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WO2025053222A1 - Nouveaux composés à base d'acide anthranilique, inhibiteur de pin 1, agent thérapeutique et agent préventif pour maladies infectieuses, etc l'utilisant - Google Patents

Nouveaux composés à base d'acide anthranilique, inhibiteur de pin 1, agent thérapeutique et agent préventif pour maladies infectieuses, etc l'utilisant Download PDF

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Publication number
WO2025053222A1
WO2025053222A1 PCT/JP2024/031880 JP2024031880W WO2025053222A1 WO 2025053222 A1 WO2025053222 A1 WO 2025053222A1 JP 2024031880 W JP2024031880 W JP 2024031880W WO 2025053222 A1 WO2025053222 A1 WO 2025053222A1
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virus
group
therapeutic
esi
infection
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Japanese (ja)
Inventor
隆義 岡部
知一郎 浅野
剛正 坂口
祐介 中津
武 山本屋
麻智 神名
久央 伊藤
ジェフリー アダム エンスィーナス
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Amenis Bioscience Inc
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Amenis Bioscience Inc
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the present invention relates to novel low-molecular-weight organic compounds of the anthranilic acid series, and further relates to Pin1 inhibitors using the compounds, pharmaceutical compositions, therapeutic or preventive agents for coronavirus infections, therapeutic or preventive agents for infectious diseases including 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 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.
  • infectious diseases including herpes
  • Pin1 is a type of peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the cis/trans conformational change of proline in proteins, and has the characteristic of acting specifically on proline located next to phosphorylated serine or threonine to change the conformation. Therefore, Pin1 is a molecule that links protein phosphorylation to protein conformational change 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).
  • Non-Patent Documents 4-10 It has also been reported that Pin1 promotes the proliferation of several viruses, such as cytomegalovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and feline coronavirus.
  • viruses such as cytomegalovirus, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and feline coronavirus.
  • Pin1 knockout mice exhibit symptoms similar to those of Alzheimer's disease (Non-Patent Document 11).
  • 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 signaling (Non-Patent Document 3).
  • Phenylalaninol phosphate derivatives, indole or benzimidazole alanine derivatives, fredericamycin A compounds, phenylimidazole derivatives, naphthyl-substituted amino acid derivatives, glutamic acid or aspartic acid derivatives, and the like have been reported as compounds that inhibit Pin1 (Patent Documents 1 to 4 and Non-Patent Documents 12 to 15). Furthermore, it is also known that Pin1 inhibitors having a specific structure 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).
  • Non-Patent Document 10 It has also been reported that the replication of feline coronavirus (FCoV) was inhibited by dipentamethylene thiuram monosulfide, a Pin1 inhibitor (Non-Patent Document 10), and that Pin1 inhibitors can suppress the proliferation of SARS-coronavirus 2 and may therefore be used as therapeutic or preventive agents for coronavirus infection (COVID-19) caused by SARS-coronavirus 2 (SARS-CoV-2) (Patent Documents 8 and 9).
  • Coronaviruses are viruses that infect not only humans but also animals, causing various diseases.
  • livestock such as dogs, cats, cows, pigs, chickens, horses, alpacas, and camels
  • coronaviruses specific to each animal have been detected in beluga whales, giraffes, ferrets, suncus, bats, and sparrows.
  • Coronaviruses are highly species specific, and they rarely cross species barriers to infect other animals.
  • Coronaviruses that infect humans include four types of coronaviruses (Human Coronaviruses: HCoV) that commonly infect humans: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, and two types of severe pneumonia viruses that infect animals: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
  • SARS-CoV Severe Acute Respiratory Syndrome Coronavirus
  • MERS-CoV Middle East Respiratory Syndrome Coronavirus
  • SARS-CoV-2 severe Acute Respiratory Syndrome CoronaVirus 2
  • COVID-19 an infectious disease caused by SARS-CoV-2, spreads mainly by human-to-human infection through airborne droplets dispersed by coughing or sneezing from an infected person.
  • COVID-19 symptoms include fever, respiratory symptoms, headache, and fatigue, and may also cause olfactory and gustatory disorders.
  • the mortality rate of COVID-19 is particularly high in elderly people and patients with underlying diseases (cardiovascular disease, diabetes, chronic respiratory disease, chronic kidney disease, hypertension, and obesity).
  • Coronaviruses are a type of RNA virus (single-stranded RNA virus) that carry RNA as genetic information, and have a double membrane made of lipids called an "envelope" on the outermost surface of the particle. They are spherical with a diameter of about 100 nm, with protrusions on their surface, and their shape resembles a crown. Coronaviruses cannot multiply on their own, but they attach to and penetrate human cells such as mucous membranes and grow there.
  • Virologically they are classified into the order Nidovirales, subfamily Orthocoronavirinae, and family Coronaviridae, and are divided into four groups based on genetic characteristics: ⁇ , ⁇ , ⁇ , and ⁇ .
  • HCoV-229E and HCoV-NL63 are classified as ⁇ coronaviruses, while MERS-CoV, SARS-CoV, SARS-CoV-2, HCoV-OC43, and HCoV-HKU1 are classified as ⁇ coronaviruses.
  • Herpes simplex virus Zika virus, respiratory syncytial virus, hantavirus, rhinovirus, Gamak virus, vaccinia virus, poliovirus, and coxsackievirus infections.
  • HSV which infects humans through the skin or mucous membranes, invades cells by fusing its envelope with the host cell membrane. Tegument and nucleocapsid are released into the cell. Viral protein synthesis and DNA synthesis proceed in the nucleus, producing child viruses, which finally escape outside the cell. At this point, it may infect neighboring cells.
  • Zika virus is a spherical virus with a diameter of 40-50 nm that belongs to the Flavivirus genus of the Flaviviridae family.
  • the viral RNA is present within a core particle with a diameter of 25-35 nm, which is composed of a basic protein core protein of about 12 kDa.
  • the core particle is surrounded by an envelope composed of two types of proteins, a membrane protein (M protein) of about 8 kDa and a glycoprotein (E protein) of about 53 kDa.
  • M protein membrane protein
  • E protein glycoprotein
  • the E protein is involved in host affinity and cell adsorption, and is the main protein that induces protective immunity against Zika virus.
  • the viral RNA is a single-stranded RNA of 10,794 bases, and is a positive-stranded RNA that acts as mRNA when released into the host cell due to viral infection.
  • Zika virus infection is mainly transmitted by mosquitoes in a human-mosquito-human cycle, and symptoms begin with generalized discomfort and fatigue, followed by fever, headache, and generalized muscle pain almost simultaneously.
  • the respiratory syncytial virus 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 surface of the virus 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, and two serotypes, A and B, are known.
  • RSV can cause severe symptoms in immunocompromised adults and in infants, leading to bronchitis and pneumonia.
  • Hantavirus is a general term for viruses belonging to the genus Hantavirus in the family Bunyavirales.
  • the natural hosts are small mammals such as rodents and shrecomorpha, and they are not pathogenic to these animals. However, when they infect humans, they cause severe diseases such as Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS).
  • HFRS Hemorrhagic Fever with Renal Syndrome
  • HPS Hantavirus Pulmonary Syndrome
  • Hantavirus particles contain three negative-stranded RNAs, called the S, M, and L segments.
  • the S segment encodes the nucleoprotein (N)
  • the M segment encodes the glycoprotein precursor (GPC) of two envelope glycoproteins (Gn, Gc)
  • the L segment encodes the RNA-dependent RNA polymerase (RdRp).
  • the base sequences at both ends of each genome are complementary to each other, so they combine to form a ring structure.
  • Hantavirus particles are spherical or ovoid, with a diameter of 80 to 120 nm. Hantaviruses infect vascular endothelial cells, epithelial cells, macrophages, follicular dendritic cells, lymphocytes, etc., through the binding of the envelope glycoprotein to a receptor on the host cell surface.
  • ⁇ 3 integrin, DAF/CD55, and gC1qR/p32 have been reported as receptors for hantaviruses. It has also been reported that nonpathogenic hantaviruses use ⁇ 1 integrin as a receptor. Hantaviruses are transported to early endosomes via clathrin-coated pits, and then transported to late endosomes or lysosomes. When the pH in the endolysosomal compartment drops below 6.4, they fuse with the cell membrane and uncoat. The entire replication process of hantaviruses takes place 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.
  • the nucleocapsids bind to envelope glycoproteins on the cytoplasmic side of the Golgi apparatus and bud off into the Golgi apparatus.
  • the budded virions are released outside the cell.
  • 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, such as the common cold, it has also been pointed out that it may be closely related to other respiratory diseases such as asthma.
  • Human rhinovirus is a single-stranded RNA virus.
  • Gamak virus 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 disease-causing pathogens. The genus Henipavirus, to which Gamak virus belongs, is an important zoonotic pathogen that can cause 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 upregulation of several human innate antiviral genes in vitro.
  • Vaccinia virus (VACV or VV) is an enveloped DNA virus belonging to the Poxviridae family. It has a genome of linear double-stranded DNA 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 generally healthy individuals who are infected will either show no symptoms or may develop a mild rash and fever, which will heal naturally. However, immunocompromised individuals and those with poor overall condition (homeostasis stability) may become seriously ill.
  • Poliovirus is a type C Enterovirus belonging to the Enterovirus genus of the Picornaviridae family. It is divided into three types, type 1, type 2, and type 3, based on antigenicity. Poliovirus is an RNA virus composed of a positive-stranded genome of single-stranded RNA (ssRNA) consisting of approximately 7,500 base pairs and a capsid made of protein. The virus particle also has a regular icosahedral structure with a diameter of approximately 30 nm. Poliovirus is a virus that has a human host. It enters the human body orally, grows in the mucous membrane of the pharynx and small intestine, and enters the bloodstream via lymph nodes.
  • ssRNA single-stranded RNA
  • polio acute poliomyelitis
  • Coxsackievirus is a non-enveloped, linear, single-stranded, positive-stranded RNA virus belonging to the Enterovirus genus of the Picornaviridae family. Coxsackieviruses are classified as "Enterovirus type A” and "Enterovirus type B” by the International Committee on Taxonomy of Viruses. Coxsackieviruses are divided into two groups, A and 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 nerve tissue). Both groups A and B cause nonspecific febrile illness, rash, and upper respiratory tract infections, and are the causative virus of summer colds. They can also cause viral meningitis (aseptic meningitis) and encephalitis.
  • Influenza A virus is a single-stranded, negative-sense RNA virus belonging to the family Orthomyxoviridae 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, with nomenclature such as H3N2 (which caused the 1968 "Hong Kong flu” pandemic, resulting in significant morbidity and mortality worldwide) and H5N3 (which causes highly pathogenic avian influenza that occasionally infects humans and is thought to have the potential to cause a pandemic if successfully adapted to human infection).
  • HA hemagglutinin
  • NA neuraminase
  • Influenza A viruses are a major public health concern because of their potential to cause large-scale outbreaks and pandemics.
  • Feline calicivirus 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 and eye discharge, or respiratory droplets from an infected cat. Infection causes respiratory symptoms such as sneezing, stuffy nose, and stomatitis, as well as systemic symptoms such as fever, loss of appetite, and lethargy. There is a vaccine to prevent infection, but no specific treatment for infected cats.
  • Feline infectious peritonitis virus is a variant of feline coronavirus (FCoV), 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 to FIVP after intestinal infection. Infected cats develop either exudative peritonitis, with fluid accumulation in the abdomen and chest, leading to respiratory distress, anorexia, fever, weight loss, jaundice, and diarrhea, or nonexudative peritonitis, with granulomatous lesions in various organs, leading to jaundice, neurological signs, eye changes, and gastrointestinal disorders. There is no vaccine available to prevent FIPV, and no specific therapy to treat infection.
  • Severe fever with thrombocytopenia syndrome 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.
  • SFTSV can be transmitted from 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.
  • Mortality rates among infected individuals who develop severe fever with thrombocytopenia syndrome are estimated to range from 6% to 27%, with the difference in mortality probably related to different genotypes of the virus prevalent in the affected areas.
  • the virus has been found primarily in East Asia, namely China, Korea, and Japan; however, 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.
  • IBV Infectious bronchitis virus
  • coronavirus a virus belonging to the coronavirus family that infects and causes disease in chickens.
  • the virus is mainly transmitted between birds by direct and indirect contact, aerosol transmission, and sometimes vertical transmission from chicken to egg. Infection causes avian infectious bronchitis, a disease affecting the respiratory, intestinal, renal and reproductive systems. IBV affects the productivity of both meat and layer chickens and is the cause of major economic losses in the poultry industry.
  • IBV Infectious bronchitis virus
  • Adenoviruses are non-enveloped, double-stranded DNA viruses of the Adenoviridae family.
  • Adenoviruses of the Mastadenovirus genus infect humans and cause diseases such as respiratory illness (including the common cold), conjunctivitis, and gastroenteritis, and are associated with human obesity.
  • the most common cause of adenoviral keratoconjunctivitis has been reported to be type 8, followed by types 19 and 37.
  • the virus is primarily transmitted via respiratory droplets, but also via the fecal-oral route.
  • 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 while swimming in public pools.
  • Murine norovirus 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 main route of infection is through ingestion of contaminated feces. In most cases, infection is asymptomatic in immunocompetent mice. However, in immunocompromised mice, it can cause a variety of symptoms similar to human norovirus infection, including diarrhea, weight loss, and dehydration. MNV is prevalent in laboratory mouse colonies worldwide and is of major concern to researchers. Infection with MNV can affect research outcomes, especially in studies involving 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.
  • Rotavirus is a non-enveloped, double-stranded RNA virus belonging to the family Sedreoviridae.
  • the primary mode of infection is ingestion of the virus via the fecal-oral route from contaminated hands, surfaces, food, or water.
  • Infection with RoV causes severe diarrhea and gastroenteritis, accompanied by fever and severe, sometimes life-threatening, dehydration, especially in young children.
  • a vaccine to prevent rotavirus infection is available for vaccination of infants and young children and is recommended in vaccination programs around the world.
  • supportive care such as oral rehydration therapy and intravenous fluids to prevent dehydration, and drug therapy to reduce fever and pain, is available for individuals with rotavirus infection.
  • Epstein-Barr virus also known as human herpesvirus 4 (HHV-4)
  • HHV-4 human herpesvirus 4
  • the primary route of infection is through the exchange of saliva, such as kissing or sharing drinks, eating utensils, and other personal items.
  • 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, which is characterized by fever, sore throat, swollen lymph nodes, and fatigue. In some cases, EBV infection can remain chronically active, resulting in disease that continues for a long period of time.
  • EBV infection is associated with certain cancers, such as 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 EBV vaccine has yet been approved. The only treatment available is supportive care, such as rest, hydration, and painkillers, as needed depending on symptoms.
  • MS multiple sclerosis
  • JEV Japanese encephalitis virus
  • Flaviviridae 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, but a small percentage of infected individuals develop severe encephalitis. Symptoms of severe encephalitis include high fever, headache, neck stiffness, impaired consciousness, coma, spastic paralysis, and death. Infected individuals who develop encephalitis may suffer from long-term neurological or psychiatric complications. Although there is a vaccine to prevent JEV infection, there is no specific antiviral treatment for JEV. Only supportive care is available to relieve symptoms and manage complications.
  • Theileria parasites are obligate intracellular protozoan parasites belonging to the phylum Apicomplexa. 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, mainly in tropical and subtropical regions. Of the species of Theileria that infect domestic animals, 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 reduced milk production.
  • Theileria orientalis causes theileriosis in cattle, characterized by fever, anemia, jaundice, swollen lymph nodes, emaciation, and reduced milk production.
  • Theileria equi causes piroplasmosis in horses, which is characterized by fever, anemia, jaundice, abdominal swelling, and weight loss.
  • Antiprotozoal drugs such as buparvaquone are available to treat infection, but resistance to the drugs has recently begun to develop and they are less effective. Supportive care is usually given to relieve the symptoms of the disease.
  • tick populations can be reduced with acaricides to prevent infection, and a vaccine against Theileria parva is available.
  • infection with Theileria parasites has 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.
  • 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) ⁇ and/or ⁇ 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).
  • PPAR peroxisome proliferator-activated receptors
  • the present invention aims to develop a novel group of compounds that have the activity of inhibiting the function of Pin1, and to develop them as candidate compounds for pharmaceuticals.
  • the inventors conducted intensive research and developed a novel group of compounds by synthesizing a large number of derivatives of anthranilic acid containing a phenyl group or a thienyl group having as a substituent 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.
  • novel compounds have activity that inhibits the function of Pin1, and have been found to be therapeutic or preventive agents for coronavirus infections, 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 infections, and therapeutic or preventive agents for non-alcoholic steatohepatitis, cancer, etc., leading to the completion of the present invention.
  • the present invention provides a novel compound or a salt thereof that is a candidate compound for a pharmaceutical product, a Pin1 inhibitor, a pharmaceutical composition, a therapeutic or preventive agent for coronavirus infection, 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 thrombocytopenia syndrome virus, infectious bronchitis virus, adenovirus, murine norovirus, rotavirus, Epstein-Barr virus, Japanese encephalitis virus, or Theileria parasite infection, a therapeutic or preventive agent for inflammatory diseases including non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, and pulmonary fibrosis, a therapeutic or preventive agent for cancer, and a therapeutic or preventive agent for obesity.
  • NASH non-alcoholic
  • the compound of the present invention or a salt thereof is represented by 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 ;
  • R4 is a halogen atom, 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, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group;
  • X is a single bond, a -CH 2 - group, or a -CH 2 -O- group. However, this does not include compounds in which R 1 is a thienyl group, R 2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond. or a salt thereof.
  • R 4 may be a halogen, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.
  • the total number of halogen atoms contained in R 1 and R 2 may be 3 or more.
  • R 3 may be a hydrogen atom or a methyl group.
  • the Pin1 inhibitor of the present invention includes any of the above compounds or a salt thereof.
  • the pharmaceutical composition of the present invention comprises any of the above compounds or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.
  • the above-mentioned therapeutic or preventive agent for coronavirus infection may be used in combination with at least one or more other drugs selected from those classified as therapeutic or preventive agents for coronavirus infection to treat or prevent coronavirus infection.
  • the present invention also provides use of the above-mentioned therapeutic or prophylactic 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 a coronavirus infection, which comprises administering an effective amount of the above-mentioned therapeutic or preventive agent for coronavirus infection to a subject in need thereof.
  • the therapeutic or preventive agent for 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 of the present invention is a compound represented by the formula (I'): (In the formula, 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
  • 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, a -CH 2 - group, or a -CH 2 -O- group. or a salt thereof as an active ingredient.
  • R 4 may be a halogen atom, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.
  • the total number of halogen atoms contained in R 1 and R 2 may be 3 or more.
  • R3 may be a hydrogen atom or a methyl group.
  • the above-mentioned therapeutic or preventive agent may be used in combination with at least one drug 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 thrombocytopenic 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 infection.
  • at least one drug 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 thrombocytopenic syndrome virus, infectious bronchitis 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.
  • the present invention also provides a method 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, which comprises administering an effective amount of any of the above-mentioned therapeutic or preventive agents to a subject in need thereof.
  • the above-mentioned therapeutic or preventive agent may be used for treating or preventing an inflammatory disease accompanied by fibrosis in combination with at least one or more other agents selected from those classified as therapeutic or preventive agents for inflammatory diseases accompanied by fibrosis.
  • 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 an inflammatory disease accompanied by fibrosis.
  • the present invention also provides a method for treating or preventing an inflammatory disease accompanied by fibrosis, comprising administering an effective amount of any of the above-mentioned therapeutic or prophylactic agents to a subject in need thereof.
  • the cancer treatment or prevention agent of the present invention contains any one of the above compounds or a pharma- ceutically acceptable salt thereof as an active ingredient.
  • the cancer may be colon cancer or prostate cancer.
  • the above-mentioned therapeutic or preventive agent may further contain at least one or more active ingredients of other drugs selected from other drugs classified as therapeutic or preventive agents for cancer.
  • the above-mentioned therapeutic or preventive agent may be used for treating or preventing cancer in combination with at least one or more other agents selected from those classified as therapeutic or preventive agents for cancer.
  • the present invention also provides use of any of the above-mentioned therapeutic or prophylactic agents for the manufacture of a medicament for treating or preventing cancer.
  • the present invention also provides a method for treating or preventing cancer, which comprises administering an effective amount of any of the above-mentioned therapeutic or prophylactic agents to a subject in need thereof.
  • the therapeutic or preventive agent for obesity of the present invention contains any one of the above compounds or a pharma- ceutical acceptable salt thereof as an active ingredient. Furthermore, the above-mentioned therapeutic or preventive agent may further contain the active ingredient of at least one or more other drugs selected from other drugs classified as therapeutic or preventive agents for obesity. Furthermore, the above-mentioned therapeutic or preventive agent may be used in combination with at least one or more other drugs selected from those classified as therapeutic or preventive agents for obesity to treat or prevent obesity.
  • the present invention also provides use of any of the above-mentioned therapeutic or prophylactic agents for the manufacture of a medicament for treating or preventing obesity.
  • the present invention also provides a method for treating or preventing obesity, which comprises administering an effective amount of any of the above-mentioned therapeutic or prophylactic agents to a subject in need thereof.
  • novel compound or salt thereof of the present invention can be a compound or a precursor thereof that has activity to inhibit the function of Pin1, or can be a therapeutic or preventive agent or a prodrug thereof for viral infections, parasitic infections, inflammatory diseases, cancer, obesity, etc., and therefore can be used in the development of Pin1 inhibitors or pharmaceuticals for viral infections, parasitic infections, inflammatory diseases, cancer, obesity, etc.
  • A shows the quantitative real-time quantitative PCR values of Zika virus NS1 gene after treatment with various concentrations of H-958
  • B shows the nonlinear regression analysis results
  • C shows the plaque assay results and calculated plaque forming units per mL (PFU/ml).
  • A shows the quantitative values of 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 thereof.
  • A shows the quantitative values of real-time quantitative PCR of the S segment of Seoul-type hantavirus after treatment with various concentrations of H-958
  • B shows the results of nonlinear regression analysis thereof.
  • Quantitative real-time quantitative PCR of Gamaku virus N9 gene after treatment with various concentrations of H-958 is shown.
  • A shows the quantitative real-time quantitative PCR values of hRV-A virus VP1 gene after treatment with various concentrations of H-958
  • B shows the nonlinear regression analysis results
  • C shows the plaque assay results and calculated plaque forming units per mL (PFU/ml).
  • A shows the quantitative real-time quantitative PCR values of vaccinia virus E9L gene after treatment with various concentrations of H-958
  • B shows the nonlinear regression analysis results
  • C shows the plaque assay results and calculated plaque forming units per mL (PFU/ml).
  • Quantitative real-time PCR values of the HSV-1 UL30 gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days are shown.
  • Quantitative real-time quantitative PCR values of FIPV ORF1ab gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days are shown.
  • Quantitative real-time quantitative PCR values of SFTSV genome S segment after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days are shown.
  • Real-time quantitative PCR quantification of CV genome after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days is shown.
  • Quantitative real-time PCR values of MNV nsp genes after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 1 day are shown.
  • Quantitative real-time quantitative PCR values of RoV VP1 gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days are shown.
  • 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 ;
  • R4 is a halogen atom, 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, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group;
  • X is a single bond, a -CH 2 - group, or a -CH 2 -O- group.
  • R 1 is a thienyl group
  • R 2 is 2,4-difluorophenyl or 2,4-dichlorophenyl
  • X is a single bond
  • R1 is a phenyl group or a thienyl group, which may be substituted with at least one R4 substituent, and is not substituted with any substituent other than R4 .
  • R1 is a phenyl group, it may be substituted with 1 to 5 R4 substituents, and when R1 is a thienyl group, it may be substituted with 1 to 3 R4 substituents, and hydrogen is bonded to the carbon that is not substituted with the R4 substituent.
  • R1 is a thienyl group, it may be linked to the -O-CH2- of the skeleton structure at the 2 -position or the 3-position.
  • R 1 and R 2 that are not substituted with an R 4 substituent are as follows:
  • R 4 At least one of R 1 and R 2 is substituted with at least one R 4 substituent, and R 1 and R 2 are not substituted with a substituent other than R 4. That is, R 1 is substituted with at least one R 4 substituent and is not substituted with a substituent other than R 4 , and R 2 is not substituted with a substituent, R 1 is not substituted with a substituent, R 2 is substituted with at least one R 4 substituent and is not substituted with a substituent other than R 4 , and both R 1 and R 2 are substituted with an R 4 substituent and are not substituted with a substituent other than R 4.
  • R 1 and R 2 substituted with one R 4 substituent are as follows:
  • R 1 and R 2 substituted with two R 4 substituents are as follows: The two R 4 substituents may be the same or different.
  • R1 and R2 substituted with three R4 substituents are as follows: The three R4 substituents may be the same or different.
  • R 1 and R 2 substituted with four and five R 4 substituents are exclusively phenyl groups and are as follows: The four R 4 substituents may be the same or different.
  • R 4 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.
  • the halogen is fluorine (F), chlorine (Cl), bromine (Br), iodine (I) or astatine (At).
  • An example of R 1 and R 2 when R 4 is a halogen is shown below.
  • R 1 and R 2 when R 4 is a hydroxyl group is shown below.
  • the alkyl group having 1 to 6 carbon atoms includes, as chain alkyl groups, C1-6 alkyl 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, and as cycloalkyl groups, C3-6 cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
  • Examples 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 may contain, in addition to a carbon atom 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
  • acylamino group for example, C 1-6 acylamino group such as formylamino group, acetylamino group, propionylamino group, etc.
  • thiol group for example, thioether group, thioester group.
  • a halogenoalkyl group for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a bromoethyl group, a dibromoethyl group, a tribromoethyl group, etc.), an aminoalkyl group (for example, an aminomethyl group, an aminoethyl group, a morpholinylmethyl group, etc.), an alkoxycarbonylamino
  • R1 and R2 when R4 is an alkyl group having 1 to 6 carbon atoms which may have a substituent, where Boc is a t-butoxycarbonyl group (--COOC( CH3 ) 3 ) and Ac is an acetyl group ( --COCH3 ).
  • the methylenedioxy group is a group containing -O-CH 2 -O-, and may be an alkoxymethoxy group in which an alkyl group is bonded to oxygen (for example, a methoxymethoxy group (-O-CH 2 -O-CH 3 ), an ethoxymethoxy group (-O-CH 2 -O-C 2 H 5 )), 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 of R 1 and R 2 is shared.
  • substituted methylenedioxy group can be bonded to oxygen or carbon and include alkyl groups (methyl groups) and halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.).
  • alkyl groups methyl groups
  • halogen atoms for example, fluorine, chlorine, bromine, iodine, etc.
  • R 1 and R 2 when R 4 is a methylenedioxy group which may have a substituent is shown below.
  • the total number of halogen atoms contained in R 1 and R 2 i.e., the total number of halogen atoms contained in the R 4 substituent, is preferably 2 or more, and more preferably 3 or more.
  • R 4 may be 3 or more halogens, or R 4 may be an alkyl group having 1 to 6 carbon atoms containing 2 or 3 or more halogens as a substituent, or a methylenedioxy group containing 2 or 3 or more halogens as a substituent.
  • Either R 1 or R 2 may contain 2 or 3 or more halogens, or both R 1 and R 2 may contain halogens, so that the total number of halogens is 2 or 3 or more.
  • R 1 or R 2 may be a di-, tri-, tetra-, or penta-halogenophenyl group, or a di-, tri-, or tetra-halogenothienyl group.
  • R 4 may have two or three or more halogenoalkyl groups containing one halogen, it may have one or two or more halogenoalkyl groups containing two halogens, or it may have one or more halogenoalkyl groups containing two or three or more halogens.
  • R 4 may be a halogen, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, or a trichloromethyl group.
  • R 3 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, it is preferable to use a compound in which R 3 is a hydrogen atom or a methyl group, and it is particularly preferable to use a compound in which R 3 is a hydrogen atom and the -CO 2 R 3 group is a carboxyl group (-CO 2 H).
  • R 3 is 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 has low activity, it may be easily substituted with a hydrogen atom by hydrolysis to become a carboxyl group, thereby increasing the activity. Therefore, such a compound can also be used as a prodrug.
  • hydrocarbon group refers to a group of a compound made of carbon atoms and hydrogen atoms, and may be, but is not limited to, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, or an aromatic hydrocarbon group, with those having 1 to 16 carbon atoms being preferred. Specific examples include, but are not limited to, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group.
  • 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.
  • alkynyl group examples include an ethynyl group, a propargyl group, and a 1-propynyl group.
  • cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • aryl group examples 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 may contain, in addition to carbon atom 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
  • acylamino group for example, a C 1-6 acylamino group such as a formylamino group, an acetylamino group, or a propionylamino group
  • a thiol group for example, a thioether group, and a thioester group.
  • heterocyclic group refers to a group of a cyclic compound consisting of carbon atoms and atoms other than carbon. As the “heterocyclic group”, it is preferable to use an aromatic 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 one or two heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as heteroatoms in addition to carbon atoms.
  • 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.
  • it can be a 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon 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, and N-oxide-3- or 4-pyridazinyl group.
  • 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 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 quinolizinyl group, a 1,8-naphthyridinyl group, a dibenzofuranyl group, a carbazolyl group, an acridinyl group, a phenanthridinyl group, a perimidinyl group, a phenazinyl
  • Examples of the "substituent" of the heterocyclic 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 may contain, in addition to carbon atom 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,
  • acylamino group for example, a C 1-6 acylamino group such as a formylamino group, an acetylamino group, or a propionylamino group
  • a thiol group for example, a thioether group, and a thioester group.
  • Formula (I') is a compound in which R 1 is a thienyl group, R 2 is 2,4-difluorophenyl or 2,4-dichlorophenyl, and X is a single bond, a compound in which R 1 is substituted with at least one R 4 substituent and is not substituted with any other substituent than R 4 , and R 2 is substituted with any other substituent than R 4 , and a compound in which R 2 is substituted with at least one R 4 substituent and is not substituted with any other substituent than R 4 , and R 1 is substituted with any other substituent than R 4 , and except for these points, R 1 , R 2 , and X are the same as those in formula (I).
  • Example 1-3 Synthesis of Compounds (H-1024, 1025, 1042, 1043) Using Intermediate (S-2)
  • intermediate (S-2) used for synthesizing the compound of the present invention was produced.
  • methyl 2-acetamido-5-hydroxybenzoate (H-122) a known compound, as a raw material, and 3,5-difluorobenzyl bromide instead of benzyl bromide in intermediate (S-1)
  • preS-2 a precursor methyl 2-acetamido-5-(3,5-difluorobenzyloxy)benzoate
  • preS-2 methyl 2-amino-5-(3,5-difluorobenzyloxy)benzoate
  • Methyl 2-amino-5-(3,5-difluorobenzyloxy)benzoate (S-2) and the corresponding carboxylic acid containing R 2 -X were used to carry out dehydration and hydrolysis in the same manner as in Example 1-1 to synthesize compounds H-1024, 1025, 1042, and 1043 of the present invention.
  • the structures of the respective compounds are as shown in Table 1.
  • 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)
  • intermediate (S-3) used for synthesizing the compound of the present invention was produced.
  • 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)
  • intermediate (S-4) used for synthesizing the compound of the present invention was produced.
  • Example 1-6 Synthesis of Compounds (H-1083, 1084, 1085, 1086, 1119, 1120, 1127, 1128, 1135, 1136) Using Intermediate (S-5)
  • intermediate (S-5) used for synthesizing the compound of the present invention was produced.
  • Methyl 2-amino-5-(3,4,5-trifluorobenzyloxy)benzoate (S-5) and the corresponding carboxylic acid containing R 2 -X were used to carry out dehydration and hydrolysis in the same manner as in the synthesis of Example 1-1 to synthesize compounds H-1083, 1084, 1085, 1086, 1119, 1120, 1127, 1128, 1135, and 1136 of the present invention.
  • the structures of the respective compounds are as shown in Table 1.
  • 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)
  • intermediate (S-6) used for synthesizing the compounds of the present invention was produced.
  • Methyl 2-amino-5-(4-(trifluoromethyl)benzyloxy)benzoate (S-6) and a carboxylic acid containing the corresponding R 2 -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 carrying out dehydration and hydrolysis in the same manner as in the synthesis of Example 1-1.
  • the structures of the respective compounds are as shown in Table 1.
  • 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)
  • intermediate (S-7) used for synthesizing the compound of the present invention was produced.
  • Methyl 2-amino-5-(thiophen-3-ylmethoxy)benzoate (S-7) and the corresponding carboxylic acid containing R 2 -X were used to carry out dehydration and hydrolysis in the same manner as in the synthesis of 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 the respective compounds are as shown in Table 1.
  • preS-8 2-nitro-5-(thiophen-2-ylmethoxy)benzoate
  • 1M HCl (0.76 mL) was added dropwise 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) at 60° C., and the mixture was refluxed for 1 hour.
  • Methyl 2-amino-5-(thiophen-2-ylmethoxy)benzoate (S-8) and a carboxylic acid containing the corresponding R 2 -X were used to carry out dehydration and hydrolysis in the same manner as in the synthesis of 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 the respective compounds are as shown in Table 1.
  • Example 2 SARS-CoV-2 Proliferation Inhibitory Effect
  • the inhibitory effect of the compound of the present invention on SARS-CoV-2 proliferation was confirmed using VeroE6/TMPRSS2 cells and an infection model of SARS-CoV-2.
  • the compound of the present invention was added to VeroE6/TMPRSS2 cells at a final concentration of 5 or 10 ⁇ M, and after 2 hours, the cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 10. After 8 hours of infection, cell lysates were collected, and intracellular SARS-CoV-2 nucleocapsids and actin as an internal standard protein were detected by Western blotting.
  • MOI multiplicity of infection
  • the band area of nucleocapsid when no compound was added was set as an inhibition rate of 0%, and the inhibition rate was calculated as the ratio of the band area when the compound was added.
  • the band area was 0 (when no band was observed), the inhibition rate was 100%.
  • Example 3 Inhibitory effect of Zika virus proliferation
  • VeroE6 cells in 10% FBS-supplemented medium were seeded in a 6-well microtiter plate at a density of 1 x 106 cells/well and incubated overnight at 37°C and 5% CO2 .
  • the next day the cells were washed with pre-warmed PBS and replaced with 2% FBS-supplemented medium containing Zika virus at a multiplicity of infection (MOI) of 0.01.
  • MOI multiplicity of infection
  • the infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing Pin1 inhibitor (compound H-958) at concentrations of 0, 0.1, 1, 5, and 10 ⁇ M and 0.1% DMSO. The cells were then incubated at 37°C and 5% CO2 for 24 hours. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, and then cultured for another 24 hours. 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 Zika virus NS1 gene in cell lysates was used.
  • Pin1 inhibitor compound H-958
  • the inhibition rate was calculated as the reduction in the copy number of NS1 gene with the addition of Pin1 inhibitor compared to the copy number of NS1 gene without the addition of Pin1 inhibitor.
  • the copy number of NS1 gene without the addition of Pin1 inhibitor to the infected cell line was set as 0% inhibition rate.
  • Zika virus growth was determined by testing the collected supernatants in a limiting dilution plaque assay. Supernatants from different treatment groups were serially diluted 10-fold and added to a monolayer of VeroE6 cells in a 12-well plate. 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 ⁇ M).
  • 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, and the EC50 value obtained from nonlinear regression analysis of the results was 2.6 ⁇ M (Figure 1B).
  • Figure 1C shows the results of the plaque assay after treatment with H-958 and the calculated plaque forming units per milliliter (PFU/ml). 10 ⁇ M H-958 reduced plaque formation in the supernatant of treated cells by 96% ( 8x102 PFU/ml) compared to untreated cells ( 1.8x104 PFU/ml).
  • Example 4 RS virus proliferation inhibitory effect
  • the inhibitory effect of the compound of the present invention on RS virus was confirmed.
  • HEp-2 cells in 10% FBS-supplemented medium were seeded in a 6-well microtiter plate at a density of 1 x 106 cells/well and incubated overnight at 37°C and 5% CO2 .
  • the next day the cells were washed with pre-warmed PBS and replaced with 2% FBS-supplemented medium containing RS virus at a multiplicity of infection (MOI) of 0.01.
  • MOI multiplicity of infection
  • the infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing Pin1 inhibitor (compound H-958) at concentrations of 0, 0.1, 1, 5, and 10 ⁇ M and 0.1% DMSO. The cells were then incubated at 37°C and 5% CO2 for 24 hours. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, and then cultured for another 24 hours. Finally, the supernatant from each well was collected, and the cells were lysed with TRIzol reagent. To estimate RS virus genome replication, real-time quantitative PCR of RS virus N gene in cell lysates was used. The inhibition rate was calculated as the reduction in the N gene copy number when Pin1 inhibitor was added compared to the N gene copy number when Pin1 inhibitor was not added. The N gene copy number when Pin1 inhibitor was not added to the infected cell line was set as 0% inhibition rate.
  • Pin1 inhibitor compound H-958
  • Figure 2 shows the inhibitory effect of adding a Pin1 inhibitor to 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, and the EC50 value obtained from nonlinear regression analysis of the results was 0.7 ⁇ M ( Figure 2B).
  • Example 5 Inhibitory effect on hantavirus proliferation
  • VeroE6 cells in 10% FBS-supplemented medium were seeded in a 6-well microtiter plate at a density of 1 x 106 cells/well and incubated overnight at 37°C and 5% CO2 . The next day, the cells were washed with pre-warmed PBS and replaced with 2% FBS-supplemented medium containing Seoul-type hantavirus at a multiplicity of infection (MOI) of 0.01.
  • MOI multiplicity of infection
  • the infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing Pin1 inhibitor (compound H-958) at concentrations of 0, 0.1, 1, 5, and 10 ⁇ M and 0.1% DMSO. The cells were then incubated at 37°C and 5% CO2 for 24 hours. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, and then cultured for another 24 hours. Finally, the supernatant from each well was collected, and the cells were lysed with TRIzol reagent.
  • Pin1 inhibitor compound H-958
  • Figure 3 shows the inhibitory effect of the addition of a Pin1 inhibitor on Seoul-type hantavirus-infected cells.
  • Figure 3A shows the quantitative real-time quantitative PCR values of the S segment of Seoul-type hantavirus after treatment with various concentrations of H-958, and the EC50 value obtained from nonlinear regression analysis of the results was 1.1 ⁇ M ( Figure 3B).
  • Example 6 Inhibitory effect on the proliferation of Gamaku virus
  • VeroE6 cells in 10% FBS-supplemented medium were seeded in a 6-well microtiter plate at a density of 1 x 106 cells/well and incubated overnight at 37°C and 5% CO2 . The next day, the cells were washed with pre-warmed PBS and replaced with 2% FBS-supplemented medium containing Gamaku virus at a multiplicity of infection (MOI) of 1.0.
  • MOI multiplicity of infection
  • the infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing Pin1 inhibitor (compound H-958) at concentrations of 0, 0.1, 1, 5, and 10 ⁇ M and 1% DMSO. The cells were then incubated at 37°C and 5% CO2 for 24 hours. The next day, the medium was removed from the cells and replaced with 2% FBS-supplemented medium, and then cultured for another 24 hours. Finally, the supernatant from each well was collected, and the cells were lysed with TRIzol reagent. To estimate the genome replication of Gamaku virus, real-time quantitative PCR of Gamaku virus N9 gene in cell lysate was used.
  • Pin1 inhibitor compound H-958
  • the inhibition rate was calculated as the reduction in the copy number of N9 gene when Pin1 inhibitor was added compared to the copy number of N9 gene when Pin1 inhibitor was not added.
  • the copy number of N9 gene when Pin1 inhibitor was not added to the infected cell line was set as 0% inhibition rate.
  • Figure 4 shows the inhibitory effect of adding a Pin1 inhibitor to Gamaku virus-infected cells, and shows the quantitative real-time quantitative PCR values of the Gamaku virus N9 gene after treatment with various concentrations of H-958.
  • Example 7 Growth Inhibitory Effect of Human Rhinovirus Type A (hRV-A) HeLa cells in 10% heat-inactivated FBS-supplemented DMEM medium and 1% Antibiotic-Antimycotic (Gibco, cat# 15240062) were seeded into a 6-well microtiter plate at a density of 1 x 10 cells per well and cultured at 34°C, 5% CO for 48 hours. Cells were then washed with pre-warmed PBS and replaced with serum-free medium containing human rhinovirus type A at a multiplicity of infection (MOI) of 0.01.
  • MOI multiplicity of infection
  • infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing the Pin1 inhibitor H-958 at 0, 0.1, 1, 5, and 10 ⁇ M concentrations and 0.1% DMSO.
  • supernatants from 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 hRV-A virus VP1 gene in cell lysates was used to estimate hRV-A virus genome replication.
  • the inhibition rate was calculated as the reduction in the copy number of VP1 gene with the addition of Pin1 inhibitor compared to the copy number of VP1 gene without the addition of Pin1 inhibitor (0 ⁇ M Pin1 inhibitor).
  • the copy number of VP1 gene without the addition of Pin1 inhibitor to the infected cell line was defined as 0% inhibition rate.
  • hRV-A 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 6-well plates. To obtain accurate titers, wells that formed plaques were selected and counted.
  • the number of plaque-forming units per milliliter was calculated as the average number of plaques in the test wells multiplied by the dilution factor divided by the volume of supernatant. Inhibition of virus growth was calculated as the reduction in PFU/ml with the addition of Pin1 inhibitor compared to PFU/ml without Pin1 inhibitor (0 ⁇ M Pin1 inhibitor).
  • Figure 5 shows the inhibitory effect of adding a Pin1 inhibitor to hRV-A virus-infected cells.
  • Figure 5A shows the quantitative values of real-time quantitative PCR of the hRV-A virus VP1 gene after treatment with different concentrations of H-958
  • Figure 5B shows the EC50 calculation results obtained from nonlinear regression analysis of the results.
  • Figure 5C shows the results of plaque assay after treatment with H-958 and the calculated plaque forming units per mL (PFU/ml). Treatment with 1.1 ⁇ M or greater H-958 inhibited hRV-A viral replication by more than 50%.
  • H-958 reduced hRV-A viral titers by 81%, as measured by plaque-forming units/ml (8 ⁇ 10 4 PFU/ml) in the supernatant of H-958-treated cells, compared with untreated cells (4.2 ⁇ 10 5 PFU/ml).
  • Example 8 Inhibitory effect on the proliferation of vaccinia virus (VACV) VeroE6 cells in 10% FBS-supplemented DMEM medium and 0.1% gentamicin were seeded into 6-well microtiter plates at a density of 1 x 106 cells per well and cultured at 37°C, 5% CO2 for 48 hours. Cells were then washed with pre-warmed PBS and replaced with serum-free medium containing vaccinia type A at a multiplicity of infection (MOI) of 0.01.
  • VACV vaccinia virus
  • infected cells were washed with pre-warmed PBS and the medium was replaced with serum-free medium containing 0, 0.1, 1, 5, and 10 ⁇ M concentrations of the Pin1 inhibitor H-958 and 1% DMSO.
  • supernatants from 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 cell lysates was used to estimate vaccinia virus genome replication.
  • the inhibition rate was calculated as the reduction in the E9L gene copy number with the addition of Pin1 inhibitor compared to the copy number of the E9L gene without the addition of Pin1 inhibitor (0 ⁇ M Pin1 inhibitor).
  • the copy number of the E9L gene without the addition of Pin1 inhibitor to the infected cell line was set as 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 6-well plates. To obtain accurate titers, wells that formed plaques were selected and counted.
  • the number of plaque-forming units per milliliter was calculated as the average number of plaques in the test wells multiplied by the dilution factor divided by the volume of supernatant. Inhibition of virus growth was calculated as the reduction in PFU/ml with the addition of Pin1 inhibitor compared to PFU/ml without Pin1 inhibitor (0 ⁇ M Pin1 inhibitor).
  • 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 vaccinia virus E9L gene after treatment with different concentrations of H-958
  • Figure 6B shows the EC50 calculation results obtained from nonlinear regression analysis of the results.
  • Figure 6C shows the results of plaque assay after treatment with H-958 and the calculated plaque forming units per mL (PFU/ml). Treatment with 1.3 ⁇ M or greater H-958 inhibited vaccinia virus replication by more than 50%.
  • H-958 reduced vaccinia virus titers by more than 99.9%, as measured by plaque forming units in the supernatants of H-958-treated cells (6 x 10 2 PFU/ml) compared with untreated cells (5.4 x 10 6 PFU/ml).
  • Example 9 Inhibitory effect on proliferation of herpes simplex virus-1 (HSV-1) VeroE6 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded at a density of 1.5 x 10 cells per well in a 24-well plate and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • HSV-1 herpes simplex virus-1
  • HSV-1 herpes simplex virus-1
  • MOI multiplicity of infection
  • Example 10 Growth Inhibitory Effect of Influenza A Virus (IAV) H3N2 MDCK(+) cells (Arch Virol (1998) 143: 1893-1909) in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded at a density of 1.5 x 10 cells per well in a 24-well plate and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • IAV Influenza A Virus
  • treated cells were infected with influenza A virus subtype H3N2 (A/Udorn/72) at a multiplicity of infection (MOI) of 0.05.
  • Culture supernatants were harvested on day 1 for quantification of viral replication.
  • RNA was extracted from the virus in the supernatant and quantitative real-time reverse transcription (RT)-PCR of the IAV HA gene was performed.
  • the copy number of the HA gene in the sample was quantified using a plasmid containing a DNA fragment amplified by RT-PCR (target DNA) as a standard.
  • 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.
  • MOI multiplicity of infection
  • culture supernatants were harvested and viral replication was quantified. Real-time quantitative PCR of IAV viral HA gene in the supernatant was used to estimate IAV H5N3 viral genome replication.
  • Figure 9 shows the inhibitory effect of adding a Pin1 inhibitor to IAV virus-infected cells by showing the quantitative real-time PCR values of the IAV virus (H5N3) HA gene after treatment with 10 ⁇ M H-1134 for 3 days. Treatment with 10 ⁇ M H-1134 inhibited IAV H5N3 virus replication by more than 98.8%.
  • Example 12 Inhibitory effect on the proliferation of poliovirus (PoV) HEp-2 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded into a 24-well plate at a density of 1.5 x 10 cells per well and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • PoV poliovirus
  • treated cells were infected with poliovirus (Sabin-1 strain) at a multiplicity of infection (MOI) of 0.01. Culture supernatants were harvested on day 3 and viral replication was quantified. Real-time quantitative PCR of PoV genome in the supernatant was utilized to estimate PoV viral genome replication.
  • Figure 10 shows the inhibitory effect of adding Pin1 inhibitors to PoV-infected cells by showing the quantification of PoV genome by real-time quantitative PCR after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced PoV viral replication by more than 99.9%.
  • Example 13 Inhibitory effect on feline calcivirus (FCV) proliferation CRFK cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded onto a 24-well plate at a density of 1.5 x 10 cells per well and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • FCV feline calcivirus
  • FCV VP1 FCV viral genome replication
  • Figure 11 shows the inhibitory effect of adding Pin1 inhibitors to FCV-infected cells by showing the quantitative real-time PCR values of FCV VP1 gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced FCV viral replication by more than 99.8%.
  • Example 14 Inhibitory effect on the proliferation of feline infectious peritonitis virus (FIPV) CRFK cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded into a 24-well plate at a density of 1.5 x 10 cells per well and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • FBS feline infectious peritonitis virus
  • FIPV multiplicity of infection
  • Figure 12 shows the inhibitory effect of adding Pin1 inhibitors to FIPV-infected cells by showing the quantitative real-time PCR values of FIPV ORF1ab gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced FIPV viral replication by more than 99.9%.
  • Example 15 Inhibitory effect on the proliferation of severe fever with thrombocytopenia syndrome virus (SFTSV) VeroE6 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded into a 24-well plate at a density of 1.5 x 10 cells per well, and cultured overnight at 37°C in 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 ⁇ M in 0.1% DMSO.
  • SFTSV thrombocytopenia syndrome virus
  • treated cells were infected with SFTSV 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 the SFTSV genome S segment in the supernatant was used to estimate SFTSV viral genome replication.
  • MOI multiplicity of infection
  • Figure 13 shows the inhibitory effect of adding Pin1 inhibitors to SFTSV-infected cells by showing the quantitative real-time quantitative PCR values of the SFTSV genome S segment after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced SFTSV viral replication by more than 99.9%.
  • Example 16 Inhibitory effect on the proliferation of Coxsackievirus (CV) HEp-2 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 10% FBS were seeded into a 24-well plate at a density of 1.5 x 10 cells per well, and cultured overnight at 37°C in 5% CO . 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 ⁇ M in 0.1% DMSO.
  • CV Coxsackievirus
  • treated cells were infected with CV (group B, type 5) at a multiplicity of infection (MOI) of 0.1.
  • MOI multiplicity of infection
  • cells including culture supernatants 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 ⁇ M of each Pin1 inhibitor significantly reduced CV viral replication.
  • Figure 14 shows the inhibitory effect of adding Pin1 inhibitors to CV-infected cells by showing the quantitative real-time PCR values of CV genome after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced CV viral replication by more than 99.4%.
  • Example 17 Inhibitory effect on proliferation of infectious bronchitis virus (IBV) BHK-21 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and 5% FBS were seeded at a density of 1.5 x 10 cells per well in a 24-well plate and cultured overnight at 37°C and 5% CO2 . The next day, cells are washed with pre-warmed PBS and the medium is replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 ⁇ M in 0.1% DMSO.
  • IBV infectious bronchitis virus
  • treated cells are infected with IBV at a multiplicity of infection (MOI) of 0.1.
  • MOI multiplicity of infection
  • Culture supernatants are harvested on day 3 and viral replication is quantified. Real-time quantitative PCR of the IBV S gene in the supernatant was used to estimate IBV viral genome replication.
  • Treatment with 10 ⁇ M of each Pin1 inhibitor significantly reduced IBV viral replication.
  • Example 18 Inhibitory effect on the proliferation of adenovirus (AdV) HEK 293 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and supplemented with 10% FBS were seeded into a 24-well plate at a density of 1.5 x 105 cells per well and cultured overnight at 37°C, 5% CO2 . The next day, cells are washed with prewarmed PBS and the medium is replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 ⁇ M in 0.1% DMSO.
  • AdV adenovirus
  • Example 19 Inhibitory effect on proliferation of mouse norovirus (MNV) RAW 264.7 cells in Iscove's modified Dulbecco's medium containing penicillin G and streptomycin and supplemented with 5% FBS were seeded at a density of 1.5 x 10 cells per well in a 24 -well plate 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, and H-1211 at 10 ⁇ M concentration in 0.1% DMSO.
  • MNV mouse norovirus
  • FIG. 15 shows the inhibitory effect of adding Pin1 inhibitors to MNV-infected cells by showing the quantitative real-time quantitative PCR of MNV nsp genes after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 1 day. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced MNV viral replication by more than 99.9%.
  • Example 20 Inhibitory effect on proliferation of rotavirus (RoV) MA104 cells were seeded at a density of 1.5 x 10 cells per well in a 24-well plate using Dulbecco's modified Eagle medium supplemented with 5% FBS containing penicillin G and streptomycin, 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 ⁇ M in 0.1% DMSO.
  • RoV rotavirus
  • Figure 16 shows the inhibitory effect of adding Pin1 inhibitors to RoV-infected cells by showing the results of real-time PCR quantification of the RoV VP1 gene after treatment with 10 ⁇ M H-958, H-1134, H-1209, or H-1211 for 3 days. Treatment with 10 ⁇ M of each Pin1 inhibitor reduced RoV replication by more than 96.0%.
  • Example 21 Inhibitory effect on the proliferation of Epstein-Barr virus (EBV) P3HR1 cells in serum-free Dulbecco's modified Eagle medium containing penicillin G and streptomycin are seeded in microtiter plates at 1 x 10 6 cells/mL, and 20 ng/mL of 12-O-tetradecanoylphorbol-13-acetate (TPA) is added to induce EBV production. After 24 hours, the cells are washed with pre-warmed PBS, and the medium is replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 ⁇ M in 0.1% DMSO. On the 7th day of culture, the cells are harvested and DNA is extracted. Real-time quantitative PCR of the EBV EBNA1 gene in extracted DNA was used to estimate EBV replication in cells. Treatment with 10 ⁇ M of each Pin1 inhibitor significantly reduced EBV replication.
  • EBV Epstein-Barr virus
  • Example 22 Inhibitory effect on the proliferation of Japanese encephalitis virus (JEV) BHK-21 cells in Dulbecco's modified Eagle medium containing penicillin G and streptomycin and 5% FBS were seeded into a microtiter plate at a density of 1 x 106 cells per well and incubated overnight at 37°C in 5% CO2 . The next day, cells are washed with pre-warmed PBS and the medium is replaced with serum-free medium containing Pin1 inhibitors H-958, H-1134, H-1209, or H-1211 at a concentration of 10 ⁇ M in 0.1% DMSO.
  • JEV Japanese encephalitis virus
  • JEV multiplicity of infection
  • Example 23 Inhibitory effect on proliferation of Theileria parasites TBL-3 or TpMD409 cells (infected with Theileria parasites) in RPMI 1640 supplemented with 10% FCS, 4 mM L-glutamine, 25 mM HEPES, 10 mM ⁇ -mercaptoethanol and 100 mg/ml penicillin/streptomycin are seeded in microtiter plates at a density of 1 x 106 cells per well and cultured overnight at 37°C, 5% CO2 . The next day, cells are washed with pre-warmed PBS and the medium is replaced with serum-free medium containing a Pin1 inhibitor at a concentration of 10 ⁇ M in 0.1% DMSO.
  • the parasite-infected cells are plated onto slides using a CytoSpin centrifuge and fixed with 3.7% formaldehyde in PBS for 15 minutes at room temperature.
  • the DNA in the cells is stained with DAPI.
  • the cells are photographed under a fluorescent microscope and the number of parasites per cell is counted. Treatment with 10 ⁇ M Pin1 inhibitor significantly reduces the number of parasites in the cells.

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Abstract

Le problème décrit par la présente invention est de développer de nouveaux composés ayant une activité qui inhibe la fonction de Pin1 et l'utilisation de ces composés en tant que composés candidats pour des produits pharmaceutiques. La solution selon l'invention porte sur des composés représentés par la formule (I) et des sels de ceux-ci. (Dans la formule : R1 et R2 sont chacun un groupe phényle ou un groupe thiényle, au moins l'un de R1 et R2 est substitué par au moins un substituant R4 et n'est pas substitué par un substituant autre que R4, R4 étant un halogène, un groupe hydroxyle, un groupe alkyle en C1-C6, qui peut avoir un substituant, ou un groupe méthylènedioxy, qui peut avoir un substituant ; R3 est un atome d'hydrogène, un groupe hydrocarboné, qui peut avoir un substituant, un groupe hétérocyclique qui peut avoir un substituant, ou un groupe amino qui peut avoir un substituant ; et X est une liaison simple, un groupe -CH2-, ou un groupe -CH2-O-. Cependant, les composés dans lesquels R1 est un groupe thiényle, R2 est 2,4-difluorophényle ou 2,4-dichlorophényle, et X est une liaison simple sont exclus).
PCT/JP2024/031880 2023-09-08 2024-09-05 Nouveaux composés à base d'acide anthranilique, inhibiteur de pin 1, agent thérapeutique et agent préventif pour maladies infectieuses, etc l'utilisant Pending WO2025053222A1 (fr)

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WO2003005025A1 (fr) * 2001-07-03 2003-01-16 Biovitrum Ab Procedes d'identification de composes modulant l'activite du ppar-gamma
JP2006523669A (ja) * 2003-03-10 2006-10-19 ファイザー・インク Ｎｉｍａ調節タンパク質（ｐｉｎ１）を阻害するための、リン酸／硫酸エステル化合物および医薬組成物
JP2015518902A (ja) * 2012-06-07 2015-07-06 ベス イスラエル デアコネス メディカル センター インコーポレイテッド Ｐｉｎ１の阻害のための方法および組成物
WO2017044551A1 (fr) * 2015-09-11 2017-03-16 Mitobridge, Inc. Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales
WO2019031472A1 (fr) * 2017-08-07 2019-02-14 国立大学法人広島大学 NOUVEAU COMPOSÉ À BASE D'ACIDE ANTHRANILIQUE, ET INHIBITEUR DE Pin1, AGENT THÉRAPEUTIQUE CONTRE LES MALADIES INFLAMMATOIRES AINSI QU'AGENT THÉRAPEUTIQUE CONTRE LE CANCER METTANT EN ŒUVRE CELUI-CI
WO2022107745A1 (fr) * 2020-11-17 2022-05-27 国立大学法人広島大学 Agent thérapeutique ou agent prophylactique contre la covid-19

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003005025A1 (fr) * 2001-07-03 2003-01-16 Biovitrum Ab Procedes d'identification de composes modulant l'activite du ppar-gamma
WO2003004458A1 (fr) * 2001-07-03 2003-01-16 Biovitrum Ab Composes nouveaux
JP2006523669A (ja) * 2003-03-10 2006-10-19 ファイザー・インク Ｎｉｍａ調節タンパク質（ｐｉｎ１）を阻害するための、リン酸／硫酸エステル化合物および医薬組成物
JP2015518902A (ja) * 2012-06-07 2015-07-06 ベス イスラエル デアコネス メディカル センター インコーポレイテッド Ｐｉｎ１の阻害のための方法および組成物
WO2017044551A1 (fr) * 2015-09-11 2017-03-16 Mitobridge, Inc. Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales
WO2019031472A1 (fr) * 2017-08-07 2019-02-14 国立大学法人広島大学 NOUVEAU COMPOSÉ À BASE D'ACIDE ANTHRANILIQUE, ET INHIBITEUR DE Pin1, AGENT THÉRAPEUTIQUE CONTRE LES MALADIES INFLAMMATOIRES AINSI QU'AGENT THÉRAPEUTIQUE CONTRE LE CANCER METTANT EN ŒUVRE CELUI-CI
WO2022107745A1 (fr) * 2020-11-17 2022-05-27 国立大学法人広島大学 Agent thérapeutique ou agent prophylactique contre la covid-19

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DATABASE REGISTRY 30 August 2004 (2004-08-30), "Benzoic acid, 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)- (CA INDEX NAME)", XP093287045, Database accession no. 735260-59-0 *

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