows: H-1082 1 H NMR (400 MHz, DMSOd6)d 5.13 (2H, s), 7.16-7.22 (1H, m),7.45 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.56 (1H, d, J= 2.7 Hz), 7.82 (2H, s), 8.34 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcdfor C 21 H 13 Cl4NO4Na [M+Na] + 505.9496, found 505.9497.

[0186] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1117 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.07 (2H, s),7.23-7.28 (1H, m), 7.38 (4H, s), 7.64-7.69 (2H, m), 7.81 (1H, d, J = 7.8Hz), 8.19 (1H, d, J = 7.7 Hz), 8.33 (1H, bs), 8.85 (1H, d, J =9.6 Hz), 11.93 (1H, s); 23 H 16 ClF3NO4[MH] + 462.0720, found 462.0723.

[0187] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1118 are as follows: H-1118 1H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.14 (1H, bd, J= 9.2 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz),7.67 (1H, bs), 7.80 (1H, t, J = 7.7 Hz), 8.26 (2H, bs), 8.55 (1H, d, J= 9.2 Hz); HRMS(ESI-TOF) calcd for C 22 H 15 ClF3NO4Na[M+Na] + 472.0539, found 472.0535.

[0188] The NMR spectrum and mass spectrometry results for H-1125 by HR-ESI-MS are as follows: H-1125 1 H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.07 (2H, s),7.23-7.28 (1H, m), 7.38 (4H, s), 7.68 (1H, d, J = 3.2 Hz), 8.06 (1H,bs), 8.48 (2H, s), 8.81 (1H, d, J = 9.1 Hz), 12.10 (1H, s); HRMS(ESI-TOF)calcd for C 24 H 16 ClF6NO4Na [M+Na] + 554.0570, found 554.0571.

[0189] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1126 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.13 (2H, s), 7.19 (1H, d, J= 8.7 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz),7.64 (1H, d, J = 2.3 Hz), 8.39 (1H, bs), 8.45 (1H, d, J = 9.1Hz), 8.55 (2H, s); HRMS(ESI-TOF) calcd for C 23 H 14 ClF6NO4Na[M+Na] + 540.0413, found 540.0413.

[0190] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1133 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.07 (2H, s),7.23-7.27 (1H, m), 7.38 (4H, s), 7.67 (1H, d, J = 3.2 Hz), 7.79 (2H, d, J= 8.2 Hz), 8.14 (2H, d, J = 8.2 Hz), 8.86 (1H, d, J = 9.1 Hz),11.94 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 17 ClF3NO4Na[M+Na] + 486.0696, found 486.0696.

[0191] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1134 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.12 (1H, dd, J= 9.1, 2.8 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7Hz), 7.65 (1H, d, J = HRMS(ESI-TOF)calcd for C 22 H 14 ClF3NO4[MH] + 448.0563, found 448.0563.

[0192] The NMR spectrum and mass spectrometry results for H-1212 by HR-ESI-MS are as follows: H-1212 1 H NMR (400 MHz, CDCl3)d 3.86 (2H, s), 3.87 (3H, s), 5.02(2H, s), 7.14 (1H, dd, J = 9.1, 3.2 Hz), 7.28(1H, dd, J = 8.2, 1.8 Hz), 7.35 (4H, HRMS(ESI-TOF) calcd for C 23 H 18 Cl3NO4[M+Na] + 500.0199, found 500.0199.

[0193] The NMR spectrum and mass spectrometry results for H-1213 by HR-ESI-MS are as follows: H-1213 1H NMR (400 MHz, DMSOd6)d 3.80(2H, s), 5.06 (2H, s), 7.03(1H, bd, J = 8.7 Hz), 7.38-7.47 (5H, m), 7.49(1H, d, J = 8.3 Hz), 7.56-7.60 (1H, m), 7.60(1H, d, J = 1.9 Hz), 8.35 (1H, d, J= 9.1 Hz); HRMS(ESI-TOF) calcd for C 22 H 15 Cl3NO4[MH] + 462.0067, found 462.0067.

[0194] The NMR spectrum and mass spectrometry results for H-1214 by HR-ESI-MS are as follows: H-1214 1 H NMR (400 MHz, CDCl3)d 3.69 (2H, s), 3.89 (3H, s), 5.02(2H, s), 7.15 (1H, dd, J = 9.2, 3.2 Hz), 7.21(1H, dd, J = 8.2, 2.0 Hz), 7.35 (4H, HRMS(ESI-TOF)calcd for C 23 H 18 Cl3NO4[M+Na] + 500.0199, found 500.0201.

[0195] The NMR spectrum and mass spectrometry results for H-1215 by HR-ESI-MS are as follows: H-1215 1H NMR (400 MHz, DMSOd6)d 3.69 (2H, s), 5.06 (2H, s), 7.05(1H, dd, J = 9.2, 3.2 Hz), 7.32 (1H,dd, J = 8.2, 1.8 Hz), 7.43 (2H, d, J= 9.1 Hz), 7.45 (2H, d, J = 9.1 Hz), 7.53-7.57 (1H, m), 7.58 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 1.8 Hz), 8.31 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF)calcd for C 22 H 15 Cl3NO4[MH] + 462.0067, found 462.0069.

[0196] The NMR spectrum and mass spectrometry results for H-1216 by HR-ESI-MS are as follows: H-1216 1 H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 4.67 (2H, s), 5.04(2H, s), 6.91 (1H, d, J = 9.1 Hz), 7.18(1H, dd, J = 9.2, 3.2 Hz), 7.21 (1H,dd, J = HRMS(ESI-TOF) calcd for C 23 H 17 Cl3NO5[MH] + 492.0172, found 492.0172.

[0197] The NMR spectrum and mass spectrometry results for H-1217 by HR-ESI-MS are as follows: H-1217 1H NMR (400 MHz, DMSOd6)d 4.82 (2H, s), 5.11 (2H, s), 7.16(1H, d, J = 8.7 Hz), 7.21 (1H, bd, J= 7.8 Hz), 7.36 (1H, dd, J = 8.7, 2.3Hz), 7.44 (2H, d, J = 9.1 Hz), 7.47 (2H, d, J = 9.1 Hz), 7.55 (1H, d, J = 2.8 Hz), 7.61 (1H, d, J = 2.8 Hz), 8.50 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF)calcd for C 22 H 15 Cl3NO5[MH] + 478.0016, found 478.0020.

[0198] Example 1-6 Synthesis of Compounds (H-1083, 1084, 1085, 1086, 1119, 1120, 1127, 1128, 1135, 1136) Using Intermediate (S-5) In this example, intermediate (S-5) used to synthesize the compounds of the present invention was first produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material and 3,4,5-trifluorobenzyl bromide instead of the benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(3,4,5-trifluorobenzyloxy)benzoate (preS-5) was synthesized as shown in the following reaction scheme. Then, methyl 2-amino-5-(3,4,5-trifluorobenzyloxy)benzoate (S-5) was further synthesized. The NMR spectrum of preS-5 is as follows: Methyl 2-acetamido-5-((3,4,5-trifluorobenzyl)oxy)benzoate (preS-5) 1H NMR (400 MHz, CDCl3)d 2.22 (3H, s), 3.93 (3H, s), 4.99 (2H, s), 7.02-7.10 (2H, m), 7.16 (1H, dd, J = 9.2, 3.2 Hz), 7.56 (1H, d, J = 3.2 Hz), 8.65 (1H, d, J = 9.2 Hz), 10.80 (1H, s). The NMR spectrum and mass analysis results by HR-ESI-MS for S-5 are as follows: Methyl 2-amino-5-((3,4,5-trifluorobenzyl)oxy)benzoate (S-5) 1 H NMR (400 MHz, CDCl3)d 3.88 (3H, s), 4.92 (2H, s), 5.48(2H, bs), 6.65 (1H, d, J = 9.2 Hz), 6.99 (1H, dd, J = 9.2, 3.2Hz), 7.02-7.10 (2H, m), 7.39 (1H, d, J = 3.2 Hz); HRMS(ESI-TOF) calcdfor C 15 H 12 F3NO3Na [M+Na] + 334.0667, found 334.0661.

[0199] Methyl 2-amino-5-(3,4,5-trifluorobenzyloxy)benzoate (S-5) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-1083, 1084, 1085, 1086, 1119, 1120, 1127, 1128, 1135, and 1136 of the present invention by dehydration and hydrolysis in the same manner as in Example 1-1. The structures of each compound are shown in Table 1.

[0200] The NMR spectrum and mass spectrometry results for H-1083 by HR-ESI-MS are as follows: H-1083 1H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.02 (2H, s), 7.08(2H, t, J = 6.9 Hz), 7.23 (1H, dd, J = 9.2, 3.2 Hz), 7.60 (1H, d,J = 8.7 Hz), 7.83 (1H, dd, J = 9.3, 2.3 Hz), 8.14 (1H, d, J= 1.8 Hz), 8.83 (1H, d, J = 9.1 Hz), 11.86 (1H, s); HRMS(ESI-TOF) calcdfor C 22 H 13 Cl2F3NO4[MH] + 482.0174, found 482.0174.

[0201] The NMR spectrum and mass spectrometry results for H-1084 by HR-ESI-MS are as follows: H-1084 1 H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 7.35 (1H, dd, J= 9.1, 3.2 Hz), 7.46 (2H, t, J = 6.8 Hz), 7.60 (1H, d, J = 3.2Hz), 7.87 (2H, s), 8.12 (1H, s), 8.41 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF)calcd for C 21 H 12 Cl2F3NO4Na[M+Na] + 491.9993, found 491.9991.

[0202] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1085 are as follows: 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.02 (2H, s), 7.08(2H, t, J = 6.9 Hz), 7.23 (1H, dd, J = 9.2, 3.2 Hz), 7.26-7.34(1H, m), 7.64 (1H, HRMS(ESI-TOF) calcd for C 22 H 14 F5NO4Na[M+Na] + 474.0741, found 474.0737.

[0203] The NMR spectrum and mass spectrometry results for H-1086 by HR-ESI-MS are as follows: H-1086 1 H NMR (400 MHz, DMSOd6)d 5.14 (2H, s), 7.32 (1H, dd, J= 9.1, 2.7 Hz), 7.46 (2H, t, J = 6.9 Hz), 7.61 (1H, d, J = 3.2Hz), 7.62-7.71 (1H, m), 7.77-7.83 (1H, m), 7.89-7.96 (1H, m), 8.44 (1H, d, J= 9.1 Hz); HRMS(ESI-TOF) calcd for C 21 H 12 F5NO4Na[M+Na] + 460.0584, found 460.0580.

[0204] The NMR spectrum and mass spectrometry results for H-1119 by HR-ESI-MS are as follows: H-1119 1H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.03 (2H, s), 7.09(2H, t, J = 6.9 Hz), 7.22-7.27 (1H, m), 7.63-7.70 (2H, m), 7.81 (1H, d, J= 8.2 HRMS(ESI-TOF) calcd for C 23 H 15 F6NO4Na[M+Na] + 506.0803, found 506.0803.

[0205] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1120 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.12 (2H, s), 7.22 (1H, d, J= 7.3 Hz), 7.45 (2H, t, J = 6.9 Hz), 7.64 (1H, d, J = 2.8 Hz),7.81 (1H, t, J = 8.3 Hz), 7.98 (1H, d, J = 7.8 Hz), 8.26 (2H,bs), 8.52 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF) calcd for C 22 H 13 F6NO4Na[M+Na] + 492.0646, found 492.0646.

[0206] The NMR spectrum and mass spectrometry results for H-1127 by HR-ESI-MS are as follows: H-1127 1H NMR (400 MHz, CDCl3)d 4.00 (3H, s), 5.04 (2H, s), 7.09(2H, t, J = 6.9 Hz), 7.23-7.28 (1H, m), 7.66 (1H, d, J = 2.7 Hz),8.06 (1H, bs), 8.48 (2H, s), 8.83 (1H, d, J = 9.1 Hz), 12.11 (1H, s); HRMS(ESI-TOF)calcd for C 24 H 14 F9NO4Na [M+Na] + 574.0677, found 574.0678.

[0207] The NMR spectrum and mass spectrometry results for H-1128 by HR-ESI-MS are as follows: H-1128 1 H NMR (400 MHz, DMSOd6)d 5.13 (2H, s), 7.24 (1H, d, J= 9.1 Hz), 7.45 (2H, t, J = 7.4 Hz), 7.64 (1H, d, J = 2.7 Hz),8.40 (1H, bs), 8.43 (1H, d, J = 8.7 Hz), 8.54 (2H, s); HRMS(ESI-TOF)calcd for C 23 H 11 F9NO4[MH] + 536.0544, found 536.0546.

[0208] The NMR spectrum and mass spectrometry results for H-1135 by HR-ESI-MS are as follows: H-1135 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.03 (2H, s),7.04-7.12 (2H, m), 7.24 (1H, dd, J = 9.6, 3.2 Hz), 7.65 (1H, d, J= 3.2 Hz), 7.79 (2H, HRMS(ESI-TOF) calcd for C 23 H 15 F6NO4Na[M+Na] + 506.0803, found 506.0804.

[0209] The NMR spectrum and mass spectrometry results for H-1136 by HR-ESI-MS are as follows: H-1136 1 H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.16 (1H, d, J= 8.3 Hz), 7.45 (2H, t, J = 7.8 Hz), 7.65 (1H, d, J = 2.8 Hz),7.93 (2H, d, J = 8.2 Hz), 8.15 (2H, d, J = 8.2 Hz), 8.55 (1H, d, J= 8.7 Hz); HRMS(ESI-TOF) calcd for C 22 H 12 F6NO4[MH] + 468.0671, found 468.0670.

[0210] Example 1-7 Synthesis of Compounds (H-1105, 1106, 1107, 1108, 1153, 1154, 1161, 1162, 1169, 1170, 1200, 1201, 1202, 1203, 1204, 1205) Using Intermediate (S-6) In this example, first, intermediate (S-6) used to synthesize the compounds of the present invention was produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material, and using 4-(trifluoromethyl)benzyl bromide instead of benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(4-(trifluoromethyl)benzyloxy)benzoate (preS-6) was synthesized, as shown in the following reaction scheme. Further, methyl 2-amino-5-(4-(trifluoromethyl)benzyloxy)benzoate (S-6) was synthesized. The NMR spectrum of preS-6 is as follows: Methyl 2-acetamido-5-((4-(trifluoromethyl)benzyl)oxy)benzoate (preS-6) 1 H NMR (400 MHz, CDCl3) 2.22 (3H, s), 3.93 (3H, s), 5.12 (2H, s), 7.18 (1H, dd, J = 9.2, 3.2 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.60 (1H, d, J = 3.2 Hz), 7.65 (2H, d, J = 8.3 Hz), 8.64 (1H, d, J = 9.2 Hz), 10.79 (1H, s). The NMR spectrum and mass analysis by HR-ESI-MS for S-6 are as follows: Methyl 2-amino-5-((4-(trifluoromethyl)benzyl)oxy)benzoate (S-6) 1H NMR (400 MHz, CDCl3)d 3.87 (3H, s), 5.05 (2H, s), 6.66(1H, d, J = 9.1 Hz), 7.01 (1H, dd, J = 9.1, 3.2 Hz), 7.43 (1H, d,J = 3.2 Hz), 7.54 (2H, d, J = 8.2 Hz), 7.63 (2H, d, J =8.2 Hz); HRMS(ESI-TOF) calcd for C 16 H 14 F3NO3Na[M+Na] + 348.0823, found 348.0817.

[0211] Methyl 2-amino-5-(4-(trifluoromethyl)benzyloxy)benzoate (S-6) and the corresponding carboxylic acid containing R-X were used to synthesize compounds H-1105, 1106, 1107, 1108, 1153, 1154, 1161, 1162, 1169, 1170, 1200, 1201, 1202, 1203, 1204, and 1205 of the present invention by dehydration and hydrolysis in the same manner as in Example 1-1. The structures of each compound are shown in Table 1.

[0212] The NMR spectrum and mass spectrometry results for H-1105 by HR-ESI-MS are as follows: H-1105 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.16 (2H, s), 7.25(1H, dd, J = 9.1, 3.2 Hz), 7.57 (2H, d, J = 7.7 Hz), 7.60 (1H, d,J = 8.7 Hz), 7.67 (2H, d, J = 7.7 Hz), 7.68 (1H, d, J =3.2 Hz), 7.84 (1H, dd, J = 8.7, 1.3 Hz), 8.14 (1H, d, J = 2.3Hz), 8.82 (1H, d, J = 9.1 Hz), 11.86 (1H, s); HRMS(ESI-TOF) calcd for C 23 H 16 Cl2F3NO4Na[M+Na] +520.0306, found 520.0303.

[0213] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1106 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.23 (2H, s), 7.12 (1H, d, J= 9.1 Hz), 7.67 (1H, bs), 7.68 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J= 8.7 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.93 (1H, d, J = 8.2 Hz),8.13 (1H, bs), 8.51 (1H, d, J = 9.1 Hz); HRMS(ESI-TOF) calcd for C 22 H 14 Cl2F3NO4Na[M+Na] + 506.0150, found 506.0151.

[0214] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1107 are as follows: H-1107 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.16 (2H, s),7.23-7.34 (2H, m), 7.57 (2H, d, J = 7.7 Hz), 7.66 (2H, d, J = 7.7Hz), 7.67 (1H, d, J = HRMS(ESI-TOF) calcd for C 23 H 16 F5NO4Na[M+Na] + 488.0897, found 488.0897.

[0215] The NMR spectrum and mass spectrometry results for H-1108 by HR-ESI-MS are as follows: H-1108 1H NMR (400 MHz, DMSOd6)d 5.26 (2H, s), 7.26 (1H, d, J= 8.3 Hz), 7.61-7.70 (2H, m), 7.68 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J= 8.3 Hz), 7.79-7.84 (1H, m), 7.90-7.96 (1H, m), 8.46 (1H, d, J = 9.1Hz); HRMS(ESI-TOF) calcd for C 22 H 13 F5NO4[MH] + 450.0765, found 450.0765.

[0216] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1153 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.17 (2H, s), 7.27(1H, dd, J = 8.9, 3.2 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.64-7.70(4H, m), 7.82 (1H, HRMS(ESI-TOF) calcdfor C 24 H 17 F6NO4Na [M+Na] + 520.0959, found 520.0958.

[0217] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1154 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.27 (2H, s), 7.27-7.33 (1H, m),7.63 (1H, d, J = 2.3 Hz), 7.69 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J= 7.8 Hz), 7.82 (1H, t, J = 7.8 Hz), 7.99 (1H, d, J = 7.3 Hz),8.22-8.27 (2H, m), 8.49 (1H, d, J = 8.9 Hz); HRMS(ESI-TOF) calcd for C 23 H 15 F6NO4Na[M+Na] + 506.0803, found 506.0804.

[0218] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1161 are as follows: 1 H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.17 (2H, s), 7.27(1H, dd, J = 9.7, 3.2 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.67 (2H, d,J = 7.8 Hz), 7.68 (1H, d, J = 3.2 Hz), 7.79 (2H, d, J =8.3 Hz), 8.14 (2H, d, J = 7.8 Hz), 8.87 (1H, d, J = 9.1 Hz),11.95 (1H, s); HRMS(ESI-TOF) calcd for C 24 H 17 F6NO4Na[M+Na] + 520.0959, found 520.0961.

[0219] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1162 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.24 (2H, s), 7.11-7.16 (1H, m),7.66 (1H, bs), 7.68 (2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.2Hz), 7.92 (2H, d, J = HRMS(ESI-TOF) calcd for C 23 H 15 F6NO4Na[M+Na] + 506.0803, found 506.0803.

[0220] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1169 are as follows: 1 H NMR (400 MHz, CDCl3)d 4.00 (3H, s), 5.17 (2H, s), 7.28(1H, dd, J = 9.2, 3.2 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.67 (2H, d,J = 8.2 Hz), 7.70 (1H, d, J = 3.2 Hz), 8.06 (1H, s), 8.48 (2H,s), 8.82 (1H, d, J = 9.2 Hz), 12.10 (1H, s); HRMS(ESI-TOF) calcd for C 25 H 16 F9NO4Na[M+Na] + 588.0833, found 588.0833.

[0221] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1170 are as follows: 1H NMR (400 MHz, DMSOd6)d 5.29 (2H, s), 7.36 (1H, dd, J= 8.7, 3.2 Hz), 7.61 (1H, d, J = 3.2 Hz), 7.69 (2H, d, J = 8.2Hz), 7.77 (2H, d, J = 8.2 Hz), 8.36 (1H, d, J = 9.1 Hz), 8.42(1H, s), 8.53 (2H, s); HRMS(ESI-TOF) calcd for C 24 H 14 F9NO4Na[M+Na] + 574.0677, found 574.0676.

[0222] The NMR spectrum and mass spectrometry results for H-1200 by HR-ESI-MS are as follows: H-1200 1 H NMR (400 MHz, CDCl3)d 3.86 (2H, s), 3.87 (3H, s), 5.11(2H, s), 7.16 (1H, dd, J = 9.1, 3.2 Hz), 7.23-7.30(2H, m), 7.35 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 2.3Hz), 7.54 (2H, d, J = 7.8 Hz), 7.57 (1H, d, J = 3.2 Hz), 7.64(2H, d, J = 8.2 Hz), 8.64 (1H, d, J = 9.1 Hz), 10.84 (1H, s); HRMS(ESI-TOF)calcd for C 24 H 18 Cl2F3NO4[M+Na] + 534.0463, found 534.0466.

[0223] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1201 are as follows: H-1201 1H NMR (400 MHz, DMSOd6)d 3.79 (2H, s), 5.18 (2H, s), 7.03(1H, dd, J = 9.2, 2.8 Hz), 7.40 (1H,dd, J = 8.2, 2.3 Hz), 7.48 (1H, d, J= 8.2 HRMS(ESI-TOF)calcd for C 23 H 16 Cl2F3NO4[M+Na] + 520.0306, found 520.0306.

[0224] The NMR spectrum and mass spectrometry results for H-1202 by HR-ESI-MS are as follows: H-1202 1 H NMR (400 MHz, CDCl3)d 3.69 (2H, s), 3.89 (3H, s), 5.11(2H, s), 7.16 (1H, dd, J = 9.1, 3.2 Hz), 7.22(1H, dd, J = 8.3, 2.3 Hz), 7.43 (1H, d,J = 8.3 Hz), 7.48 (1H, d, J = 2.3 Hz), 7.54 (2H, d, J =8.2 Hz), 7.58 (1H, d, J = 3.2 Hz), 7.64 (2H, d, J = 8.2 Hz), 8.61(1H, d, J = 9.1 Hz), 10.89 (1H, s); HRMS(ESI-TOF) calculation for C 24 H 17 Cl2F3NO4[MH] + 510.0487, found 510.0483.

[0225] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1203 are as follows: 1H NMR (400 MHz, DMSOd6)d 3.72 (2H, s), 5.20 (2H, s),7.10-7.18 (1H, m), 7.33 (1H, d, J = 8.3Hz), 7.52-7.68 (5H, m), 7.74 (2H, d, J= 8.2 Hz), 8.31 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 23 H 16 Cl2F3NO4[M+Na] + 520.0306, found 520.0306.

[0226] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1204 are as follows: H-1204 1 H NMR (400 MHz, CDCl3) d 3.90 (3H, s), 4.67 (2H,s), 5.14 (2H, s), 6.91 (1H, d, J = 8.7 Hz), 7.18-7.23 (2H, m), 7.44 (1H,d, J = 2.8 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.62 (1H, d, J =3.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 8.67 (1H, d, J = 9.2 Hz),11.58 (1H, s); HRMS(ESI-TOF) calcd for C 24 H 17 Cl2F3NO5[MH] + 526.0436, found 526.0436.

[0227] The NMR spectrum and mass spectrometry results for H-1205 by HR-ESI-MS are as follows: H-1205 1H NMR (400 MHz, DMSOd6)d 4.78 (2H, s), 5.20 (2H, s), 7.10(1H, bd, J = 9.2 Hz), 7.13 (1H, d, J= 9.2 Hz), 7.35 (1H, dd, J = 8.7, 2.3Hz), 7.58-7.63 (2H, m), 7.66 (2H, d, J= 8.2 Hz), 7.75 (2H, d, J = 8.2 Hz), 8.47 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF)calcd for C 23 H 15 Cl2F3NO5[MH] + 512.0279, found 512.0282.

[0228] Example 1-8 Synthesis of Compounds (H-1087, 1088, 1089, 1090, 1099, 1100, 1103, 1104, 1155, 1156, 1163, 1164, 1171, 1172) Using Intermediate (S-7) In this example, intermediate (S-7) used to synthesize the compounds of the present invention was first produced. Using the known compound methyl 2-acetamido-5-hydroxybenzoate (H-122) as a starting material and 3-(bromomethyl)thiophene instead of benzyl bromide in intermediate (S-1), the precursor methyl 2-acetamido-5-(thiophen-3-ylmethoxy)benzoate (preS-7) was synthesized as shown in the following reaction scheme. Then, methyl 2-amino-5-(thiophen-3-ylmethoxy)benzoate (S-7) was further synthesized. The NMR spectrum of preS-7 is as follows: Methyl 2-acetamido-5-(thiophen-3-ylmethoxy)benzoate (preS-7) 1H NMR (400 MHz, CDCl3) 2.22 (3H, s), 3.93 (3H, s), 5.07 (2H, s), 7.15 (1H, dd, J = 5.0, 1.3 Hz), 7.18 (1H, dd, J = 9.1, 3.2 Hz), 7.31-7.37 (2H, m), 7.60 (1H, d, J = 3.2 Hz), 8.63 (1H, d, J = 9.2 Hz), 10.79 (1H, s). The NMR spectrum and mass analysis results for S-7 by HR-ESI-MS are as follows: Methyl 2-amino-5-(thiophen-3-ylmethoxy)benzoate (S-7) 1 H NMR (400 MHz, CDCl3)d 3.88 (3H, s), 5.01 (2H, s), 6.67(1H, d, J = 9.2 Hz), 7.01 (1H, dd, J = 9.2, 3.2 Hz), 7.15 (1H,dd, J = 5.0, 1.3 Hz), 7.31 (1H, bs), 7.34 (1H, dd, J = 5.0, 3.0Hz), 7.45 (1H, d, J = 3.2 Hz); HRMS(ESI-TOF) calcd for C 13 H 13 NO3SNa[M+Na] + 286.0514, found 286.0510.

[0229] Methyl 2-amino-5-(thiophen-3-ylmethoxy)benzoate (S-7) and the corresponding carboxylic acid containing R-X were used to carry out dehydration and hydrolysis in the same manner as in Example 1-1 to synthesize compounds H-1087, 1088, 1089, 1090, 1099, 1100, 1103, 1104, 1155, 1156, 1163, 1164, 1171, and 1172 of the present invention. The structures of each compound are shown in Table 1.

[0230] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1087 are as follows: H-1087 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.11 (2H, s), 7.16(1H, dd, J = 4.5, 1.3 Hz), 7.23-7.28 (1H, m), 7.34-7.38 (2H, m), 7.60(1H, d, J = 8.7 Hz), 7.67 (1H, d, J = 3.2 Hz), 7.84 (1H, dd, J= 9.7, 2.3 Hz), 8.14 (1H, d, J = 2.3 Hz), 8.81 (1H, d, J = 9.1Hz), 11.86 (1H, s); HRMS(ESI-TOF) calcd for C 20 H 15 Cl2NO4SNa[M+Na] + 457.9997, found 457.9991.

[0231] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1088 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.15-7.25 (2H, m),7.53-7.64 (3H, m), 7.85 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 8.3Hz), 8.12 (1H, s), 8.45 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 19 H 13 Cl2NO4SNa[M+Na] + 443.9840, found 443.9835.

[0232] The NMR spectrum and mass spectrometry results for H-1089 by HR-ESI-MS are as follows: H-1089 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.11 (2H, s), 7.16(1H, dd, J = 5.0, 1.3 Hz), 7.23-7.38 (4H, m), 7.67 (1H, d, J =3.2 Hz), 7.76-7.81 (1H, m), 7.86-7.92 (1H, m), 8.81 (1H, d, J = 9.1 Hz),11.84 (1H, s); HRMS(ESI-TOF) calcd for C 20 H 15 F2NO4SNa[M+Na] + 426.0588, found 426.0583.

[0233] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1090 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.12 (2H, s), 7.19 (1H, d, J= 4.6 Hz), 7.22-7.28 (1H, m), 7.53-7.70 (4H, m), 7.78-7.84 (1H, m), 7.89-7.96(1H, m), 8.45 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 19 H 13 F2NO4SNa[M+Na] + 412.0431, found 412.0428.

[0234] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1099 are as follows: 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.11 (2H, s), 7.17(1H, dd, J = 4.5, 0.9 Hz), 7.23-7.27 (1H, m), 7.33-7.38 (2H, m), 7.54(1H, t, J = HRMS(ESI-TOF) calcdfor C 20 H 15 Cl2NO4SNa [M+Na] + 457.9997, found 457.9992.

[0235] The NMR spectrum and mass spectrometry results for H-1100 by HR-ESI-MS are as follows: H-1100 1 H NMR (400 MHz, DMSOd6)d 5.10 (2H, s), 7.15-7.22 (1H, m),7.18 (1H, d, J = 5.0 Hz), 7.53-7.58 (2H, m), 7.61 (1H, d, J = 3.2Hz), 7.88 (1H, bs), 7.92 (2H, d, J = 1.8 Hz), 8.42 (1H, d, J =9.2 Hz); HRMS(ESI-TOF) calcd for C 19 H 13 Cl2NO4SNa[M+Na] + 443.9840, found 443.9835.

[0236] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1103 are as follows: 1H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 5.11 (2H, s), 7.16(1H, dd, J = 5.0, 0.9 Hz), 7.23-7.27 (1H, m), 7.33-7.38 (2H, m), 7.39(2H, s), 7.65 (1H, d, J = 2.8 Hz), 8.79 (1H, d, J = 9.1 Hz),11.13 (1H, s); HRMS(ESI-TOF) calcd for C 20 H 14 Cl3NO4SNa[M+Na] + 491.9607, found 491.9604.

[0237] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1104 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.12 (2H, s), 7.18 (1H, d, J= 5.1 Hz), 7.18-7.26 (1H, m), 7.53-7.58 (3H, m), 7.82 (2H, s), 8.31 (1H, d, J= 8.7 Hz); HRMS(ESI-TOF) calcd for C 19 H 12 Cl3NO4SNa[M+Na] + 477.9450, found 477.9446.

[0238] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1155 are as follows: 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.12 (2H, s), 7.17(1H, dd, J = 4.6, 1.4 Hz), 7.27 (1H, dd, J = 9.2, 3.2 Hz),7.34-7.38 (2H, m), 7.66 (1H, t, J = 7.8 Hz), 7.68 (1H, d, J = 3.2Hz), 7.82 (1H, d, J = 7.3 Hz), 8.19 (1H, d, J = 7.3 Hz), 8.33(1H, s), 8.84 (1H, d, J = 9.1 Hz), 11.93 (1H, s); HRMS(ESI-TOF) calcdfor C 21 H 16 F3NO4SNa [M+Na] + 458.0650, found 458.0645.

[0239] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1156 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.10 (2H, s), 7.14-7.20 (1H, m),7.19 (1H, d, J = 4.6 Hz), 7.53-7.59 (2H, m), 7.63 (1H, s), 7.81 (1H, t, J= 8.3 HRMS(ESI-TOF) calcd for C 20 H 14 F3NO4SNa[M+Na] + 444.0493, found 444.0489.

[0240] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1163 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.11 (2H, s), 7.17(1H, dd, J = 4.6, 1.3 Hz), 7.24-7.28 (1H, m), 7.34-7.38 (2H, m), 7.68(1H, d, J = HRMS(ESI-TOF) calcdfor C 21 H 16 F3NO4SNa [M+Na] + 458.0650, found 458.0647.

[0241] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1164 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.11 (2H, s), 7.15-7.22 (1H, m),7.19 (1H, d, J = 4.6 Hz), 7.53-7.58 (2H, m), 7.63 (1H, d, J = 2.8Hz), 7.93 (2H, HRMS(ESI-TOF) calcd for C 20 H 14 F3NO4SNa[M+Na] + 444.0493, found 444.0489.

[0242] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1171 are as follows: 1H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.12 (2H, s), 7.17(1H, dd, J = 5.0, 1.3 Hz), 7.25-7.30 (1H, m), 7.35-7.39 (2H, m), 7.70(1H, d, J = HRMS(ESI-TOF) calcd for C 22 H 15 F6NO4SNa[M+Na] + 526.0524, found 526.0525.

[0243] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1172 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.10 (2H, s), 7.11-7.18 (1H, m),7.19 (1H, bs), 7.53-7.58 (2H, m), 7.64 (1H, bs), 8.38 (1H, s), 8.47 (1H, d, J= 8.2 Hz), 8.56 (2H, s); HRMS(ESI-TOF) calcd for C 21 H 13 F6NO4SNa[M+Na] + 512.0367, found 512.0367.

[0244] (Examples 1-9) Synthesis of Compounds (H-1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1157, 1158, 1165, 1166, 1173, 1174) Using Intermediate (S-8) In this example, intermediate (S-8) used to synthesize the compounds of the present invention was first prepared as shown in the following reaction scheme. Potassium carbonate (4.5 g, 32.9 mmol) and 2-(bromomethyl)thiophene (1.26 g, 7.2 mmol) were added to a solution of methyl 5-hydroxy-2-nitrobenzoate (1 g, 5.1 mmol) in acetone (55 mL), and the mixture was refluxed for 12 hours. After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1 to 1:1) to obtain methyl 2-nitro-5-(thiophen-2-ylmethoxy)benzoate (preS-8) (1.5 g, 4.9 mmol, 97%). To a suspension of preS-8 (1.5 g, 4.9 mmol) and iron powder (1.1 g, 19.6 mmol) in ethanol (20 mL), 1 M HCl (0.76 mL) was added dropwise at 60°C and refluxed for 1 hour. After cooling to room temperature, 1 M aqueous NaOH solution was added dropwise to adjust the pH to 7. Ethyl acetate was added to the mixture, which was then filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1) to give methyl 2-amino-5-(thiophen-2-ylmethoxy)benzoate (S-8) (1.12 g, 4.3 mmol, 87%). The NMR spectrum of preS-8 is as follows: Methyl 2-nitro-5-(thiophen-2-ylmethoxy)benzoate (preS-8) 1H NMR (400 MHz, CDCl3) d 3.93 (3H, s), 5.32 (2H, s), 7.03 (1H, dd, J = 5.0, 3.7 Hz), 7.10 (1H, dd, J = 9.2, 2.8 Hz), 7.15 (1H, d, J = 2.8 Hz), 7.38 (1H, dd, J = 5.0, 0.9 Hz), 8.03 (1H, d, J = 9.2 Hz). The NMR spectrum and mass analysis by HR-ESI-MS for S-2 are as follows. Methyl 2-amino-5-(thiophen-2-ylmethoxy)benzoate (S-8) 1 H NMR (400 MHz, CDCl3)d 3.88 (3H, s), 5.16 (2H, s), 5.73(2H, bs), 6.67 (1H, d, J = 8.7 Hz), 6.98-7.04 (2H, m), 7.07-7.10 (1H,m), 7.32 (1H, dd, J = 5.0, 1.4 Hz), 7.47 (1H, d, J = 2.8 Hz);HRMS(ESI-TOF) calcd for C 13 H 13 NO3SNa [M+Na] + 286.0514, found 286.0511.

[0245] Methyl 2-amino-5-(thiophen-2-ylmethoxy)benzoate (S-8) and the corresponding carboxylic acid containing R-X were used to carry out dehydration and hydrolysis in the same manner as in Example 1-1 to synthesize compounds H-1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1157, 1158, 1165, 1166, 1173, and 1174 of the present invention. The structures of each compound are shown in Table 1.

[0246] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1143 are as follows: 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.26 (2H, s), 7.02(1H, dd, J = 5.1, 3.6 Hz), 7.13 (1H, d, J = 2.7 Hz), 7.25-7.36(3H, m), 7.69 (1H, HRMS(ESI-TOF) calcd for C 20 H 15 F2NO4SNa[M+Na] + 426.0588, found 426.0582.

[0247] The NMR spectrum and mass spectrometry results for H-1144 by HR-ESI-MS are as follows: H-1144 1 H NMR (400 MHz, DMSOd6)d 5.29 (2H, s), 7.00-7.05 (1H, m),7.12-7.21 (2H, m), 7.52-7.56 (1H, m), 7.59-7.68 (2H, m), 7.79-7.86 (1H, m),7.89-7.97 (1H, m), 8.47 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 19 H 13 F2NO4SNa[M+Na] + 412.0431, found 412.0426.

[0248] The NMR spectrum and mass spectrometry results for H-1145 by HR-ESI-MS are as follows: H-1145 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.26 (2H, s), 7.02(1H, dd, J = 5.0, 3.6 Hz), 7.13 (1H, d, J = 3.2 Hz), 7.25-7.28(1H, m), 7.35 (1H, d, J = 5.1 Hz), 7.59 (1H, d, J = 8.2 Hz), 7.69(1H, d, J = 2.7 Hz), 7.83 (1H, dd, J = 8.3, 2.3 Hz), 8.14 (1H, d,J = 1.9 Hz), 8.81 (1H, d, J = 9.1 Hz), 11.87 (1H, s); HRMS(ESI-TOF)calcd for C 20 H 15 Cl2NO4SNa [M+Na] + 457.9997, found 457.9992.

[0249] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1146 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.31 (2H, s), 7.03 (1H, t, J= 5.0 Hz), 7.20 (1H, d, J = 2.3 Hz), 7.18-7.24 (1H, m), 7.55 (1H, d, J= 5.0 Hz), 7.61 (1H, s), 7.85 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J= 8.3 Hz), 8.12 (1H, s), 8.45 (1H, d, J = 9.6 Hz); HRMS(ESI-TOF) calcdfor C 19 H 12 Cl2NO4S[MH] + 419.9864,found 419.9864.

[0250] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1147 are as follows: H-1147 1H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.26 (2H, s), 7.02(1H, dd, J = 5.0, 3.6 Hz), 7.13 (1H, d, J = 3.2 Hz), 7.24-7.29(1H, m), 7.35 (1H, dd, J = 5.0, 0.9 Hz), 7.54 (1H, t, J = 1.8Hz), 7.69 (1H, d, J = 3.2 Hz), 7.88 (2H, d, J = 1.8 Hz), 8.79(1H, d, J = 9.1 Hz), 11.84 (1H, s); HRMS(ESI-TOF) calcd for C 20 H 15 Cl2NO4SNa[M+Na] + 457.9997, found 457.9994.

[0251] The NMR spectrum and mass spectrometry results for H-1148 by HR-ESI-MS are as follows: H-1148 1 H NMR (400 MHz, DMSOd6)d 5.30 (2H, s), 7.03 (1H, t, J= 4.6 Hz), 7.20 (1H, bs), 7.18-7.24 (1H, m), 7.55 (1H, d, J = 5.5 Hz),7.62 (1H, bs), 7.88 (1H, bs), 7.92 (2H, bs), 8.42 (1H, d, J = 9.2 Hz); HRMS(ESI-TOF)calcd for C 19 H 13 Cl2NO4SNa [M+Na] + 443.9840, found 443.9840.

[0252] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1149 are as follows: 1H NMR (400 MHz, CDCl3)d 3.90 (3H, s), 5.26 (2H, s), 7.02(1H, dd, J = 5.0, 3.6 Hz), 7.13 (1H, d, J = 2.8 Hz), 7.27 (1H,dd, J = 9.1, 3.2 Hz), 7.35 (1H, dd, J = 5.0, 1.3 Hz), 7.39 (2H,s), 7.67 (1H, d, J = 3.2 Hz), 8.80 (1H, d, J = 9.6 Hz), 11.14(1H, s); HRMS(ESI-TOF) calcd for C 20 H 14 Cl3NO4SNa[M+Na] + 491.9607, found 491.9606.

[0253] The NMR spectrum and mass spectrometry results for H-1150 by HR-ESI-MS are as follows: H-1150 1 H NMR (400 MHz, DMSOd6)d 5.29 (2H, s), 7.02 (1H, dd, J= 5.0, 3.7 Hz), 7.09-7.16 (1H, m), 7.19 (1H, d, J = 3.2 Hz), 7.54 (1H,d, J = 5.0 Hz), 7.60 (1H, bs), 7.80 (2H, s), 8.37 (1H, d, J = 9.1Hz); HRMS(ESI-TOF) calcd for C 19 H 12 Cl3NO4SNa[M+Na] + 477.9450, found 477.9449.

[0254] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1157 are as follows: H-1157 1H NMR (400 MHz, CDCl3)d 3.98 (3H, s), 5.27 (2H, s), 7.02(1H, dd, J = 5.1, 3.2 Hz), 7.13 (1H, d, J = 3.2 Hz), 7.24-7.30(1H, m), 7.35 (1H, dd, J = 5.1, 1.0 Hz), 7.66 (1H, t, J = 7.8Hz), 7.70 (1H, d, J = 2.7 Hz), 7.81 (1H, d, J = 8.3 Hz), 8.19(1H, d, J = 7.8 Hz), 8.33 (1H, s), 8.85 (1H, d, J = 9.1 Hz),11.94 (1H, s); HRMS(ESI-TOF) calcd for C 21 H 16 F3NO4SNa[M+Na] + 458.0650, found 458.0646.

[0255] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1158 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.31 (2H, s), 7.03 (1H, dd, J= 5.0, 3.2 Hz), 7.17-7.24 (1H, m), 7.20 (1H, d, J = 3.7 Hz), 7.55 (1H,dd, J = 5.0, HRMS(ESI-TOF) calcd for C 20 H 14 F3NO4SNa[M+Na] + 444.0493, found 444.0491.

[0256] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1165 are as follows: 1H NMR (400 MHz, CDCl3)d 3.97 (3H, s), 5.27 (2H, s), 7.02(1H, dd, J = 5.1, 3.6 Hz), 7.13 (1H, d, J = 3.2 Hz), 7.27 (1H,dd, J = 9.7, 3.2 Hz), 7.35 (1H, dd, J = 5.1, 1.3 Hz), 7.70 (1H, d, J = 3.2 Hz), 7.79 (2H, d, J = 8.3 Hz), 8.14 (2H, d, J =7.7 Hz), 8.86 (1H, d, J = 9.1 Hz), 11.95 (1H, s); HRMS(ESI-TOF) calcdfor C 21 H 16 F3NO4SNa [M+Na] + 458.0650, found 458.0646.

[0257] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1166 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.29 (2H, s), 7.00-7-05(1H, m),7.14 (1H, d, J = 8.7 Hz), 7.19 (1H, bs), 7.54 (1H, d, J = 5.0Hz), 7.65 (1H, bs), 7.92 (2H, d, J = 7.8 Hz), 8.15 (2H, d, J =7.8 Hz), 8.55 (1H, d, J = 8.7 Hz); HRMS(ESI-TOF) calcd for C 20 H 15 F3NO4SNa[M+H] + 422.0674, found 422.0670.

[0258] The NMR spectrum and mass spectrometry results for H-1173 by HR-ESI-MS are as follows: H-1173 1H NMR (400 MHz, CDCl3)d 3.99 (3H, s), 5.27 (2H, s), 7.03(1H, dd, J = 5.0, 3.6 Hz), 7.14 (1H, d, J = 2.8 Hz), 7.29 (1H,dd, J = 9.1, 3.2 Hz), 7.35 (1H, dd, J = 5.0, 0.9 Hz), 7.71 (1H,d, J = 3.2 Hz), 8.06 (1H, s), 8.48 (2H, s), 8.81 (1H, d, J = 9.1Hz), 12.11 (1H, s); HRMS(ESI-TOF) calcd for C 22 H 15 F6NO4SNa[M+Na] + 526.0524, found 526.0524.

[0259] The NMR spectrum and HR-ESI-MS mass spectrometry results for H-1174 are as follows: 1 H NMR (400 MHz, DMSOd6)d 5.35 (2H, s), 7.02-7.06 (1H, m),7.22 (1H, bs), 7.30-7.36 (1H, m), 7.56 (1H, d, J = 5.0 Hz), 7.60 (1H,bs), 8.36 (1H, d, J = 9.1 Hz), 8.41 (1H, s), 8.53 (2H, s); HRMS(ESI-TOF)calcd for C 21 H 13 F6NO4SNa [M+Na] + 512.0367, found 512.0367.

[0260] 10-2. Example 2: SARS-CoV-2 Growth Inhibitory Effect In this example, the inhibitory effect of the compounds of the present invention on SARS-CoV-2 growth was confirmed using VeroE6 / TMPRSS2 cells and a SARS-CoV-2 infection model. The compounds of the present invention were added to VeroE6 / TMPRSS2 cells at a final concentration of 5 or 10 μM. Two hours later, the cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 10. Eight hours after infection, cell lysates were collected, and intracellular SARS-CoV-2 nucleocapsids and actin as an internal standard protein were detected by Western blotting. In an experiment using the same system, the nucleocapsid band area without the addition of the compound was defined as 0% inhibition, and the inhibition rate was calculated as the ratio of the band area with the addition of the compound. When the band area was 0 (when no band was observed), the inhibition rate was 100%. The results are shown in Table 2.

[0261]

[0262] 10-3. Example 3: Zika virus proliferation inhibitory effect In this example, the inhibitory effect of the compound of the present invention on Zika virus proliferation was confirmed. VeroE6 cells in a 10% FBS-supplemented medium were plated at 1 x 10 6Cells were seeded at a density of 100 cells / well and incubated overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS and replaced with 2% FBS-supplemented medium containing Zika virus at a multiplicity of infection (MOI) of 0.01. After 2 hours of incubation at 37°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing 0, 0.1, 1, 5, and 10 μM Pin1 inhibitor (compound H-958) and 0.1% DMSO. The cells were then incubated for 24 hours at 37°C and 5% CO2. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, followed by an additional 24 hours of incubation. Finally, the supernatant from each well was collected and the cells were lysed with TRIzol reagent. To estimate Zika virus genome replication, real-time quantitative PCR of the Zika virus NS1 gene in the cell lysate was performed. The inhibition rate was calculated as the amount of reduction in the NS1 gene copy number when a Pin1 inhibitor was added compared to the copy number when no Pin1 inhibitor was added. The copy number of the NS1 gene when no Pin1 inhibitor was added to the infected cell line was considered to be 0% inhibition.

[0263] Zika virus growth was determined by testing collected supernatants in a limiting dilution plaque assay. Supernatants from different treatment groups were serially diluted 10-fold and added to monolayers of VeroE6 cells in 12-well plates. To obtain accurate titers, wells containing individual plaques were selected for counting. The number of plaque-forming units per mL (PFU / ml) was calculated as the average number of plaques in the test wells multiplied by the dilution factor and divided by the volume of the supernatant. Inhibition of viral growth was calculated as the reduction in PFU / ml with the addition of Pin1 inhibitor compared to PFU / ml without Pin1 inhibitor (0 μM).

[0264] Figure 1 shows the inhibitory effect of Pin1 inhibitors on Zika virus-infected cells. Figure 1A shows the quantitative real-time quantitative PCR values ​​of Zika virus NS1 gene after treatment with various concentrations of H-958. Nonlinear regression analysis of the results yielded an EC50 value of 2.6 μM (Figure 1B). Figure 1C shows the results of a plaque assay after treatment with H-958 and the calculated plaque-forming units per milliliter (PFU / ml). 10 μM H-958 inhibited the growth of untreated cells (1.8 × 10 4 PFU / ml) in the supernatant of treated cells was reduced by 96% (8 x 10 2 PFU / ml).

[0265] 10-4. Example 4: RS virus proliferation inhibitory effect In this example, the inhibitory effect of the compound of the present invention on RS virus proliferation was confirmed. HEp-2 cells in a 10% FBS-supplemented medium were plated at 1 x 10 6 Cells were seeded at a density of 100 cells / well and incubated overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS and replaced with 2% FBS-supplemented medium containing respiratory syncytial virus (RSV) at a multiplicity of infection (MOI) of 0.01. After 2 hours of incubation at 37°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing 0, 0.1, 1, 5, and 10 μM Pin1 inhibitor (compound H-958) and 0.1% DMSO. The cells were then incubated for 24 hours at 37°C and 5% CO2. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, followed by an additional 24 hours of incubation. Finally, the supernatant from each well was collected and the cells were lysed with TRIzol reagent. To estimate RSV genome replication, real-time quantitative PCR of the RSV N gene in the cell lysate was performed. The inhibition rate was calculated as the reduction in the N gene copy number when a Pin1 inhibitor was added compared to the copy number when no Pin1 inhibitor was added. The copy number of the N gene when no Pin1 inhibitor was added to the infected cell line was considered to be 0% inhibition rate.

[0266] Figure 2 shows the inhibitory effect of Pin1 inhibitors on RS virus-infected cells. Figure 2A shows the quantitative real-time quantitative PCR values ​​of the RS virus N gene after treatment with various concentrations of H-958. Nonlinear regression analysis of the results yielded an EC50 value of 0.7 μM (Figure 2B).

[0267] 10-5. Example 5: Inhibitory effect on hantavirus proliferation In this example, the inhibitory effect of the compound of the present invention on hantavirus was confirmed. VeroE6 cells in a 10% FBS-supplemented medium were plated at 1 x 10 6 Cells were seeded at a density of 100 cells / well and incubated overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS and replaced with 2% FBS-supplemented medium containing Seoul-type hantavirus at a multiplicity of infection (MOI) of 0.01. After 2 hours of incubation at 37°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing a Pin1 inhibitor (compound H-958) at concentrations of 0, 0.1, 1, 5, or 10 μM and 0.1% DMSO. The cells were then incubated for 24 hours at 37°C and 5% CO2. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, followed by an additional 24 hours of incubation. Finally, the supernatant from each well was collected and the cells were lysed with TRIzol reagent. To estimate Seoul-type hantavirus genome replication, real-time quantitative PCR of the Seoul-type hantavirus S segment in the cell lysate was performed. The inhibition rate was calculated as the reduction in the copy number of the S segment when the Pin1 inhibitor was added compared to the copy number of the S segment when the Pin1 inhibitor was not added. The copy number of the S segment when the Pin1 inhibitor was not added to the infected cell line was set as 0% inhibition rate.

[0268] Figure 3 shows the inhibitory effect of Pin1 inhibitors on Seoul-type hantavirus-infected cells. Figure 3A shows the quantitative values ​​of the S segment of Seoul-type hantavirus by real-time quantitative PCR after treatment with various concentrations of H-958. Nonlinear regression analysis of the results yielded an EC50 value of 1.1 μM (Figure 3B).

[0269] 10-6. Example 6: Inhibitory effect on the proliferation of Gamaku virus In this example, the inhibitory effect of the compound of the present invention on the proliferation of Gamaku virus was confirmed. Vero E6 cells in a 10% FBS-supplemented medium were plated at 1 x 10 6 Cells were seeded at a density of 100 cells / well and incubated overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS and replaced with 2% FBS-supplemented medium containing Gamaku virus at a multiplicity of infection (MOI) of 1.0. After 2 hours of incubation at 37°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing 0, 0.1, 1, 5, and 10 μM of a Pin1 inhibitor (compound H-958) and 1% DMSO. The cells were then incubated for 24 hours at 37°C and 5% CO2. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, followed by an additional 24 hours of incubation. Finally, the supernatant from each well was collected and the cells were lysed with TRIzol reagent. To estimate Gamaku virus genome replication, real-time quantitative PCR of the Gamaku virus N9 gene in the cell lysate was used. The inhibition rate was calculated as the reduction in the copy number of the N9 gene when the Pin1 inhibitor was added compared to the copy number of the N9 gene when the Pin1 inhibitor was not added. The copy number of the N9 gene when the Pin1 inhibitor was not added to the infected cell line was set as 0% inhibition rate.

[0270] FIG. 4 shows the inhibitory effect of adding a Pin1 inhibitor to Gamaku virus-infected cells, and shows the quantitative values ​​of real-time quantitative PCR of the Gamaku virus N9 gene after treatment with various concentrations of H-958.

[0271] 10-7. Example 7 Growth Inhibitory Effect of Human Rhinovirus Type A (hRV-A) HeLa cells were cultured in 10% heat-inactivated FBS-supplemented DMEM medium and 1% Antibiotic-Antimycotic (Gibco, cat# 15240062) at 1 x 10 per well. 6Cells were seeded into 6-well microtiter plates at a density of 1000 kJ / well and cultured for 48 hours at 34°C and 5% CO2. The cells were then washed with prewarmed PBS and replaced with serum-free medium containing human rhinovirus type A at a multiplicity of infection (MOI) of 0.01. After 2 hours of culture at 34°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing the Pin1 inhibitor H-958 at concentrations of 0, 0.1, 1, 5, or 10 μM and 0.1% DMSO. After 48 hours of culture, the supernatants of infected cells were stored at -80°C for plaque assays, and the infected cells were lysed in Trizol to extract total RNA for RT-PCR. Real-time quantitative PCR of the hRV-A viral VP1 gene in the cell lysates was used to estimate hRV-A viral genome replication. The percent inhibition was calculated as the reduction in VP1 gene copy number with the addition of a Pin1 inhibitor compared to the copy number without the Pin1 inhibitor (0 μM Pin1 inhibitor). The VP1 gene copy number without the addition of a Pin1 inhibitor to the infected cell line was defined as 0% inhibition. hRV-A virus growth was determined by testing harvested supernatants in a plaque assay. Supernatants from different treatment groups were serially diluted 10-fold and added to monolayers of HeLa cells in six-well plates. To obtain accurate titers, wells that formed plaques were selected and counted. The number of plaque-forming units per milliliter (PFU / ml) was calculated as the average number of plaques in the test wells multiplied by the dilution factor divided by the supernatant volume. Inhibition of viral growth was calculated as the reduction in PFU / ml with the addition of a Pin1 inhibitor compared to the PFU / ml without the addition of a Pin1 inhibitor (0 μM Pin1 inhibitor).

[0272] Figure 5 shows the inhibitory effect of adding a Pin1 inhibitor to hRV-A virus-infected cells. Figure 5A shows the quantitative real-time quantitative PCR values ​​of the hRV-A virus VP1 gene after treatment with different concentrations of H-958, and Figure 5B shows the EC50 calculation results obtained from nonlinear regression analysis of these results. Figure 5C shows the results of a plaque assay after treatment with H-958 and the calculated plaque-forming units per milliliter (PFU / ml). Treatment with 1.1 μM or more of H-958 inhibited hRV-A virus replication by more than 50%. 10 μM of H-958 inhibited hRV-A virus replication by more than 50% compared to untreated cells (4.2 × 10 5 PFU / ml) in the supernatant of H-958-treated cells compared with plaque-forming units / ml (8 x 10 4 The antibody produced an 81% reduction in hRV-A virus titer as measured by PFU / ml.

[0273] 10-8. Example 8 Inhibitory Effect on the Growth of Vaccinia Virus (VACV) VeroE6 cells in 10% FBS-supplemented DMEM medium and 0.1% gentamicin were cultured at 1 × 10 per well. 6Cells were seeded into 6-well microtiter plates at a density of 1000 kJ / well and cultured for 48 hours at 37°C and 5% CO2. The cells were then washed with prewarmed PBS and replaced with serum-free medium containing type A vaccinia at a multiplicity of infection (MOI) of 0.01. After 2 hours of culture at 37°C and 5% CO2, the infected cells were washed with prewarmed PBS and the medium was replaced with serum-free medium containing 0, 0.1, 1, 5, or 10 μM of the Pin1 inhibitor H-958 and 1% DMSO. After 48 hours of culture, the supernatants of infected cells were stored at -80°C for plaque assays, and infected cells were lysed in Trizol to extract total RNA for RT-PCR. Real-time quantitative PCR of the vaccinia virus E9L gene in the cell lysates was used to estimate vaccinia virus genome replication. The inhibition rate was calculated as the reduction in E9L gene copy number with the addition of a Pin1 inhibitor relative to the copy number without the addition of a Pin1 inhibitor (0 μM Pin1 inhibitor). The copy number of E9L gene without the addition of a Pin1 inhibitor to the infected cell line was considered 0% inhibition. Vaccinia virus growth was determined by testing the harvested supernatants in a plaque assay. Supernatants from different treatment groups were serially diluted 10-fold and added to monolayers of HeLa cells in six-well plates. To obtain accurate titers, wells that formed plaques were selected and counted. The number of plaque-forming units per milliliter (PFU / ml) was calculated as the average number of plaques in the test wells multiplied by the dilution factor divided by the supernatant volume. Inhibition of viral growth was calculated as the reduction in PFU / ml with the addition of a Pin1 inhibitor compared to PFU / ml without the addition of a Pin1 inhibitor (0 μM Pin1 inhibitor).

[0274] Figure 6 shows the inhibitory effect of adding a Pin1 inhibitor to vaccinia virus-infected cells. Figure 6A shows the quantitative real-time quantitative PCR values ​​of the vaccinia virus E9L gene after treatment with different concentrations of H-958, and Figure 6B shows the EC50 calculation results obtained from nonlinear regression analysis of these results. Figure 6C shows the results of a plaque assay after treatment with H-958 and the calculated plaque-forming units per milliliter (PFU / ml). Treatment with 1.3 μM or more of H-958 inhibited vaccinia virus replication by more than 50%. 10 μM H-958 reduced the vaccinia virus titer by more than 99.9%. This was due to the plaque-forming units (6 × 10) in the supernatant of cells treated with H-958. 2 PFU / ml), the untreated cells (5.4 × 10 6 This is clear when compared with the PFU / ml.

[0275] 10-9. Example 9 Inhibitory Effect on the Growth of Herpes Simplex Virus-1 (HSV-1) VeroE6 cells in Dulbecco's Modified Eagle Medium containing penicillin G and streptomycin and 5% FBS were plated at 1.5 × 10 cells per well in a 24-well plate. 5 Cells were seeded at a density of 1 / 3 cells per well and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing the Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of incubation at 37°C and 5% CO2, the treated cells were infected with herpes simplex virus-1 (HSV-1) at a multiplicity of infection (MOI) of 0.05. Culture supernatants were harvested on day 3 to quantify viral replication. To estimate HSV-1 proliferation, DNA was extracted from the supernatant and subjected to real-time quantitative PCR of the HSV-1 UL30 gene. The copy number of the UL30 gene in the samples was quantified using a plasmid containing the PCR-amplified DNA fragment (target DNA) as a standard.

[0276] Figure 7 shows the inhibitory effect of adding Pin1 inhibitors to HSV-1-infected cells by showing the quantification of real-time quantitative PCR for the HSV-1 UL30 gene after 3 days of treatment with 10 μM H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM H-958, H-1134, H-1209, or H-1211 inhibited HSV-1 viral replication by 98.5% or more in all cases.

[0277] 10-10. Example 10 Inhibitory Effect on the Growth of Influenza A Virus (IAV) H3N2 MDCK(+) cells (Arch Virol (1998) 143: 1893-1909) in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS were plated at 1.5 × 10 cells per well in a 24-well plate. 5 Cells were seeded at a density of 1 / 3 and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing the Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with influenza A virus H3N2 subtype (A / Udorn / 72) at a multiplicity of infection (MOI) of 0.05. Culture supernatants were harvested on day 1 for quantification of viral replication. To estimate IAV H3N2 growth, RNA was extracted from the virus in the supernatant and real-time quantitative reverse transcription (RT)-PCR of the IAV HA gene was used. The copy number of the HA gene in the samples was quantified using a plasmid containing the RT-PCR-amplified DNA fragment (target DNA) as a standard.

[0278] Figure 8 shows the inhibitory effect of adding Pin1 inhibitors to IAV H3N2 virus-infected cells by showing the quantitative real-time quantitative PCR values ​​of the IAV (H3N2) HA gene after 3 days of treatment with 10 μM H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM H-958, H-1134, H-1209, or H-1211 inhibited IAV H3N2 virus replication by 90.5% or more in all cases.

[0279] 10-11. Example 11 Growth Inhibitory Effect of Influenza A Virus (IAV) H5N3 MDCK(+) cells (Arch Virol (1998) 143: 1893-1909) in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS were plated at 1.5 × 10 cells per well in a 24-well plate. 5 Cells were seeded at a density of 1000 kJ / ml and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing the Pin1 inhibitor H-1134 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with influenza A virus subtype H5N3 (A / whistling swan / Shimane / 499 / 83) at a multiplicity of infection (MOI) of 0.01. On day 3, the culture supernatant was collected and viral replication was quantified. Real-time quantitative PCR of the IAV virus HA gene in the supernatant was used to estimate IAV H5N3 viral genome replication.

[0280] Figure 9 shows the inhibitory effect of adding a Pin1 inhibitor to IAV-infected cells by showing the quantitative real-time quantitative PCR values ​​of the IAV virus (H5N3) HA gene after treatment with 10 μM H-1134 for 3 days. Treatment with 10 μM H-1134 inhibited IAV H5N3 virus replication by more than 98.8%.

[0281] 10-12. Example 12: Inhibitory effect on the proliferation of poliovirus (PoV) HEp-2 cells were cultured in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS at a concentration of 1.5 × 10 per well. 5Cells were seeded into 24-well plates at a density of 10 μM and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with poliovirus (Sabin-1 strain) at a multiplicity of infection (MOI) of 0.01. On day 3, culture supernatants were collected and viral replication was quantified. Real-time quantitative PCR of the PoV genome in the supernatant was used to estimate PoV viral genome replication.

[0282] Figure 10 shows the inhibitory effect of Pin1 inhibitors on PoV-infected cells by showing the quantification of PoV genomes by real-time quantitative PCR after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced PoV viral replication by more than 99.9%.

[0283] 10-13. Example 13 Growth Inhibitory Effect of Feline Calcivirus (FCV) CRFK cells were cultured in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS at a density of 1.5 × 10 per well. 5 Cells were seeded into 24-well plates at a density of 10 μM each and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with feline calcivirus at a multiplicity of infection (MOI) of 0.01. On day 3, culture supernatants were collected and viral replication was quantified. FCV viral genome replication was estimated using real-time quantitative PCR of the FCV VP1 gene in the supernatants.

[0284] Figure 11 shows the inhibitory effect of Pin1 inhibitors on FCV-infected cells by quantifying the FCV VP1 gene by real-time quantitative PCR after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced FCV viral replication by more than 99.8%.

[0285] 10-14. Example 14 Growth Inhibitory Effect of Feline Infectious Peritonitis Virus (FIPV) CRFK cells in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS were plated at 1.5 x 10 cells per well in a 24-well plate. 5 Cells were seeded at a density of 1000 kJ / ml and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with FIPV at a multiplicity of infection (MOI) of 0.01. On day 2, culture supernatants were harvested and viral replication was quantified. FIPV viral genome replication was estimated using real-time quantitative PCR of the FIPV ORF1ab gene in the supernatant.

[0286] Figure 12 shows the inhibitory effect of Pin1 inhibitors on FIPV-infected cells by showing the quantification of real-time quantitative PCR of the FIPV ORF1ab gene after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced FIPV viral replication by more than 99.9%.

[0287] 10-15. Example 15 Growth Inhibitory Effect of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) VeroE6 cells were cultured in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS at a concentration of 1.5 × 10 per well. 5Cells were seeded at a density of 1 / 3000 in 24-well plates and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with SFTSV at a multiplicity of infection (MOI) of 0.1. On day 3, the culture supernatant was collected and viral replication was quantified. SFTSV viral genome replication was estimated using real-time quantitative PCR of the SFTSV genome S segment in the supernatant.

[0288] Figure 13 shows the inhibitory effect of Pin1 inhibitors on SFTSV-infected cells by showing the quantification of real-time quantitative PCR of the S segment of the SFTSV genome after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced SFTSV viral replication by more than 99.9%.

[0289] 10-16. Example 16: Inhibitory effect on the proliferation of Coxsackievirus (CV) HEp-2 cells in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 10% FBS were plated at 1.5 x 10 cells / well in a 24-well plate. 5 Cells were seeded at a density of 1000 kJ / ml and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing the Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with CV (Group B, Type 5) at a multiplicity of infection (MOI) of 0.1. On day 3, cells including the culture supernatant were harvested, and RNA was extracted to quantify viral replication. Real-time quantitative PCR of the CV genome in the supernatant was used to estimate CV viral genome replication. Treatment with 10 μM of each Pin1 inhibitor significantly reduced CV viral replication.

[0290] Figure 14 shows the inhibitory effect of Pin1 inhibitors on CV-infected cells by showing the quantification of CV genomes by real-time quantitative PCR after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced CV viral replication by more than 99.4%.

[0291] 10-17. Example 17 Growth Inhibitory Effect of Infectious Bronchitis Virus (IBV) BHK-21 cells in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS were plated at 1.5 × 10 cells per well in a 24-well plate. 5 Cells were seeded at a density of 1000 kJ / ml and cultured overnight at 37°C, 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C, 5% CO2, the treated cells were infected with IBV at a multiplicity of infection (MOI) of 0.1. On day 3, culture supernatants were harvested and viral replication was quantified. Real-time quantitative PCR of the IBV S gene in the supernatants was used to estimate IBV viral genome replication. Treatment with 10 μM of each Pin1 inhibitor significantly reduced IBV viral replication.

[0292] 10-18. Example 18. Adenovirus (AdV) Proliferation Inhibitory Effect HEK 293 cells were cultured in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 10% FBS at a concentration of 1.5 x 10 cells per well. 5Cells were seeded into 24-well plates at a density of 10 μM and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with AdV at a multiplicity of infection (MOI) of 0.1. Culture supernatants were harvested on day 3, and viral replication was quantified. Real-time quantitative PCR of AdV genomes in the supernatants was used to estimate AdV viral genome replication. Treatment with 10 μM of each Pin1 inhibitor significantly reduced AdV viral replication.

[0293] 10-19. Example 19 Growth Inhibitory Effect of Murine Norovirus (MNV) RAW 264.7 cells in Iscove's modified Dulbecco's medium containing penicillin G and streptomycin and 5% FBS were cultured at 1.5 × 10 cells / well in a 24-well plate. 5 Cells were seeded at a density of 1 / 3 and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing 10 μM of the Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 in 0.1% DMSO. After 2 hours of incubation at 37°C and 5% CO2, the treated cells were infected with MNV at a multiplicity of infection (MOI) of 5. On day 1 of infection, cells and supernatants were combined and viral replication was quantified. To estimate MNV viral genome replication, real-time quantitative PCR of MNV nsp genes was performed. Figure 15 shows the inhibitory effect of adding Pin1 inhibitors to MNV-infected cells by showing the quantification of real-time quantitative PCR of MNV nsp genes after 1 day of treatment with 10 μM H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced MNV viral replication by more than 99.9%.

[0294] 10-20. Example 20: Inhibitory effect on proliferation of rotavirus (RoV) MA104 cells were cultured in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS at 1.5 × 10 cells / well in a 24-well plate. 5Cells were seeded at a density of 1 / 3 and cultured overnight at 37°C, 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C, 5% CO2, the treated cells were infected with RoV at a multiplicity of infection (MOI) of 0.1. On day 3, cells and supernatants were harvested together, and viral replication was quantified. RoV genome replication was estimated using real-time quantitative PCR of the RoV VP1 gene in the supernatant.

[0295] Figure 16 shows the inhibitory effect of Pin1 inhibitors on RoV-infected cells by real-time PCR quantification of the RoV VP1 gene after 3 days of treatment with 10 μM of H-958, H-1134, H-1209, or H-1211. Treatment with 10 μM of each Pin1 inhibitor reduced RoV replication by more than 96.0%.

[0296] 10-21. Example 21 Inhibitory effect on the proliferation of Epstein-Barr virus (EBV) 1 × 10 P3HR1 cells were cultured in serum-free Dulbecco's modified Eagle's medium containing penicillin G and streptomycin. 6 Cells were seeded into microtiter plates at 1000 cells / mL and EBV production was induced by the addition of 20 ng / mL 12-O-tetradecanoylphorbol-13-acetate (TPA). After 24 hours, the cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing the Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at 10 μM in 0.1% DMSO. On day 7 of culture, cells were harvested and DNA was extracted. Real-time quantitative PCR of the EBV EBNA1 gene in the extracted DNA was used to estimate intracellular EBV replication. Treatment with 10 μM of each Pin1 inhibitor significantly reduced EBV replication.

[0297] 10-22. Example 22 Inhibitory effect on the proliferation of Japanese encephalitis virus (JEV) BHK-21 cells in Dulbecco's modified Eagle's medium containing penicillin G and streptomycin and 5% FBS were plated at 1 x 10 per well in a microtiter plate. 6 Cells were seeded at a density of 1000 kJ / ml and cultured overnight at 37°C and 5% CO2. The next day, cells were washed with prewarmed PBS, and the medium was replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 μM in 0.1% DMSO. After 2 hours of culture at 37°C and 5% CO2, the treated cells were infected with JEV at a multiplicity of infection (MOI) of 0.1. Sixty hours postinfection, culture supernatants were harvested and viral replication was quantified. Real-time quantitative PCR of the JEV E gene in the supernatants was used to estimate JEV genome replication. Treatment with 10 μM of each Pin1 inhibitor significantly reduced JEV replication.

[0298] 10-23. Example 23 Growth Inhibitory Effect of Theileria Parasites TBL-3 or TpMD409 cells (infected with Theileria parasites) were cultured at 1 x 10 per well in RPMI 1640 medium supplemented with 10% FCS, 4 mM L-glutamine, 25 mM HEPES, 10 mM β-mercaptoethanol, and 100 mg / ml penicillin / streptomycin. 6 Cells were seeded onto microtiter plates at a density of 10 μM and cultured overnight at 37°C and 5% CO2. The next day, the cells were washed with pre-warmed PBS, and the medium was replaced with serum-free medium containing 10 μM Pin1 inhibitor in 0.1% DMSO. After 72 hours, the parasite-infected cells were plated onto slides using a CytoSpin centrifuge and fixed with 3.7% formaldehyde in PBS at room temperature for 15 minutes. DNA in the cells was stained with DAPI. The cells were photographed under a fluorescent microscope, and the number of parasites per cell was counted. Treatment with 10 μM Pin1 inhibitor significantly reduced the number of parasites in the cells.

Claims

1. Formula (I) (wherein R1 and R2 are each a phenyl group or a thienyl group, at least one of R1 and R2 is substituted with at least one R4 substituent, and R1 and R2 are not substituted with any substituent other than R4, where R4 is a halogen, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a methylenedioxy group which may have a substituent, R3 is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent, X is a single bond, -CH ２ - group, or -CH ２ -O- group, except for compounds in which R1 is a thienyl group, R2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond, or a salt thereof.

2. The compound or salt thereof according to claim 1, wherein R4 is a halogen atom, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.

3. The compound or salt thereof according to claim 1, wherein the total number of halogen atoms contained in R1 and R2 is 3 or more.

4. The compound or salt thereof according to claim 1, wherein R3 is a hydrogen atom or a methyl group.

5. A Pin1 inhibitor comprising the compound or a salt thereof according to any one of claims 1 to 4.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

7. A therapeutic or preventive agent for coronavirus infections, comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof.

8. The therapeutic or preventive agent according to claim 7, wherein the coronavirus infection is an infection caused by a β-coronavirus.

9. The therapeutic or preventive agent according to claim 8, wherein the coronavirus infection is an infection caused by SARS-CoV-2.

10. The therapeutic or preventive agent according to claim 7, further comprising the active ingredient of at least one or more other drugs selected from those classified as therapeutic or preventive agents for coronavirus infections.

11. The therapeutic or prophylactic agent according to claim 7, for treating or preventing coronavirus infection in combination with at least one other drug selected from those classified as therapeutic or prophylactic agents for coronavirus infection.

12. Use of the therapeutic or prophylactic agent according to claim 7 for the manufacture of a medicament for treating or preventing a coronavirus infection.

13. A method for treating or preventing a coronavirus infection, comprising administering an effective amount of the therapeutic or prophylactic agent according to claim 7 to a subject in need thereof.

14. Formula (I') (wherein R1 and R2 are each a phenyl group or a thienyl group; (1) R1 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4; or (2) R2 is substituted with at least one R4 substituent and is not substituted with any other substituent than R4; or (3) R1 and R2 are substituted with at least one R4 substituent and are not substituted with any other substituent than R4; wherein R4 is a halogen, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a methylenedioxy group which may have a substituent; R3 is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent; X is a single bond, -CH ２ - group, or -CH ２ 5. A therapeutic or preventive agent for herpes simplex virus, Zika virus, RS virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenic syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection, comprising a compound represented by the formula:

15. The therapeutic or prophylactic agent according to claim 14, wherein R4 is a halogen atom, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.

16. The therapeutic or prophylactic agent according to claim 14, wherein the total number of halogen atoms contained in R1 and R2 is 3 or more.

17. The therapeutic or prophylactic agent according to claim 14, wherein R3 is a hydrogen atom or a methyl group.

18. The therapeutic or preventive agent according to any one of claims 14 to 17, further comprising at least one active ingredient selected from herpes simplex virus, Zika virus, RS virus, Hantavirus, Rhinovirus, Gamak virus, vaccinia virus, poliovirus, Coxsackie virus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenic syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or other agents classified as therapeutic or preventive agents for Theileria parasitic infection.

19. The use of a medicament for the treatment or prevention of herpes simplex virus, Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenic syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection in combination with at least one drug selected from other drugs classified as therapeutic or preventive agents for ... the infection. The therapeutic or prophylactic agent according to any one of claims 14 to 17, for treating or preventing an infection caused by a virus, such as rabies virus, vaccinia virus, poliovirus, coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite.

20. Use of the therapeutic or prophylactic agent according to any one of claims 14 to 17 for the manufacture of a medicament for treating or preventing herpes simplex virus, Zika virus, RS virus, Hantavirus, Rhinovirus, Gamak virus, vaccinia virus, poliovirus, Coxsackievirus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenic syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection.

21. A method for treating or preventing herpes simplex virus, Zika virus, RS virus, Hantavirus, Rhinovirus, Gamak virus, vaccinia virus, poliovirus, Coxsackie virus, influenza A virus, feline calicivirus, feline infectious peritonitis virus, severe fever with thrombocytopenic syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection, comprising administering an effective amount of the therapeutic or preventive agent according to any one of claims 14 to 17 to a subject in need thereof.

22. A therapeutic or preventive agent for inflammatory diseases accompanied by fibrosis, comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof.

23. The therapeutic or preventive agent for an inflammatory disease accompanied by fibrosis according to claim 22, wherein the inflammatory disease accompanied by fibrosis is non-alcoholic steatohepatitis, inflammatory bowel disease or pulmonary fibrosis.

24. The therapeutic or preventive agent according to claim 22, further comprising at least one active ingredient selected from other drugs classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis.

25. The therapeutic or preventive agent according to claim 22, for treating or preventing an inflammatory disease accompanied by fibrosis in combination with at least one other drug selected from those classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis.

26. Use of the therapeutic or prophylactic agent according to claim 22 for the manufacture of a medicament for treating or preventing an inflammatory disease accompanied by fibrosis.

27. A method for treating or preventing an inflammatory disease accompanied by fibrosis, comprising administering an effective amount of the therapeutic or prophylactic agent according to claim 22 to a subject in need thereof.

28. A cancer treatment or prevention agent comprising, as an active ingredient, the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof.

29. The cancer treatment or prevention agent according to claim 28, wherein the cancer is colon cancer or prostate cancer.

30. The therapeutic or preventive agent according to claim 28, further comprising the active ingredient of at least one other drug selected from other drugs classified as therapeutic or preventive agents for cancer.

31. The therapeutic or preventive agent according to claim 28, for treating or preventing cancer in combination with at least one other drug selected from those classified as therapeutic or preventive agents for cancer.

32. Use of the therapeutic or prophylactic agent according to claim 28 for the manufacture of a medicament for treating or preventing cancer.

33. A method for treating or preventing cancer, comprising administering an effective amount of the therapeutic or prophylactic agent according to claim 28 to a subject in need thereof.

34. A therapeutic or preventive agent for obesity, comprising as an active ingredient the compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof.

35. The therapeutic or preventive agent according to claim 34, further comprising the active ingredient of at least one other drug selected from other drugs classified as therapeutic or preventive agents for obesity.

36. The therapeutic or preventive agent according to claim 34, for treating or preventing obesity in combination with at least one other drug selected from those classified as therapeutic or preventive agents for obesity.

37. Use of the therapeutic or prophylactic agent according to claim 34 for the manufacture of a medicament for treating or preventing obesity.

38. A method for treating or preventing obesity, comprising administering an effective amount of the therapeutic or preventive agent according to claim 34 to a subject in need thereof.

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