Anti-coronavirus applications of poly-ADP-ribose polymerase inhibitors

Abstract

The present invention provides a poly ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof for use in preparing an antiviral agent or a medicament for treating a disease caused by a virus, the virus being a β-coronavirus. The present invention also provides a compound represented by Formula III and / or a compound represented by Formula IV, or a pharmaceutically acceptable salt thereof, for use in preparing an antiviral agent or a medicament for treating a disease caused by a virus, the virus being HIV, HPV, EBV, IFV, and / or a coronavirus. The poly ADP-ribose polymerase inhibitor includes a compound represented by Formula III and / or a compound represented by Formula IV, or a pharmaceutically acceptable salt thereof, and can reduce the effective concentration for inhibiting the virus and increase antiviral activity while ensuring low toxicity and high safety when used in the human body. As a result, the inhibitor can effectively inhibit the virus when used in the clinical treatment of diseases caused by coronavirus.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2020101117554 filed on 24 February 2020. The aforementioned Chinese Patent Application is incorporated into this application in its entirety by reference.

[0002] This invention belongs to the field of biomedical technology and, more particularly, relates to the application of pharmaceuticals using a poly-ADP-ribose polymerase inhibitor as a main component and its pharmaceutically acceptable salt, as well as pharmaceutical compositions and kits containing the same, to anti-coronavirus-induced diseases. [Background technology]

[0003] Coronaviruses (CoVs) are a class of enveloped, single-stranded, positive-chain RNA viruses that can infect humans and various animals. They have a targeting of the respiratory, gastrointestinal, and nervous systems, causing serious illness in livestock and companion animals (such as pigs, cattle, chickens, dogs, and cats), and can lead to illnesses ranging from the common cold to severe acute respiratory syndrome in humans. In the ninth report of the International Committee on Taxonomy of Viruses, coronaviruses are classified into four groups, α, β, γ, and δ, according to their evolutionary characteristics. Of these, the hosts of groups α and β are mainly mammals, while groups γ and δ are mainly found in birds and poultry.

[0004] As of February 2020, seven types of coronaviruses capable of infecting humans are currently known. These include human coronaviruses that cause cold and upper respiratory tract infection symptoms: 229E (HCoV-229E), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1), OC43 (HCoV-OC43), and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), as well as Severe Acute Respiratory Syndrome (SARS)-related coronaviruses: coronavirus SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus) and SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Coronaviruses account for 15-30% of human respiratory tract infections annually and can cause more severe illness in neonates, the elderly, and other susceptible populations with even higher incidences of lower respiratory tract infections. Among these, SARS-CoV and MERS-CoV, which are highly fatal coronaviruses, have high case mortality rates of 10% and 36%, respectively. Between 2019 and early 2020, the novel coronavirus SARS-CoV-2, which primarily originated in Hubei and other parts of China, infected over 70,000 people. This can lead to severe COVID-19 pneumonia (novel coronavirus pneumonia), with a severity rate of 15-30% and a mortality rate of approximately 2%, drawing renewed attention to coronaviruses. However, currently, no specific drugs for infections caused by coronaviruses have been approved. Even for patients with severe acute respiratory infections caused by SARS-CoV, SARS-CoV-2, and MERS-CoV infections, clinical treatment mainly consists of symptomatic therapy to reduce patient complications. Therefore, the development of effective drugs to treat infections caused by coronaviruses is urgently needed.

[0005] Small molecule compounds are a hotspot in the study of antiviral drug candidates. Exploring new applications for existing drugs has become an important approach in drug research and development. Candidate drugs have a good prospect for application because they already have data on their pharmacological efficacy, functional targets, and clinical safety, which is useful for further toxicity evaluation, pharmacokinetic evaluation, and formulation development. This significantly reduces R&D risks, shortens research time, and lowers R&D costs.

[0006] Currently, the first-line treatment for infections caused by coronaviruses is mostly broad-spectrum antiviral drugs such as the anti-HIV drugs lopinavir / ritonavir (Aluvia) and Arbidol, and the anti-Ebola drug remdesivir. Arbidol is a broad-spectrum antiviral drug that primarily treats upper respiratory tract infections caused by influenza A and B viruses. In recent years, many studies have demonstrated that Arbidol has certain inhibitory activity against SARS-CoV and MERS-CoV coronaviruses. On February 4, 2020, the latest results from in vitro cell experiments conducted by the Li Lanjuan team showed that Arbidol effectively inhibits coronaviruses, demonstrating up to 60 times greater efficacy than the untreated control group at concentrations of 10-30 micromoles, significantly inhibiting the disease-causing effects of the virus on cells. However, current data suggest that achieving concentrations of 10-30 micromoles is difficult in current clinical treatment. The Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 6) recommends a dose of 200 mg of arbidol three times daily. However, as stated in the package insert for "Arbidol Tablets (Manuosu)," after oral administration of single doses of 200 mg, 400 mg, and 600 mg of arbidol, the peak concentrations were 614.1 ± 342.5 ng / mL, 904.2 ± 355.6 ng / mL, and 975.1 ± 661.0 ng / mL, respectively. These correspond to levels of only 1-2 micromoles, which are far lower than the in vitro inhibitory concentration, suggesting limited in vivo antiviral activity. On the other hand, adverse events occurred in approximately 6.2% of those taking arbidol, and the package insert states that these mainly consisted of nausea, diarrhea, dizziness, and increased serum transaminases. Furthermore, it should be noted that in domestic human bioequivalence studies of arbidol preparations, some healthy subjects developed bradycardia (among these, some healthy subjects had a heart rate of less than 60 beats / min, and some experienced a decrease of 2-24 beats / min three hours after drug administration). The relationship between this event and the drug remains unclear.In addition, this drug should be used cautiously or under the direction of a physician in pregnant and breastfeeding women, as well as women with severe renal failure. Because the significance of this drug in patients with nodular disease or failure is unclear, caution is recommended when using this product in this population. Based on the above data, it is inferred that currently available drugs, despite being included in recommended treatments, are not the optimal choice for treating coronavirus due to their low antiviral activity, insufficient clinical evidence, and safety concerns.

[0007] In addition to arbidol, other antiviral drugs are also undergoing in vitro screening and clinical trials for their anti-COVID-19 efficacy. However, there is evidence that not all antiviral drugs are effective against COVID-19. In particular, Alvia, an anti-AIDS drug, is ineffective in treating pneumonia caused by COVID-19 and its continued use is no longer recommended due to its toxicity and side effects. Remdesivir is also undergoing clinical research but carries a relatively serious risk of hepatotoxicity. Therefore, based on existing evidence and experience, the treatment of coronavirus is unique, and the development of dedicated drugs with innovative mechanisms of action, as well as good efficacy and safety, remains necessary.

[0008] Poly(ADP-ribose) polymerase (PARP) plays a crucial role in DNA damage repair and apoptosis, and is also involved in a range of cellular processes, including infection and immunomodulation. This protein family consists of 17 members, including PARP1 and PARP2. PARP inhibitors were originally developed in the industry to produce anticancer effects through the accumulation of "toxic damage" and "synergistic lethality" by blocking DNA damage repair in highly mutated cancer cells. Currently, there are four PARP inhibitors marketed worldwide, named olaparib, niraparib, lucaparib, and talazoparib. At the same time, several other PARP inhibitors, including fluzoparib, mefuparib, simmiparib, IMP4297, BGB-290, and ABT-888, are in clinical trials both domestically and internationally.

[0009] The literature has reported that PARP may be closely involved in viral entry, integration, and replication, as well as capsid protein formation. In 2001, Hyo Chol Ha et al. reported that the PARP-1 enzyme played a crucial role in HIV-1 replication, integration, and transcription during HIV viral replication, and Proc Natl Acad Sci US A.2001;98(6):3364-8 mentioned that PARP inhibitors were helpful in inhibiting HIV infection. It has also been reported that inhibiting the nuclear localization of PARP-1 by participating in the process of stimulating gene transcription and expression by the inflammatory pathway NF-KB can inhibit the NFKB transcription pathway and thereby achieve an effect of inhibiting viral replication. Finally, since PARP-1 can induce apoptosis of immune cells, including T cells, inhibition of PARP-1 can block HIV integration in host cells, thereby achieving an effect of treating AIDS. Similar findings have been demonstrated in HPV, EBV, HSV, and other viruses. In 2010, Tempera et al. confirmed that PARP1 inhibitors have an inhibitory effect against EBV (J Virol. 2010; 84(10): 4988-97). In 2012, Grady et al. confirmed that PARP1 inhibitors have an inhibitory effect against HSV (J Virol. 2012; 86(15): 8259-68). In 2017, Matthew E. Grunewald et al. proposed that coronavirus capsid proteins are modified by ADP-ribosylation and speculated that several subtypes of PARP are involved in the formation of coronavirus capsid proteins (Virology. 2018, 517: 62-68), but they did not further clarify which PARP subtype selectivity is extremely important, nor did they suggest whether PARP inhibitors can inhibit viral replication or capsid protein formation. On the other hand, in 2016, Chad V. Kuny et al. published a paper discussing the role of PARP enzymes in the interaction between viruses and hosts.Among these, PARP13 can degrade viral reverse transcription RNA and block viral replication, while PARP10, 12, 13, and 14 can inhibit viral replication through interferon production (PLoS pathogens, 2016, 12(3):e1005453). In 2019, Matthew E. Grunewald noted that PARP enzymes possess both antiviral and immunomodulatory functions, and confirmed that the presence of PARP12 and PARP14 can inhibit viral entry and replication (PLoS pathogens, 2019, 15(5):e1007756). It is known that several subtypes of PARP enzymes can inhibit viral infection. Currently, the function of PARP is not definitively understood both domestically and internationally, and the inhibitory effects of PARP inhibitors on various viruses remain unclear.

[0010] In summary, there is an urgent need to find drugs that are highly effective at low concentrations and exhibit high antiviral activity, while ensuring high safety and fewer side effects, so that they can effectively inhibit the virus when used in the clinical treatment of diseases caused by coronavirus. [Overview of the project]

[0011] The technical problem that the present invention aims to solve is to overcome the problems of the prior art, for example, that the effective concentration of drugs for treating diseases caused by coronaviruses is too high and the antiviral activity is insufficient, thus limiting the in vivo antiviral activity when used clinically. Therefore, the present invention provides a poly-ADP-ribose polymerase (PARP) inhibitor for use against viruses, such as coronaviruses, and pharmaceutical compositions and kits containing the same, wherein the antiviral treatment can be either the PARP inhibitor of the present invention as an antiviral agent or the PARP inhibitor for the treatment of diseases caused by viruses. The poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions and kits containing the same, can reduce the effective concentration for inhibiting viruses and increase antiviral activity while ensuring low toxicity and high safety when used in humans, thereby enabling effective inhibition of viruses by the inhibitor of the present invention when used for the clinical treatment of diseases caused by coronaviruses.

[0012] Through a wide range of experiments, it was unexpectedly discovered that the poly-ADP-ribose polymerase inhibitor of the present invention or a pharmaceutically acceptable salt thereof can significantly inhibit coronavirus replication in vitro. The present invention demonstrates that the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof can inhibit coronavirus infection of host cells and coronavirus replication, and can be used to treat diseases caused by coronavirus infection, demonstrating great significance for the prevention, management, and treatment of coronavirus infection, particularly that caused by the coronavirus SARS-CoV-2.

[0013] To solve the above-mentioned technical problems, a first aspect of the present invention provides the application of a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof to the preparation of an antiviral agent or a pharmaceutical for the treatment of a disease caused by a virus, wherein the virus is a β-coronavirus.

[0014] In this invention, SARS-related coronavirus is a coronavirus that causes severe acute respiratory syndrome (SARS). The disease caused by SARS-related coronavirus is a symptom or illness of viral infection, the initial stage of which is mainly seen as a respiratory illness, and clinical findings include fever, fatigue, dry cough, cough, increased respiratory rate or acute respiratory distress syndrome, shortness of breath, and in a small number of patients, symptoms such as nasal congestion, runny nose, and sore throat. Imaging findings include varying degrees of changes in the lungs, such as multiple spotted and ground-glass opacities. The virus is transmitted mainly by contact with droplets at close range or respiratory secretions of a patient. Gastrointestinal symptoms such as diarrhea and acute gastroenteritis in infants and neonates, and in rare cases neurological syndromes may also occur. In the later stages, many complications can occur, ranging from difficult-to-treat metabolic acidosis and coagulation disorders, respiratory failure, and fulminant myocarditis to multiple organ failure such as heart failure, liver failure, kidney failure, and septic shock. Severely ill patients often develop dyspnea and / or hypoxemia within one week of symptom onset, and in severe cases, the condition rapidly progresses to acute respiratory distress syndrome, septic shock, incurable metabolic acidosis and coagulation disorders, and multiple organ failure. All of these diseases are expected to be treatable with the PARP inhibitor of the present invention. In addition, some virus carriers do not have the above symptoms, but even so, they may be administered the PARP inhibitor of the present invention to inhibit viral replication and spread in order to prevent them from becoming ill or spreading the virus and creating new patient cases. In one embodiment, the virus of the β-coronavirus genus is a virus that causes acute respiratory syndromes, such as SARS-related coronavirus, and preferably, the SARS-related coronavirus is SARS-CoV (severe acute respiratory syndrome coronavirus) and / or SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2).

[0015] In one embodiment, the poly-ADP-ribose polymerase inhibitor is an inhibitor of PARP 1 and / or PARP 2.

[0016] In one embodiment, the polyADP-ribose polymerase inhibitor is substance A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0017] Substance A is selected from the group consisting of one or more of the following: talazoparib, fluzoparib, simmiparib, IMP4297, BGB-290, ABT-888, the PARP inhibitors described in CN1342161A, the PARP inhibitors described in CN1788000A, the PARP inhibitors described in CN103242273A, the PARP inhibitors described in CN101415686A, and the PARP inhibitors described in CN101578279A. These are merely examples as provided herein and do not preclude the possibility that Substance A may be selected from other compounds not listed herein. [ka]

[0018] In this invention, "one or more selected from..." includes situations in which the listed compounds are used in combination. In some embodiments of this invention, the therapeutic effect is better when two or more compounds are used in combination.

[0019] In one embodiment, the PARP inhibitor described in CN1342161A is a compound represented by formula I, [ka] In the formula, R 11 However, H, halogen, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, 3-6 membered heterocycloalkyl, C6-C, containing "one or more heteroatoms selected from O, N, and S" 10 Aryl, containing one or two heteroatoms selected from one or more heteroatoms O, N, and S, 5-10 membered heteroaryl, one or more R 11-1 C1-C4 alkyl substituted by, one or more R 11-1C2-C4 alkenyl substituted by, one or more R 11-1 C2-C4 alkynyl substituted by, one or more R 11-1 C3-C4 cycloalkyl substituted by, 3-6 membered heterocycloalkyl containing "1-2 heteroatoms selected from one or more of the 1-2 heteroatoms O, N, and S", one or more R 11-1 C6-C substituted by 10 aryl ("C6-C 10 aryl" is, for example,

Chemical Structure

[0020] In one embodiment, the PARP inhibitor described in CN1788000A is a compound shown in formula II, [ka] In the formula, X 2 , Y 2 , and the carbon atoms connected to them, together form C6-C 10 Aryl (e.g., phenyl), or one or more R X2-1 C6-C substituted by 10 Forming an aryl group, R X2-1 However, independently, halogen, nitro, hydroxyl, sulfhydryl, amino, C1-C7 alkyl, C6-C 20 Aryl, 3-20 membered heterocyclyl, containing 1-6 heteroatoms selected from one or more of O, N, and S, -OR X2-1-1 , or -SR X2-1-2 And, R X2-1-1 and R X2-1-2 However, independently, C1-C7 alkyl, C6-C 20 An aryl, or a 3-20 membered heterocycline containing 1-6 heteroatoms selected from one or more of O, N, and S, R 21 However, it is H or a halogen (for example, fluorine, chlorine, or bromine), Z, -NR Z-1 - or -CR Z-2 R Z-3 -and, When Z is -NR Z-1 -, m is 1 or 2, and when Z is -CR Z-2 R Z-3 -, m is 1, R Z-1 and R Z-2 are, independently, C1-C 20 alkyl, C6-C 20 aryl, 3- to 20-membered heterocyclyl containing "1 to 6 heteroatoms selected from one or more of O, N, and S", -C(=O)NR Z-1-1 R Z-1-2 , -C(=O)R Z-1-3 [[ID=2"](for example,

Chemical Structure

[0021] In one embodiment, the PARP inhibitor described in CN103242273A is a compound represented by formula III, [ka] R 31 and R 32 However, independently, they are hydrogen, C1-C4 alkyl (e.g., methyl), C3-C4 cycloalkyl, or a 5- or 6-membered heterocycloalkyl "containing one to three heteroatoms selected from one or more of O and N", Alternatively, R 31 , R 32 , and the N atoms connected thereto together form a 5-6 membered heterocycloalkyl group containing "one or more heteroatoms selected from O, N, and S", or one or more R 31-1 A 5-6 membered heterocycloalkyl group is formed by substituted by "containing 1-3 heteroatoms selected from one or more of O, N, and S", R 31-1 However, it is a C1-C4 alkyl group (for example, methyl) on N, X 3 However, it is CH, CF, or N, Y 3 However, it is CH, CF, or N, R 33 However, it is either H or Cl, R 34 However, it is either H or F.

[0022] In one embodiment, the PARP inhibitor described in CN101415686A is a compound represented by formula IV, [ka] fm is 0, 1, 2, or 3. R 41 However, independently, hydroxyl, halogen (e.g., fluorine), cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl or C halogenated 1-6 It is an alkoxy, A 4 However, it is CH or N, fn is 0, 1, 2, 3, 4, 5, or 6, Y 4 However, single bond, C 3-5 Cycloalkyl, a 4-membered saturated heterocycle containing one N atom, a 5, 6, or 7-membered saturated or partially saturated heterocycle containing one, two, or three heteroatoms independently selected from N, O, and S, a 5-membered unsaturated heterocycle containing one, two, three, or four heteroatoms independently selected from O, N, and S, but with only one being O or S, a 6-membered unsaturated heterocycle containing one, two, or three nitrogen atoms, "6-13 membered saturated, partially saturated, or unsaturated hydrocarbon rings" (e.g., C6-C 10 An aryl (or, for example, phenyl), or "an 8-13 member unsaturated or partially saturated heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S," z is 1, 2, or 3, fp is 0, 1, 2, 3, 4, 5, or 6. R 46 and R 47 However, independently, hydrogen or C 1-6 It is alkyl, q is 0 or 1, t is 0 or 1, R 42 However, hydrogen, C 1-6Alkyl, or C 3-10 It is a cycloalkyl, v is 0 or 1, X 4 However, C or S = O, w is 0 or 1, x is 0, 1, 2, 3, 4, 5, or 6, R 48 and R 49 However, independently, hydrogen, C 1-6 Alkyl, hydroxy, halo C 1-6 Alkyl, Hydroxyl C 1-6 Alkyl, amino, C 1-6 Alkylamino, or di(C) 1-6 It is an alkyl(amino) amino, a is 0 or 1, y is 0 or 1, R 43 However, hydrogen or C 1-6 It is alkyl, R 44 However, hydrogen, hydroxyl, cyano, halogen (e.g., fluorine, chlorine, or bromine), C 1-6 Alkyl, C 2-10 Alkenil, Halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, carboxyl, nitro, R 44-1 , or one or more -(CH2) b R 44-2 R replaced by 44-3 And, R 44-1 and R 44-3 However, independently, C 6-10 Ariel, C 6-10 Aryloxy, C 6-10 Arylcarbonyl, C 3-10 Cycloalkyl, a 4-membered saturated heterocycle containing one N atom, a 5- or 6-membered saturated or partially saturated heterocycle containing one, two, or three atoms independently selected from N, O, and S (for example, [ka] ), "a five-membered aromatic heterocycle containing one, two, three, or four heteroatoms independently selected from O, N, and S, but with only one being either O or S", "a six-membered aromatic heterocycle containing one, two, or three nitrogen atoms", or "an unsaturated, partially saturated, or saturated heterocycle of 7 to 15 members containing one, two, three, or four heteroatoms independently selected from N, O, and S", b is independently 0, 1, 2, 3, 4, 5, or 6. R 44-2 However, independently, hydroxy, oxo, cyano, halogen, and C 1-6 Alkyl, C 2-10 Alkenil, Halo C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxycarbonyl, carboxyl, -NR a R b -C(=O)NR a R b , S(=O) fr R e , R 44-2-1 , or one or more R 44-2-2 R replaced by 44-2-3 And, R a and R b However, independently, hydrogen, C 1-6 Alkyl, C 1-6 Alkylcarbonyl, Halo C 1-6 Alkyl, Hydroxyl C 1-6 Alkyl, S(O) sr R c , or S(O) tr N(R d )2, sr and tr are independently 0, 1, or 2. R c However, C 1-6 Alkyl, R c-1 , or one or more R c-2R replaced by c-3 And, R c-1 and R c-3 However, independently, C 6-10 An aryl is a "5-membered aromatic heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with only one being O or S," a "6-membered aromatic heterocycle containing 1, 2, or 3 nitrogen atoms," or a "7-10 membered unsaturated or partially saturated heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S." R c-2 However, independently, hydroxy, cyano, halogen, C 1-6 Alkyl, C 2-10 Alkenyl, or Halo C 1-6 It is alkyl, R d However, independently, hydrogen or C 1-6 Is it alkyl? Alternatively, R a , R b , and the N atoms connected to them, together form R a-1 , or one or more R a-2 R replaced by a-3 Forming, R a-1 and R a-3 However, independently, they are either "a 4-membered saturated heterocycle containing one N atom" or "a 5, 6, or 7-membered saturated or partially saturated heterocycle containing 1, 2, or 3 N atoms and 0 or 1 O atom," R a-2 However, independently, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenyl, or Halo C 1-6 It is alkyl, fr is 0, 1, or 2, R e However, C 1-6 Alkyl, R e-1 , or one or more R e-2 R replaced by e-3 And, Re-1 and R e-3 However, independently, C 6-10 Aryl, a five-membered aromatic heterocycle containing one, two, three, or four heteroatoms independently selected from N, O, and S, with only one of them being either O or S, a six-membered aromatic heterocycle containing one, two, or three nitrogen atoms, or a seven- to ten-membered unsaturated or partially saturated heterocycle containing one, two, three, or four heteroatoms independently selected from N, O, and S, R e-2 However, independently, hydroxy, cyano, halogen, C 1-6 Alkyl, C 2-10 Alkenyl, or Halo C 1-6 It is alkyl, R 44-2-1 and R 44-2-3 However, independently, C 6-10 Ariel, C 6-10 Aryl C 1-6 Alkyl, "a 4-membered saturated heterocycle containing one N atom", "a 5, 6, or 7-membered saturated or partially saturated heterocycle containing one, two, or three atoms independently selected from N, O, and S", "a 5-membered aromatic heterocycle containing one, two, three, or four heteroatoms independently selected from O, N, and S, with only one of them being O or S", "a 6-membered heterocycle containing one, two, or three nitrogen atoms", or "a 7- to 10-membered unsaturated or partially saturated heterocycle containing one, two, three, or four heteroatoms independently selected from N, O, and S", R 44-2-2 However, independently, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Alkenil, Halo C 1-6 Alkyl, amino, C 1-6 Alkylamino and di(C) 1-6 The application described in claim 1 is an alkyl(amino) amino.

[0023] In one embodiment, the compound represented by formula I is In the formula, R 11 However, one or more R 11-1C6-C substituted by 10 Ariel ("C6-C 10 "aryl" is, for example, phenyl, and "one or more R 11-1 C6-C substituted by 10 "Aryl" is, for example, [ka] (is) and R 11-1 However, independently, halogen, hydroxyl, carboxyl, nitro, amino, C1-C4 alkyl, or one or more NR 11-1-1 R 11-1-2 A C1-C4 alkyl group substituted by (where "C1-C4 alkyl" is, for example, methyl), R 11-1-1 and R 11-1-2 However, independently, they are hydrogen or C1-C4 alkyl (e.g., methyl), Y 1 However, -(CR Y1-1 R Y1-2 )(CR Y1-3 R Y1-4 ) n -and, n is 0 or 1, R Y1-1 and R Y1-2 However, independently, they are H or C1-C4 alkyl, R Y1-3 and R Y1-4 However, independently, they are H or C1-C4 alkyl, R 12 However, it is H or C1-C4 alkyl, X 1 However, it is either O or S, R 14 However, it is H or a halogen (for example, fluorine, chlorine, or bromine), R 13 However, it has the definition that it is H or C1-C4 alkyl.

[0024] In one embodiment, the compound represented by formula II is X 2 , Y 2, and the carbon atoms connected to them, together form C6-C 10 Aryl (e.g., phenyl), or one or more R X2-1 C6-C substituted by 10 Forming an aryl group, R X2-1 However, independently, halogen, nitro, hydroxyl, sulfhydryl, amino, C1-C7 alkyl, C6-C 20 Aryl, 3-20 membered heterocyclyl, containing 1-6 heteroatoms selected from one or more of O, N, and S, -OR X2-1-1 , or -SR X2-1-2 And, R X2-1-1 and R X2-1-2 However, independently, C1-C7 alkyl, C6-C 20 An aryl, or a 3-20 membered heterocycline containing 1-6 heteroatoms selected from one or more of O, N, and S, R 21 However, it is H or a halogen (for example, fluorine, chlorine, or bromine), Z, -NR Z-1 - and m is 1 or 2, R Z-1 However, independently, -C(=O)NR Z-1-1 R Z-1-2 -C(=O)R Z-1-3 (for example, [ka] ), -C(=O)OR Z-1-4 -C(=S)NR Z-1-5 R Z-1-6 , or -S(=O)2R Z-1-7 And, R Z-1-1 , R Z-1-2 , R Z-1-3 , R Z-1-4 , R Z-1-5 , R Z-1-6 , and R Z-1-7 However, independently, hydrogen, C1-C7 alkyl, C6-C 20An aryl, or a 3-20 membered heterocycline containing 1-6 heteroatoms selected from one or more of O, N, and S, Alternatively, R Z-1-1 , R Z-1-2 , and the carbon atoms connected to them together form a 4-8 membered heterocycline containing "one or more heteroatoms selected from one or more of O, N, and S", Alternatively, R Z-1-5 , R Z-1-6 , and the carbon atoms connected to them together form a 4-8 membered heterocycline containing "one or more heteroatoms selected from one or more of O, N, and S". R 22 and R 23 Both have the definition that they are hydrogen.

[0025] In one embodiment, the compound represented by formula III is R 31 However, the active ingredient is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, piperidine-4-yl, or (R)-tetrahydrofuran-3-yl. R 32 However, the active ingredient is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, piperidine-4-yl, or (R)-tetrahydrofuran-3-yl. Alternatively, R 31 , R 32 , and the N atoms connected to them together form unsubstituted or substituted morpholinyl, piperadinyl, homopiperazinyl, thiomorpholinyl, piperidinyl, or tetrahydropyrrolyl, where substitution means substitution of N by methyl, X 3 However, it is CH, CF, or N, Y 3 However, it is CH, CF, or N, R 33 However, H is, R 34 However, it has the definition that F.

[0026] In one embodiment, the compound represented by formula III is R 31 However, it is hydrogen or methyl, R 32 However, it is methyl, isopropyl, cyclopropyl, piperidine-4-yl, or (R)-tetrahydrofuran-3-yl, Alternatively, R 31 , R 32 , and the N atoms connected to them together form unsubstituted or substituted morpholinyl, piperadinyl, homopiperazinyl, thiomorpholinyl, piperidinyl, or tetrahydropyrrolyl, where substitution means substitution of N by methyl, X 3 However, it is CH, CF, or N, Y 3 However, it is CH, CF, or N, R 33 However, H is, R 34 However, it has the definition that F.

[0027] In one embodiment, the compound represented by formula IV is fm is 0, 1, 2, or 3. R 41 However, independently, hydroxy, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl or C halogenated 1-6 It is an alkoxy, A 4 However, it is CH or N, fn is 0, Y 4 However, a saturated or partially saturated heterocycle of 5, 6, or 7 members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; an unsaturated heterocycle of 5 members containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, but with only one being O or S; an unsaturated heterocycle of 6 members containing 1, 2, or 3 nitrogen atoms; a saturated, partially saturated, or unsaturated hydrocarbon ring of 6 to 13 members (e.g., C6-C 10An aryl (or, for example, phenyl), or "an 8-13 member unsaturated or partially saturated heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S," z is 1 or 2, fp is 0, q is 0, t is 0, v is 0, w is 0, x is 0, a is 0, y is 0, R 44 However, halogen or R 44-1 And, R 44-1 However, C 3-10 Cycloalkyl, a 4-membered saturated heterocycle containing one N atom, a 5- or 6-membered saturated or partially saturated heterocycle containing one, two, or three atoms independently selected from N, O, and S (for example, [ka] ), or it has the definition of "an unsaturated, partially saturated, or saturated heterocycle with 7 to 15 members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S."

[0028] In one embodiment, the compound represented by formula IV is [ka] fm is 0 or 1, R 41 However, it is a halogen (for example, fluorine), R 44 However, it has the definition that it is hydrogen or a halogen (for example, fluorine).

[0029] In one embodiment, the compound represented by formula IV is one of the following compounds. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0030] In one embodiment, the compound represented by formula II is one of the following compounds. [ka] [ka] [ka] [Table 1] [ka] [Table 2] [ka] [Table 3-1] Table 3-2

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[0031] In one embodiment, the compound shown in formula III is one of the following compounds. [Table 12]

[0032] In one embodiment, the compound represented by formula IV is any of the following compounds: 2-phenyl-2H-indazole-7-carboxamide; 2-(3-chlorophenyl)-2H-indazole-7-carboxamide; and 2-{4-[(dimethylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(N,N-dimethylglycyl)amino]phenyl}-2H-indazole-7-carboxamide; 2-benzyl-2H-indazole-7-carboxamide; 2-(4-chlorophenyl)-2H-indazole-7-carboxamide; 2-(2-chlorophenyl)-2H-indazole Indazole-7-carboxamide; 2-{4-[(4-methylpiperazine-1-yl)methyl]phenyl}-2H-indazole-7-carboxamide; 2-[4-(morpholine-4-ylmethyl)phenyl]-2H-indazole-7-carboxamide; 2-{4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 2-[4-(pyrrolidine-1-ylmethyl)phenyl]-2H-indazole-7-carboxamide; 2-[4-(piperidine-1-ylmethyl)phenyl]-2H-indazole-7 -Carboxamide;{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N,N-dimethylmethaneammonium chloride;4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)methyl]pyridinium trifluoroacetate;2-{4-[1-(methylamino)ethyl]phenyl}-2H-indazole-7-carboxamide;N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}cyclohexane trifluoroacetate;{4-[ 7-(aminocarbonyl)-4-chloro-2H-indazole-2-yl]phenyl}-N-trifluoroacetate methylmethaneammonium; 2-phenyl-2H-1,2,3-benzotriazole-4-carboxamide; 2-benzyl-2H-1,2,3-benzotriazole-4-carboxamide; 2-{3-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 4-({3-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)trifluoroacetate piperidinium;{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-methylmethaneammonium chloride; 2-{3-chloro-4-[(dimethylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 1-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)-2-oxoethyl]-4-methylpiperazine-1-trifluoroacetate onium; 2-(4-{[(4-pyrrolidine-1-ylpiperidine-1-yl)acetyl]amino}phenyl)-2H-indazole- 7-Carboxamide; 2-{4-[(pyrrolidine-1-ylacetyl)amino]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(piperidine-1-ylacetyl)amino]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(morpholine-4-ylacetyl)amino]phenyl}-2H-indazole-7-carboxamide; 4-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)-2-oxoethyl]morpholine-4-onium chloride; 2-{4-[(E [(Isopropylamino)methyl]phenyl]-2H-indazole-7-carboxamide; 2-{4-[(Isopropylamino)methyl]phenyl}-2H-indazole-7-carboxamide; N-{4-[7-(Aminocarbonyl)-2H-indazole-2-yl]benzyl}propane-2-ammonium chloride; 2-(4-{[(2-fluoroethyl)amino]methyl}phenyl)-2H-indazole-7-carboxamide; 2-(4-{[(2,2-difluoroethyl)amino]methyl}phenyl)-2H-indazole-7-carboxamide; 2 -{4-[(cyclopropylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 4-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}-1,4-diazabicycloheptan-1-onium; 2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)-N,N-dimethylethaneammonium trifluoroacetate; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)methyl]piperidinium trifluoroacetate;N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-N,N',N'-trimethylethane-1,2-diammonium dichloride; 4-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}-1-methylpiperazine-1-trifluoroacetate onium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]trifluoroacetate azacyclobutanium; (2S)-2-[({4-[7-(aminocarbonyl)-2H-indazole [-2-yl]phenyl}amino)carbonyl]-1-trifluoroacetate methylpyrrolidinium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoroacetate methylpiperidinium; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoroacetate methylpiperidinium; 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)-1-trifluoroacetate Indylpiperidinium; 2-{4-[(pyridine-4-ylamino)carbonyl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(4-phenylpiperazine-1-yl)carbonyl]phenyl}-2H-indazole-7-carboxamide; 2-(4-{[methyl(quinoxaline-6-ylmethyl)amino]carbonyl}phenyl)-2H-indazole-7-carboxamide; 2-(4-formylphenyl)-2H-indazole-7-carboxamide; 1-[2-({4-[7-(aminocarbonyl)-2H-indazole [Ir-2-yl]benzoyl}amino)ethyl]pyrrolidinium trifluoroacetate; 1-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)ethyl]piperidinium trifluoroacetate; 4-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)ethyl]morpholine-4-trifluoroacetate onium; 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzoyl}amino)-1-trifluoroacetate methylpiperidinium;2-[4-[(4-methylpiperazine-1-yl)methyl]-3-(trifluoromethyl)phenyl]-2H-indazole-7-carboxamide; 2-[4-[(methylamino)methyl]-3-(trifluoromethyl)phenyl]-2H-indazole-7-carboxamide; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-methylethaneammonium chloride; 2-[4-(pyrrolidine-1-ylmethyl)-3-(trifluoromethyl)phenyl]-2H-indazole-7-carboxamide Luboxamide; 2-[4-(piperidine-1-ylmethyl)-3-(trifluoromethyl)phenyl]-2H-indazole-7-carboxamide; 2-[4-[(ethylamino)methyl]-3-(trifluoromethyl)phenyl]-2H-indazole-7-carboxamide; 4-{4-[7-(aminocarbonyl)-4-chloro-2H-indazole-2-yl]benzyl}-1-methylpiperazine-1-trifluoroacetate onium; 1-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl [Zyl Ammonio)ethyl]bis(trifluoroacetic acid)piperidinium; 4-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)ethyl]morpholine-4-bis(trifluoroacetic acid)onium; bis(trifluoroacetic acid)1-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)ethyl]pyrrolidinium; 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-1-bis( Methylpiperidinium (trifluoroacetic acid); 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-1-bis(trifluoroacetic acid)benzylpiperidinium; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-bis(trifluoroacetic acid)benzylpiperidinium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-(dimethylamino)-2-oxoethylalkyltrifluoroacetate ammonium;2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]bis(trifluoroacetic acid)pyridinium; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]bis(trifluoroacetic acid)pyridinium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-methylpropane-2-trifluoroacetate ammonium; N'-{4-[7-(aminocarbonyl)-2H-indazole {-2-yl]benzyl}-N,N-dimethylethane-1,2-bis(trifluoroacetic acid)diammonium; {4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-(1,3-oxazole-2-ylmethyl)methaneammoniumtrifluoroacetic acid; 7-[7-(aminocarbonyl)-2H-indazole-2-yl]-1,2,3,4-tetrahydroisoquinolinium chloride; 6-[7-(aminocarbonyl)-2H-indazole-2-yl]-1,2,3,4-tetrahydroisoquinolinium Umum chloride; 5-[7-(aminocarbonyl)-2H-indazole-2-yl]-1,2,3,4-Tetrahydroisoquinolinium trifluoroacetate; 3-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}amino)carbonyl]azacyclobutanium trifluoroacetate; 2-(4-{[(azetidine-3-ylcarbonyl)(methyl)amino]methyl}phenyl)-2H-indazole-7-carboxamide; 3-[({4-[7-(aminocarbonyl)-2H-indazole Azacyclobutanium 2-(4-bromophenyl)-5-fluoro-2H-indazole-7-carboxamide; 5-fluoro-2-(4-pyridine-3-ylphenyl)-2H-indazole-7-carboxamide; 2-(4-pyridine-3-ylphenyl)-2H-indazole-7-carboxamide; 4-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-1-methylpiperazine-1-trifluoroacetate onium;4-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}trifluoroacetate piperidinium; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-trifluoroacetate methylethaneammonium; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]trifluoroacetate azacyclobutanium; 2-{5-[(methylamino)methyl]pyridine-2-yl}-2H-indazole-7-carboxamide; 5-fluoro-2-{3-fluoro-4-[(methylamino)methyl]phenyl}-2H-indazole-7-carbo; Xamide; 5-Fluoro-2-{4-[(methylamino)methyl]phenyl}-2H-indazole-7-trifluoroacetate carboxamide; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-methylpropane-2-trifluoroacetate ammonium; 2-(6-phenylpyridazin-3-yl)-2H-indazole-7-carboxamide; {4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}-N-{[1-(hydroxylmethyl) Cyclohexyl]methyl}trifluoroacetate methaneammonium; 5-chloro-2-(4-formylphenyl)-2H-indazole-7-carboxamide; 2-{3-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl}-2H-indazole-7-carboxamide; 2-{3-methoxy-4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 5-chloro-2-{4-[(4-methylpiperazine-1-yl)methyl]phenyl}-2H-indazole-7-carboxamide Ruboxamide; 5-Chloro-2-{4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; {4-[7-(aminocarbonyl)-4-fluoro-2H-indazole-2-yl]phenyl}-N-methylmethaneammonium chloride; {4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}-N-methylmethaneammonium chloride; 1-{4-[7-(aminocarbonyl)-4-fluoro-2H-indazole-2-yl]benzyl}-4- Methylpiperazine-1-onium chloride; 1-{4-[7-(aminocarbonyl)-5-lo-2H-indazole-2-yl]benzyl}-4-methylpiperazine-1-onium chloride; 1-{3-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-bis(trifluoroacetic acid)methylpiperazinium; 2-[4-(1-hydroxy-1-methylethyl)phenyl]-2H-indazole-7-carboxamide; 2-(4-acetylphenyl)-2H-indazole-7-carboxamide;3-{[{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}(methyl)amino]carbonyl}-1-methylpiperidinium trifluoroacetate; 2-{4-[1-(formylamino)-1-methylylethyl]phenyl}-2H-indazole-7-carboxamide; 2-[3-(1,4-diazabicycloheptan-1-ylcarbonyl)phenyl]-2H-indazole-7-carboxamide; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}amino)carbonyl]-1-tri Methylpiperidinium fluoroacetate; (2S)-2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]pyrrolidinium trifluoroacetate; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]pyrrolidinium trifluoroacetate; (2R)-2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]pyrrolidinium trifluoroacetate; 3-[({4-[7-(aminocarbonyl )-2H-indazole-2-yl]phenyl}amino)carbonyl]piperidinium trifluoroacetate; (3R)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylpyrrolidinium trifluoroacetate; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylpiperidinium trifluoroacetate; 4-chloro-2-(4-formylphenyl)-2H-indazole-7-carboxamide; (3S)-3- [({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylpyrrolidinium trifluoroacetate; (R)-1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-methylethaneammonium chloride; (S)-1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-methylethaneammonium chloride; 2-{3-fluoro-4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide;{4-[7-(aminocarbonyl)-2H-indazole-2-yl]-2-fluorophenyl}-N-trifluoroacetate methaneammonium; 2-{4-[1-methyl-1-(methylamino)ethyl]phenyl}-2H-indazole-7-carboxamide; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]-2-hydroxybenzyl}-4-methylpiperazine-1-trifluoroacetate onium; (3R)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}a [Mino)carbonyl]-1-methylpiperidinenium chloride; (3S)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylchloridepiperidinenium chloride; 1-(2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}ethyl)-4-bis(trifluoroacetic acid)methylpiperazinenium; {4-[7-(aminocarbonyl)-4-hydroxy-2H-indazole-2-yl]phenyl}-N-trifluoroacetic acid ammonia Phenyrmethane; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-4-Phenyrmyrrolidinium trifluoroacetate; (1R,3S)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]cyclopentanammonium trifluoroacetate; (1R,3R)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]cyclopentanammonium trifluoroacetate ammonium; (1S,3R)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]cyclopentanammonium trifluoroacetate; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-2-methylazetidinium trifluoroacetate; 4-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)-2-oxoethyl]-1-methylpiperidinium trifluoroacetate;9-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)-2-oxoethyl]-3-azaspiro[5.5]trifluoroacetate undecane;4-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)-2-oxoethyl]-4-phenylpiperidinium trifluoroacetate;2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]pyridinium trifluoroacetate;4-{3-[({4-[7-( [((aminocarbonyl)-2H-indazole-2-yl]phenyl]((aminocarbonyl)-2H-indazole-2-yl)aminocarbonyl)-2H-indazole-2-yl)((aminocarbonyl)-2H-indazole-2-yl)((aminocarbonyl)-2H-indazole-2-yl)((aminocarbonyl)-2H-indazole-2-yl)((aminocarbonyl)-2H-indazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2-yl)((aminocarbonyl)-2H-inazole-2- [Mino)carbonyl]trifluoroacetate quinolinium; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]trifluoroacetate isoquinolinium; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoroacetate methylazepanium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-2-methyl-1,2,3,4-trifluoroacetate tetrahydroxyl Soquinolinium; 2-{4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]piperidine-1-yl}pyrimidine-1-trifluoroacetate onium; 1-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]benzyl}-4-methylpiperazine-1-onium chloride; 5-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-3-oxosweinsonin-2-trifluoroacetate ammonium;2-{3-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]piperidine-1-yl}pyridinium trifluoroacetate; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-4-methylmorpholine-4-trifluoroacetate onium; (1R,4R)-N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-1'-(methylsulfonyl)-1',2'-dihydrospiro[cyclohexane-1,3'-yl [Ndol]-4-carboxamide; 1-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]octahydro-1H-trifluoroacetate isonidorium; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-4-benzylmorpholine-4-trifluoroacetate onium; (3S,4R)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-4-(methoxycarbonyl) Pyrrolidinium rifluoroacetate; 4-{(2S)-2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]pyrrolidinium-1-yl}bis(trifluoroacetate)piperidinium; (1S,3S)-3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]cyclopentanammonium trifluoroacetate; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoro Methylpyrrolidinium acetate; 2-{4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]piperidine-1-yl}pyrimidine-1-trifluoroacetate onium; 2-(1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}pyrrolidinium-3-yl)bis(trifluoroacetate)pyridinium; 3-(1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}pyrrolidinium-3-yl)bis(trifluoroacetate)pyridinium;(3S,4S)-1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-3,4-trifluoroacetate difluoropyrrolidinium;3-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-6-amino-3-azabicyclo[3.1.0]hexanebis(trifluoroacetate);2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-7-methyl-2,7-bis(trifluoroacetate)diazonium heterospiro[4.4]nonane;1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl; }-3-[4-(dimethylammonio)phenyl]bis(trifluoroacetic acid)pyrrolidinium;5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-1-methyl-1,2,4,5,6,6a-hexahydropyrrolo[3,4-b]bis(trifluoroacetic acid)pyrrolidinium;3-{[{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}(methyl)amino]methyl}-1-bis(trifluoroacetic acid)methylpiperidinium;(1R,4S)-5 -{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-oxa-5-azoniabicyclo[2.2.1]trifluoroacetate heptane;N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-hydroxy-2-methylpropane-1-trifluoroacetate ammonium;N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-3,3-trifluoroacetate difluorocyclobutanammonium;4-{4-[7 -(aminocarbonyl)-2H-indazole-2-yl]benzyl}-6-fluoro-1,4-diazabicycloheptane-1-trifluoroacetate onium;1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-pyrimidine-1-onium-2-yl-1,4-diazabicycloheptane-1-bis(trifluoroacetate)onium;3-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-1-bis(trifluoroacetate) Benzylpyrrolidinium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]-1-bis(trifluoroacetic acid)methylpyrrolidinium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]-1-bis(trifluoroacetic acid)benzylpyrrolidinium; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-7-benzyl-2,7-diazaspiro[4.4] bis(trifluoroacetic acid) nonane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl] benzyl}-8-benzyl-2,8-bis(trifluoroacetic acid) diazonium heterospiro[5.5] undecane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl] benzyl}-2,6-bis(trifluoroacetic acid) diazonium heterospiro[3.3] heptane; 7-{4-[7-(aminocarbonyl)-2H-indazole-2-yl] benzyl}-2,7-bis(trifluoroacetic acid) dia Zonium heterospiro[3.5]nonane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2,6-bis(trifluoroacetic acid)diazonium heterospiro[3.5]nonane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2,8-bis(trifluoroacetic acid)diazonium heterospiro[5.5]undecane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2,8-bis(trifluoroacetic acid)diazonium hetero Spiro[4.5]decane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2,7-bis(trifluoroacetic acid)diazonium heterospiro[4.5]decane; 8-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2,8-bis(trifluoroacetic acid)diazonium heterospiro[4.5]decane; 3-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-3,9-bis(trifluoroacetic acid)diazonium heterospiro[5.5] Ndecane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}octahydropyrrolo[3,4-c]bis(trifluoroacetic acid)pyrrolidinium; 5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}octahydropyrrolo[3,4-b]bis(trifluoroacetic acid)pyrrolidinium; 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)octahydrocyclopentadieno[c]bis(trifluoroacetic acid)pyrrolidinium; N. 2-{4-[7-(amino)carbonyl)-2H-indazole-2-yl]benzyl}-N 1 ,N 1-Dimethyl-1-pyridine-2-ylethane-1,2-bis(trifluoroacetic acid)diammonium;7-(aminocarbonyl)-2-[4-({[2-(2,3-dihydro-1H-indole-1-yl)ethyl]ammonium}methyl)phenyl]2H-indazole-1-bis(trifluoroacetic acid)onium;(3S,4S)-1-[2-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]bendi [{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}amino)-1,3-benzothiazole-3-trifluoroacetate ionium; 1-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}amino)-8-bis(trifluoroacetate)diazonium heterospiro[4.5] Decane; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]-1-bis(trifluoroacetate)methylpiperidinium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-hydroxyethaneammonium trifluoroacetate; 7-[7-(aminocarbonyl)-2H-indazole-2-yl]-1,2,3,4-tetrahydroisoquinolinium trifluoroacetate; 3-[2-({4-[7-(aminocarbonyl)-2H-indazole-2 Azacyclobutanium [-yl]phenyl}amino)-2-oxoethyl]trifluoroacetate; 4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)bis(trifluoroacetate)piperidinium; (3R,4R)-4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-3-bis(trifluoroacetate)fluoropiperidinium; (3S,4R)-4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-3- Benzyl-1-bis(trifluoroacetic acid)methylpiperidinium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-1-isobutylpiperidine-4-trifluoroacetate ammonium; 2-[4-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonium)piperidine-1-yl]-3-bis(trifluoroacetic acid)methylpyridinium; 3-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonium)bis(trifluoroacetic acid) Lysinium; 3-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-1-bis(trifluoroacetic acid)benzylpiperidinium; 5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-5-aza-2-trifluoroacetate azonium heterobicyclo[2.2.2]octane; (1S,4S)-2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-5-methyl-2,5-bis(trifluoroacetic acid)diazonium heterobicyclo[2.2.1]heptane; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-(pyridine-2-ylmethyl base)bis(trifluoroacetate)diniumpiperazine; 5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-benzyl-5-aza-2-trifluoroacetate azonium heterobicyclo[2.2.2]octane; trifluoroacetate 8-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-3-benzyl-8-aza-3-azonium heterobicyclo[3 .2.1] Octane; (1S,4S)-5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-benzyl-5-aza-2-trifluoroacetate azonium heterobicyclo[2.2.1]heptane; 3-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)bis(trifluoroacetate)pyrrolidinium; 6-({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)-3-bis(trifluoroacetate)diazonium heterobicyclo[3.1.[0]Hexane; (3S,4S)-N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-hydroxytetrahydrothiophene-3-trifluoroacetate ammonium 1,1-Dioxide; 4-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}ammonio)methyl]-4-hydroxy-1-bis(trifluoroacetic acid)methylpiperidinium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-1-cyclopropyl-2-trifluoroacetic acid hydroxyethaneammonium; {4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-{[1-(hydroxymethyl)cyclopentyl]methyl}trifluoroacetic acid methane; 2-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-1,2,3,4-tetrahydro-2,7-bis(trifluoroacetic acid)diazanaphthalene; 1-{4-[7-(aminocarbonyl)-2H-indazole-2 -yl]benzyl}-3-[(dimethylammonio)methyl]bis(trifluoroacetic acid)piperidinium;4-(1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}piperidinium-4-yl)thiomorpholin-4-bis(trifluoroacetic acid)onium;1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-[(methylsulfonyl)amino]trifluoroacetic acid piperidinium;1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-(1H-imidazole-3-onium-1-ylmethyl)bis(trifluoroacetic acid)piperidinium;7-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-1-oxa-7-trifluoroacetic acid adiene hespiro[4.5] Decane; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-(1-hydroxy-1-methylethyl)trifluoroacetate piperidinium; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoroacetate benzylpiperidinium; 2-[({4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-trifluoroethyl piperidinium; 3-[({4-[7-(aminocarbonyl)-2H-indazole-2 [-yl]phenyl}amino)carbonyl]-1-trifluoroethyl piperidinium; 2-[3-(1,4-diazabicycloheptan-1-ylcarbonyl)-4-fluorophenyl]-2H-indazole-7-trifluoroacetate carboxamide; {4-[7-(aminocarbonyl)-4-chloro-2H-indazole-2-yl]benzyl}methylcarbamate tert-butyl ester; 6-[7-(aminocarbonyl)-2H-indazole-2-yl]-1,2,3,4-trifluoroacetate tetrahydroisoquinolinium; 2-{4-[7-(aminocarbonyl). -2H-indazole-2-yl]phenyl}trifluoroacetate pyrrolidinium; 6-fluoro-2-{4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 5-fluoro-2-{2-fluoro-4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide; 2-{3-hydroxy-4-[(methylamino)methyl]phenyl}-2H-indazole-7-trifluoroacetate carboxamide; 2-(4-{[formyl(methyl)amino]methyl}-3-hydroxyphenyl)-2H-in Dazole-7-carboxamide; 2-{2-chloro-4-[(methylamino)methyl]benzeneyl}-5-fluoro-2H-indazole-7-carboxamide; 5-fluoro-2-{3-fluoro-4-[(methylamino)methyl]phenyl}-2H-indazole-7-trifluoroacetate carboxamide; 2-{2,5-difluoro-4-[(methylamino)methyl]phenyl}-5-fluoro-2H-indazole-7-trifluoroacetate carboxamide; 2-(4-bromophenyl)-2H-indazole-7-carboxamide; (3R)-3- [({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylpiperidinium chloride; (3R)-3-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methylpiperidinium trifluoroacetate; 2-(1,2,3,4-tetrahydroisoquinoline-7-yl)-2H-indazole-7-carboxamide; (R)-2-[4-({3-[(dimethylamino)methyl]piperidine-1-yl}methyl )phenyl]-2H-indazole-7-carboxamide; (S)-2-[4-({3-[(dimethylamino)methyl]piperidine-1-yl}methyl)phenyl]-2H-indazole-7-carboxamide; 3-({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}amino)-2-(chloromethyl)-3-oxopropane-1-trifluoroacetate ammonium; 5-fluoro-2-{3-fluoro-4-[(methylamino)methyl]phenyl}-2H-indazole-7-carboxamide hydrochloride;2-{4-[(dimethylamino)methyl]-3-fluorophenyl}-5-fluoro-2H-indazole-7-trifluoroacetate carboxamide; 2-{4-[(azacyclobutan-3-ylcarbonyl)amino]phenyl}-5-fluoro-2H-indazole-7-carboxamide; 2-[4-(2,7-diazaspiro[4.5]deca-2-ylmethyl)phenyl]-2H-indazole-7-carboxamide; (1S,4S)-5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2- (4-chlorobenzyl)-5-aza-2-trifluoroacetate azonium heterobicyclo[2.2.1]heptane; (1S,4S)-5-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-(3-chlorobenzyl)-5-aza-2-trifluoroacetate azonium heterobicyclo[2.2.1]heptane; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-[(methylamino)carbonyl]piperazine-1-trifluoroacetate onium; N-{4-[7-( (aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-hydroxy-2-pyridine-3-trifluoroacetate ylethaneammonium; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-cyclohexyl-2-trifluoroacetate hydroxyethaneammonium; 4-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-trifluoroacetate onium; {4-[7-(aminocarbonyl) [Carbonyl)-2H-indazole-2-yl]phenyl}-N-{[1-(hydroxymethyl)cyclobutyl]methyl}methaneammonium trifluoroacetate; {4-[7-(aminocarbonyl)-2H-indazole-2-yl]phenyl}-N-{[1-(hydroxymethyl)cyclohexyl]methyl}methaneammonium trifluoroacetate; 1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-(5-methyl-1H-benzimidazole-2-yl)piperidinium trifluoroacetate;2-(1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-4-hydroxypiperidinium-4-yl)bis(trifluoroacetate)pyridinium;1-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-3,3-trifluoroacetate difluoropyrrolidinium;2-(4-{[(2R)-2-(fluoromethyl)pyrroridine-1-yl]methyl}phenyl)-2 H-Indazole-7-carboxamide; N-{4-[7-(aminocarbonyl)-2H-indazole-2-yl]benzyl}-2-oxopyrrolidine-3-ammonium trifluoroacetate; 5-Fluoro-2-(4-formylphenyl)-2H-indazole-7-carboxamide; 3-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}amino)carbonyl]-1-methyl Azacyclobutanium trifluoroacetate; 1-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]benzyl}-3-[(dimethylamino)methyl]bis(trifluoroacetate)piperidinium; 3-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-2-fluorophenyl}amino)carbonyl]azacyclobutanium trifluoroacetate; 2-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]benzyl}-2,7-bis(trifluoroacetate)diazonium heterospiro[4.5]decane; 4,5-difluoro-2-{4-[(methylamino)methyl]phenyl} -2H-indazole-7-trifluoroacetate carboxamide; 5-fluoro-2-(3-fluoro-4-{[(1-methylazetidine-3-yl)carbonyl]amino}phenyl)-2H-indazole-7-trifluoroacetate carboxamide; 5-fluoro-2-(3-fluoro-4-formylphenyl)-2H-indazole-7-carboxamide; 5-fluoro-2-(5-fluoro-2-formylphenyl)-2H-indazole-7-carboxamide; {4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-2-fluorophenyl}-N-{[1-(hydroxymethyl)cyclopentyl]methyl}trifluoroacetate ammonium;5-Fluoro-2-[3-Fluoro-4-({[(3R)-1-methylpiperidine-3-yl]carbonyl}amino)phenyl]-2H-indazole-7-trifluoroacetate carboxamide; 1-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-2-fluorobenzyl}-4-bis(trifluoroacetate)methylpiperazineium; 4-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]benzyl}ammonio)methyl]-1-bis(trifluoroacetate)methylpiperidineium; 4-[({4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-2-fluorobenzyl}ammonio)methyl]-1-bis(trifluoroacetate)methylpiperidineium; and its pharmaceutically acceptable salts or tautomers.

[0033] Other specific compounds within the scope of the present invention are, 7-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-methyl-1,2,3,4-trifluoroacetate tetrahydroisoquinolinium;3-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}-1-trifluoroethyl piperidinium;2-(4-cyanophenyl)-5-fluoro-2H-indazole-7-carboxamide;5-fluoro-2-[4-(1H-tetrazole-5-yl)phenyl]-2H-indazole-7-carboxamide;2-(4 -aminophenyl)-5-fluoro-2H-indazole-7-carboxamide hydrochloride; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]trifluoroacetate pyrrolidinium; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate methylpyrrolidinium; 3-[7-(aminocarbonyl) -5-Fluoro-2H-indazole-2-yl]-1-trifluoroethyl pyrrolidinium;3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate propylpyrrolidinium;3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate isopropylpyrrolidinium;3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate cyclohexylpyrrolidinium;3-[7 -(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate cyclobutylpyrrolidinium; 4-[7-(aminocarbonyl)-2H-indazole-2-yl]-4-methylpiperidine-1-carboxylic acid tert-butyl ester; 4-[7-(aminocarbonyl)-2H-indazole-2-yl]-4-trifluoroacetate methylpiperidinium; 2-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}trifluoroacetate pyrrolidinium;2-[4-(4,5-dihydro-1H-imidazole-2-yl)phenyl]-5-fluoro-2H-indazole-7-trifluoroacetate carboxamide; 6-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1,2,3,4-tetrahydroisoquinolinium chloride; 2-{4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]phenyl}piperidinium chloride; 5-fluoro-2-[4-(1H-pyrazole-1-yl)phenyl]-2H-indazole-7-carboxamide 5-Fluoro-2-(3-piperidine-3-ylphenyl)-2H-indazole-7-carboxamide; 2-[4-(aminosulfonyl)phenyl]-5-fluoro-2H-indazole-7-carboxamide; 5-Fluoro-2-(5,6,7,8-tetrahydro-1,7-naphthalene-3-yl)-2H-indazole-7-carboxamide; 5-Fluoro-2-(4-piperazine-2-ylphenyl)-2H-indazole-7-carboxamide; 4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]benzene Methyl formate; 5-fluoro-2-(1-methylpiperidine-3-yl)-2H-indazole-7-carboxamide; 5-fluoro-2-(1-ethylpiperidine-3-yl)-2H-indazole-7-carboxamide; 5-fluoro-2-(1-propylpiperidine-3-yl)-2H-indazole-7-carboxamide; 5-fluoro-2-(1-isopropylpiperidine-3-yl)-2H-indazole-7-carboxamide; 2-(1-cyclohexylpiperidine-3-yl)-5-fluoro-2H-indazole-7-carboxamide Mido; 5-Fluoro-2-(1-methylpiperidine-4-yl)-2H-indazole-7-carboxamide; 5-Fluoro-2-(1-ethylpiperidine-4-yl)-2H-indazole-7-carboxamide; 5-Fluoro-2-(1-propylpiperidine-4-yl)-2H-indazole-7-carboxamide; 5-Fluoro-2-(1-isopropylpiperidine-4-yl)-2H-indazole-7-carboxamide; 2-(1-cyclohexylpiperidine-4-yl)-5-Fluoro-2H-indazole-7-carboxamide;2-(1-cyclobutylpiperidine-4-yl)-5-fluoro-2H-indazole-7-carboxamide; 2-(1-cyclobutylpiperidine-3-yl)-2H-indazole-7-carboxamide; 2-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-N,N-trifluoroacetate dimethylethaneammonium; 2-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-N,N-trifluoroacetate diethylethaneammonium; N-{2-[7-(aminocarbonyl) [-5-fluoro-2H-indazole-2-yl]ethyl}propane-2-trifluoroacetate; N-{2-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]ethyl}cyclohexanetrifluoroacetate ammonium; 2-[2-(bicyclobutylamino)ethyl]-5-fluoro-2H-indazole-7-carboxamide; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]piperidine-1-carboxylic acid tert-butyl ester; 4-[7-(aminocarbonyl)-5 [7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]piperidine-1-carboxylic acid tert-butyl ester; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]trifluoroacetate piperidinium; 4-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]trifluoroacetate piperidinium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]piperidine-1-carboxylic acid tert-butyl ester; {2-[7-(aminocarbonyl)-5-fluoro-2H-yl Dazole-2-yl]ethyl}carboxylate tert-butyl ester; 2-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]trifluoroacetate ethaneammonium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]trifluoroacetate piperidinium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-trifluoroacetate methylpiperidinium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-trifluoroethyl piperidinium;3-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-trifluoroacetate propylpiperidinium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-trifluoroacetate isopropylpiperidinium; 3-[7-(aminocarbonyl)-2H-indazole-2-yl]-1-trifluoroacetate cyclohexylpiperidinium; 3-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]-1-trifluoroacetate cyclobutylpiperidinium; N-{2-[7-(aminocarbonyl)-5-fluoro-2H-indazole-2-yl]ethyl}-N-propylpropane-1-trifluoroacetate ammonium; 2-(4-piperidine-3-ylphenyl)-2H-indazole-7-carboxamide; 2-{4-[(3R)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(3S)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-Fluoro-2-(4-piperidine-3-ylphenyl)-2H-indazole-7-carboxamide; 5-Fluoro-2-{4-[(3S)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-Fluoro-2-{4-[(3R)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-Fluoro-2-(3-Fluoro-4-piperidine-3-ylphenyl)-2H-indazole-7-carboxamide; 5-Fluoro-2-{3-Fluoro-4-[(3R)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-Fluoro-2-(3-Fluoro-4-[(3S)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(3R)-piperidine-3-yl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide;

[0034] In one embodiment, the compound represented by Formula I is

Chem.

[0035] In one embodiment, the compound represented by Formula II is

Chem.

[0036] In one embodiment, the compound represented by Formula III is

Chem.

[0037] In one embodiment, the compound represented by Formula IV is

Chem.

[0038] In one embodiment, Substance A is niraparib, talazoparib, fluzoparib, simiparib, IMP4297, BGB-290, ABT-888, rucaparib, olaparib, and mefiparib;

Chem.

[0039] In one embodiment, the pharmaceutically acceptable salt is hydrochloride.

[0040] In one embodiment, the pharmaceutically acceptable salt of Substance A is

Chem.

[0041] In one embodiment, a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof exists in the form of a pharmaceutical composition containing it. Preferably, the pharmaceutical composition uses the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof as the sole active ingredient of the pharmaceutical composition, and / or the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable excipient.

[0042] In one embodiment, a polyADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof exists in the form of a kit composition comprising the same, the kit also comprising a drug for treating coronavirus-related illnesses and / or other virus-induced illnesses.

[0043] To solve the above technical problems, a second aspect of the present invention provides a compound represented by formula III and / or formula IV, or a pharmaceutically acceptable salt thereof, in the preparation of an antiviral agent or a pharmaceutical for the treatment of a disease caused by a virus, according to any one of claims 3 to 6, wherein the viruses are HIV, HPV, EBV, IFV, and / or coronaviruses, preferably from the Orthocoronavirinae subfamily.

[0044] In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt. In a preferred example of the present invention, the pharmaceutically acceptable salt is preferably mefuparib hydrochloride.

[0045] In one embodiment, the compound represented by formula III and / or the compound represented by formula IV, or a pharmaceutically acceptable salt thereof, exists in the form of a pharmaceutical composition containing it, preferably the pharmaceutical composition using the compound represented by formula III and / or the compound represented by formula IV, or a pharmaceutically acceptable salt thereof, as the sole active ingredient of the pharmaceutical composition, and / or the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable excipient.

[0046] In one embodiment, the compound represented by formula III and / or the compound represented by formula IV, or a pharmaceutically acceptable salt thereof, is present in the form of a kit composition containing it, and the kit also contains other drugs for anti-coronavirus-induced diseases.

[0047] In one embodiment, the virus of the subfamily Orthocoronavirinae is an alpha coronavirus, a beta coronavirus, a gamma coronavirus, and / or a delta coronavirus, preferably a coronavirus that causes upper respiratory tract infections, a virus that causes acute respiratory syndrome such as SARS-related coronavirus and / or Middle East respiratory syndrome coronavirus (MERS-CoV).

[0048] Preferably, the coronavirus that causes upper respiratory tract infections is human coronavirus 229E, human coronavirus HKU1 (HCoV-HKU1), human coronavirus OC43 (HCoV-OC43), human coronavirus NL63 (HCoV-NL63), and / or mouse hepatitis virus A59 (MHV-A59).

[0049] Preferably, the SARS-related coronavirus is SARS-CoV (severe acute respiratory syndrome coronavirus) or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0050] In a preferred embodiment of the present invention, the coronavirus includes severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0051] In a preferred embodiment of the present invention, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0052] In addition, to solve the above technical problems, the present invention provides the application of a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof to the preparation of pharmaceuticals for virus-related diseases.

[0053] Preferably, the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof is as described in the first aspect of the present invention.

[0054] Preferably, a pharmaceutical product for a virus-related disease is as described in a second aspect of the present invention.

[0055] To solve the above technical problems, the present invention also provides a pharmaceutical product for the treatment of a virus-related disease as described in a second aspect of the present invention, which includes a poly-ADP-ribose polymerase inhibitor as described in a first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0056] To solve the above technical problems, the present invention also provides a viral inhibitor comprising a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof as described in a first aspect of the present invention. These viruses are those described in a second aspect of the present invention.

[0057] To solve the above technical problems, the present invention also provides for the use of a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof, as described in a first aspect of the present invention, in the treatment of a virus-related disease, as described in a second aspect of the present invention.

[0058] The term "pharmaceutically acceptable" generally refers to salts, solvents, excipients, etc., that are non-toxic, safe, and suitable for use in patients. "Patient" is preferably a mammal, more preferably a human.

[0059] The term "pharmaceutically acceptable salt" refers to a salt obtained by preparing the compound of the present invention using a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. Pharmaceutically acceptable acids include, but are not limited to, organic acids such as acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citrate, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acids, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), and amino acids (e.g., glutamic acid, alginic acid). If the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.For further details, please refer to Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977) or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0060] The term "solvate" refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules in the solvate may exist in either a regular or irregular arrangement. Examples of solvents include, but are not limited to, water, methanol, and ethanol.

[0061] In the term "pharmaceutically acceptable salt solvate," "pharmaceutically acceptable salt" and "solvate" are as described above, and refer to a substance formed by combining the compound of the present invention with 1, 2 obtained by preparing a relatively non-toxic pharmaceutically acceptable compound, and a stoichiometric or non-stoichiometric solvent. Examples of "pharmaceutically acceptable salt solvates" include, but are not limited to, the hydrochloric acid monohydrate of the compound of the present invention.

[0062] The term "multiple" refers to two, three, four, or five.

[0063] any of the variables (for example, R 11-1 When the variable R appears multiple times in the definition of a compound, the definition appearing at each position of the variable is independent of the definition appearing at other positions, and their meanings are independent of and do not influence each other. Therefore, when there is one, two, or three R groups... 11-1 When substituted by a group, that is, when R has up to 3 groups 11-1 If it can be substituted by a group, then R at this position 11-1 The definition is R at the remaining position 11-1This is irrelevant to the definition. In addition, combinations of substituents and / or variables are permitted only if such combinations produce a stable compound.

[0064] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0065] The term "hydrocarbyl" refers to the monovalent moiety obtained by removing hydrogen atoms from carbon atoms in hydrocarbon compounds having 1 to 20 carbon atoms (unless otherwise specified), and may be aliphatic or alicyclic, and saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). For this reason, the term "hydrocarbyl" includes subclasses such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl.

[0066] The term "alkyl" refers to a linear or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0067] The term "alkenyl" refers to a linear or branched alkenyl group having a specified number of carbon atoms.

[0068] The term "alkynyl" refers to a linear or branched alkynyl group having a specified number of carbon atoms.

[0069] The term "alkoxy" is -OR X It refers to the base, and here, R X is an alkyl group as defined above.

[0070] The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0071] The term "heterocyclyl" or "heterocyclic" refers to a monovalent portion of a heterocyclic compound obtained by removing a hydrogen atom from a ring atom, which has 3 to 20 ring atoms (unless otherwise specified), where 1 to 10 are ring heteroatoms and can be aromatic or aromatic. Preferably, each ring has 3 to 7 ring atoms, where 1 to 4 are ring heteroatoms.

[0072] The term "heterocycloalkyl" refers to a saturated monocyclic group having heteroatoms, preferably a 3- to 7-membered saturated monocyclic group containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azacyclobutanyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, and oxazepanyl. Preferred heterocyclyl groups are morpholin-4-yl, piperidine-1-yl, pyrrolidine-1-yl, thiomorpholin-4-yl, and 1,1-dioxo-thiomorpholin-4-yl.

[0073] The terms "heteroaryl" or "heteroaromatic ring" refer to aromatic groups containing heteroatoms, preferably 1, 2, or 3 aromatic 5-6 member monocyclic rings or 9-10 member bicyclic rings independently selected from nitrogen, oxygen, and sulfur, such as furanyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolyl, and the like.

[0074] A pharmaceutical composition relating to the present invention, using the compound of the present invention as an active ingredient, can be prepared according to methods known in the art. The compound of the present invention may be formulated in any dosage form suitable for use in humans or animals. The weight content of the compound of the present invention in the pharmaceutical composition is typically 0.1 to 99.0%.

[0075] A pharmaceutically acceptable carrier may be a conventional carrier in the art, and this carrier may be any suitable physiologically or pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is preferably a conventional pharmaceutically acceptable excipient in the art, such as a pharmaceutically acceptable vehicle, expander, or diluent. More preferably, the pharmaceutically acceptable composition comprises 0.01 to 99.99% of the above-mentioned protein and / or antibody-drug conjugate, and 0.01 to 99.99% of the pharmaceutically acceptable carrier, where this percentage is the mass percentage of the pharmaceutically acceptable composition.

[0076] The compound of the present invention or a pharmaceutical composition containing the same may be administered in unit dose form and by a route that may be enteral or parenteral, for example, orally, intravenously, intramuscularly, subcutaneously, nasally, through the oral mucosa, intraocularly, through the lungs and respiratory system, through the skin, vaginally, or rectally.

[0077] The dosage form for administration may be a liquid, solid, or semi-solid form. Liquid dosage forms may include solutions (including both true and colloidal solutions), emulsions (including oil / water, water / oil, and multiple emulsions), suspensions, injections (including aqueous, powder, and injectable), eye drops, nasal drops, lotions, and topical medications. Solid dosage forms may include tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, suretable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, pellets, droppers, suppositories, films, patches, gas (powder) aerosols, and sprays. Semi-solid dosage forms may include ointments, gels, and pastes.

[0078] The compounds of the present invention can be prepared as conventional preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations, and various particulate delivery systems.

[0079] A better example of the present invention can be obtained by combining the above preferred conditions at the discretion of the present inventors, in accordance with common sense in the relevant technical field.

[0080] All reagents and raw materials used in this invention are commercially available.

[0081] The positive advancements of this invention include the fact that, for the first time, poly-ADP-ribose polymerase inhibitors can inhibit the infection of host cells by coronavirus and the replication of coronavirus, that this effect is dose-dependent without significant cytopathic effects, and that they can be used to treat diseases associated with coronavirus infection. The poly-ADP-ribose polymerase inhibitors or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions and kits containing them, can reduce the effective concentration for inhibiting the virus and increase antiviral activity while ensuring low toxicity and high safety when used in humans, and as a result, the inhibitors can effectively inhibit the virus when used in the clinical treatment of diseases caused by coronavirus. In a preferred example of this invention, the inhibition rate of the poly-ADP-ribose polymerase inhibitor against the virus can be up to 35% (under the same conditions, the inhibition rate of arbidol against the virus is only 21%). [Brief explanation of the drawing]

[0082] [Figure 1] This graph shows the results of the inhibitory activity of mefuparib hydrochloride (CVL218) and olaparib against SARS-CoV-2. [Figure 2] This graph shows the antiviral and cellular activity of mefparib hydrochloride (CVL218) against SARS-CoV-2, with A and B representing experiments from different batches. [Figure 3] This graph shows the cytotoxicity results of olaparib in Vero-E6 cells. [Figure 4]This shows the in vitro anti-SARS-CoV-2 activity of the test drug. (A) Viral nucleoprotein (NP) expression in Vero cells treated with CVL218 14 hours after SARS-CoV-2 infection was observed, using fluorescence microscopy (NP represents nucleoprotein staining, DAPI represents nuclear DNA staining, where DAPI is the dye 4',6-diamidino-2-phenylindole). (B) Relationship between the in vitro inhibitory effect of CVL218 and remdesivir against SARS-CoV-2 and different durations of action. The viral inhibitory activity of CVL218 and remdesivir was determined at the "entire process," "at viral entry," and "post-viral entry" stages, respectively. (C) Western blot analysis of viral NP expression in infected cells treated with CVL218 and remdesivir. [Figure 5] This study demonstrates that CVL218 attenuates CpG-induced IL-6 production in a time- and dose-dependent manner. [Figure 6] The effect of CVL218 on body weight in rats (A) and monkeys (B) is shown. When CVL218 was orally administered to rats and monkeys at doses of 20 / 60 / 160 mg / kg and 5 / 20 / 80 mg / kg, respectively, for 28 days, followed by a 28-day rest period, the safety of CVL218 was demonstrated. [Figure 7] This shows model structures illustrating the action of the N-terminus (N-NTD) of the SARS-CoV-2 nucleocapsid protein when complexed with a PARP1 inhibitor. (A) Simulated structures of SARS-CoV-2-N-NTD complexed with CVL218 and olaparib (both modeled using AutoDock 4.2). (B) Mode of interaction between the viral N-NTD and the PARP1 inhibitors CVL218 and olaparib. Major residues are shown as bars. Hydrogen bonds are represented by dashed lines. [Figure 8] This study shows the tissue distribution characteristics of CVL218 in rats, where the maximum concentration is reached in the lungs. After oral administration of 20 mg / kg to rats, the concentration of CVL218 was determined in different tissues at 3, 6, and 8 hours.

[0083] Specific Embodiments The present invention will be further described in the following examples, but will not be limited thereto. Experimental methods for which specific conditions are not shown in the following examples are usually carried out according to conventional conditions, such as those described in general reference books in the art, such as Molecular Cloning: A Laboratory Manual (Third Edition, Science Publishing House, 2005), or according to conditions suggested by reagent manufacturers.

[0084] (1) The main equipment (name, number) is shown in Table 1 below. [Table 13]

[0085] (2) Experimental reagents and virus strains 1) The reagents are shown in Table 2 below. [Table 14]

[0086] 2) SARS-CoV-2 strain

number

number

[0087] As identified, the genomes of the two virus strains mentioned above are completely identical, and therefore both are SARS-CoV-2 virus strains. The virus strain used in subsequent experiments will primarily be 2019-nCoV-1.

[0088] (3) Drugs Zanamivir, oseltamivir, remdesivir, baricitinib, olaparib, and arbidol were all supplied by MCE (Medchem Express, China). The PARP1 inhibitor mefuparib hydrochloride (CVL218, see also patent application 201210028895.0) was supplied by Pukang (Shanghai) Health Technology Co., Ltd. with a purity exceeding 99.0%.

[0089] Example 1. Detection of in vitro anti-SARS-CoV-2 activity of mefparib hydrochloride (CVL218) 1.1 Experimental group: 1) Arbidol group: 3 μM group and 30 μM group 2) Mefuparib hydrochloride (CVL218) 3 μM group 3) Mefuparib hydrochloride (CVL218) 30 μM group 4) Zanamivir group 5) Oseltamivir group 6) Olaparib 3.2 μM group 7) Baricitinib 3.2 μM group 8) DMSO control group 9) Virus control group: Only the virus is added, and no drugs are added. 10) Cell control group: Contains only cells; no viruses or drugs are added.

[0090] 1.2 Drug dilution: 15 μl of 1 mM stock solution was taken for each drug group, and 4985 μl of cell maintenance solution (i.e., DMEM medium) was added to obtain a 3 μM application solution. 3 μl of 20 mM stock solution of CVL218 was taken, and 1997 μl of cell maintenance solution was added to obtain a 30 μM application solution. DMSO was diluted according to the dilution ratio of the corresponding drug.

[0091] 1.3 Experimental Steps: 1.3.1 Cell preparation and drug pretreatment (cell culture room) Vero-E6 cells (purchased from ATCC cell bank) 1 × 10 4 Cells were seeded in a 96-well culture plate at a rate of one cell / well, cultured for 16 hours in DMEM containing 10% (v / v) fetal bovine serum, pelletized 80%, then the cell culture medium was aspirated and discarded from each well. The cells were washed once with sterile PBS, and different drugs (50 μl / well) diluted in the cell maintenance solution described in Section 1.2 above were added to each well according to the experimental group. Four duplicate wells were created for each group, and the plates were pre-treated for 1 hour in an incubator at 37°C and 5% CO2. Only 50 μl of cell maintenance solution was added to the virus control group and the cell control group.

[0092] 1.3.2 Viral infection and culture (BSL-3 laboratory): After 1 hour of drug pretreatment, excluding the cell control group, 2 μl of SARS-CoV-2 strain was added to each well to achieve a viral multiplicity of infection of 0.05 (MOI=0.05). The wells were then placed in a 37°C, 5% CO2 incubator for 2 hours for adsorption. Once adsorption was complete, the virus-containing medium was discarded, and new drug-containing medium was added according to the experimental group. The cells were then incubated in a 37°C, 5% CO2 incubator for 48 hours. After incubation, the cytopathic state of each experimental group was observed and recorded under a microscope. 120 μl of culture supernatant was pipetteed from each well and inactivated at 56°C for 30 minutes. After inactivation was complete, 100 μl was taken from each well and added to the lysate in the nucleic acid extraction reagent tank. After disinfecting the outside of the reagent tank, the tank was moved to a BSL-2 laboratory for viral nucleic acid extraction and genetic testing.

[0093] 1.3.3 Nucleic acid extraction: For viral nucleic acid RNA extraction, please refer to the operating instructions for the automated nucleic acid extractor and extraction kit.

[0094] 1.3.4 Fluorescence Quantitative PCR Detection The PCR reaction system was set up according to the instructions for Shanghai Bio-germ's 2019 SARS-CoV-2 nucleic acid detection kit. The specific reaction system consisted of 6 μl of qRT-PCR reaction solution, 2 μl of qRT-PCR enzyme mixture, 2 μl of primer probe, and 2.5 μl of the viral nucleic acid RNA template extracted as described above. The reaction parameters were 40 cycles of 10 minutes at 50°C, 5 minutes at 95°C, 10 seconds at 95°C, and 40 seconds at 55°C (in this step, fluorescence signals from the FAM and VIC channels were collected); viral replication levels were indicated by detecting the transcription levels of SARS-CoV-2 viral genes (ORF1ab and N). -△CT The values ​​were calculated according to the CT values ​​obtained by the PCR instrument to represent the relative viral content of the experimental group compared to the control group. Viral replication inhibition rate (%) = (1-2 -△CT ) × 100%.

[0095] 1.4 Experimental Results The inhibitory effects of compounds such as mefuparib hydrochloride (CVL218) and olaparib on the SARS-CoV-2 coronavirus are shown in Figures 1 and 2, and Table 3. No inhibitory activity was detected in any of the control groups. From Figure 1 and Table 3, it can be seen that CVL218 can effectively inhibit the replication of SARS-CoV-2 in Vero-E6 cells. At a concentration of 3 μM, CVL218 showed an inhibition rate of 35% against the virus, which is higher than the inhibition rate of the control drug arbidol (21%), while the anti-influenza virus drugs zanamivir and oseltamivir did not show inhibitory activity against the SARS-CoV-2 virus. At a concentration of 30 μM, CVL218 showed an inhibition rate of over 99% against the virus. Figure 2 shows that the EC50 of CVL218 against SARS-CoV-2 was dose-dependent, at 7.67 μM and 5.12 μM in different batches (experimental steps are shown in Example 2). Figure 1 and Table 3 also show that the PARP-1 inhibitor olaparib also has slight activity against SARS-CoV-2, with inhibition rates of approximately 12% or 15.8% against the virus at 3.2 μM, while the JAK-1 inhibitor baricitinib shows almost 0% inhibition of the virus.

[0096] In conclusion, both PARP1 inhibitors, olaparib and CVL218, exhibited inhibitory effects against SARS-CoV-2 replication, with CVL218 showing a higher inhibition rate than olaparib. It should be noted that the antiviral effect of CVL218 surpassed that of arbidol, one of the standard treatments for COVID-19 in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (6th Edition) published by the Chinese government. [Table 15]

[0097] Example 2: Cytotoxicity study of mefuparib hydrochloride (CVL218) on Vero-E6 cells 2.1 Experimental group: 1) Mefuparib hydrochloride (CVL218) group 2) DMSO control group 3) Olaparib group 4) Cell control group: Contains only cells, without any added drugs. 5) Blank control group (culture medium only, without cells)

[0098] 2.2 Drug dilution: Mefparib hydrochloride was obtained from Pukang (Shanghai) Health Technology Co., Ltd., with a purity of over 99.0%. After dissolving it in DMSO, it was diluted with a gradient according to Table 4 below (the maintenance solution was DMEM medium). Serial dilutions were performed with DMSO according to the same dilution gradient. [Table 16]

[0099] 2.3 Experimental Steps: 2.3.1 Cell preparation and drug administration culture Vero-E6 cells 1 × 10 4Cells were seeded in a 96-well culture plate at a rate of one cell / well and cultured for 16 hours in DMEM containing 10% fetal bovine serum. After pelletizing 80%, the cell culture medium was aspirated and discarded from each well. The cells were washed once with sterile PBS, and different drugs (200 μl / well) diluted in cell maintenance solution were added to each well according to the experimental group. Three duplicate wells were created for each group, and the wells were placed in an incubator at 37°C and 5% CO2 for 48 hours. The DMSO control group was given DMSO diluted in cell maintenance solution to the corresponding concentration, and the cell control group was given 200 μl of cell maintenance solution. The blank control group was given only cell maintenance solution without cells.

[0100] 2.3.2 Detection of toxicity of mefparib hydrochloride and olaparib against Vero-E6 Cellular conditions were observed and recorded under an inverted microscope, and the toxicity of the drug to Vero-E6 cells was detected according to the CCK-8 kit instructions. 20 μl of CCK-8 solution was added to all experimental and control wells, and the cell culture plates were placed in a 37°C, 5% CO2 incubator for 1 hour. The absorbance values ​​at a wavelength of 450 nm were then measured using a multifunctional microplate reader. Calculations were performed according to the formula: Cell activity inhibition rate (%) = [1 - (Drug group - Blank control group) / (Cell control group - Blank control group)] × 100%.

[0101] A graph was plotted with the drug concentrations of mefuparib hydrochloride and olaparib as the x-coordinate and the cell proliferation inhibition rate as the y-coordinate. The results are shown by the filled circles in Figure 3. As can be seen from the figure, mefuparib hydrochloride inhibited cell proliferation at approximately 92 μM in Vero-E6 cells. 50 It has a 50% cytotoxic concentration (a drug concentration that kills 50% of cells). Of these, 30 μM mefuparib hydrochloride has no inhibitory effect on cells and is essentially non-toxic. Mefuparib hydrochloride (CVL218) is considered to have good safety. Olaparib has a CC50 (50% cytotoxic concentration, a drug concentration that kills 50% of cells) of approximately 100-300 μM in Vero-E6 cells.

[0102] Example 3: 3.1 Indirect Immunofluorescence Assay Vero E6 cells were treated with 5 μM, 15 μM, and 25 μM CVL218, respectively, following the "whole process" procedure. Infected cells were fixed with 80% acetone in PBS, permeabilized with 0.5% Triton X-100, and then blocked at room temperature for 30 minutes with 5% BSA in PBS buffer containing 0.05% Tween 20. Furthermore, SARS-CoV nucleocapsid protein rabbit polyclonal antibody (Cambridgebio, USA) was used as the primary antibody, and cells were incubated at a 1:200 dilution for 2 hours. Then, Alexa 488-labeled goat anti-rabbit antibody (Beyotime, China) was used as the secondary antibody for incubation at a 1:500 dilution. Nuclei were stained with DAPI (Beyotime, China). Immunofluorescence was observed by fluorescence microscopy.

[0103] Immunofluorescence microscopy revealed that 14 hours after SARS-CoV-2 infection, viral nucleoprotein (NP) expression in CVL218-treated cells showed a dose-response relationship with the concentration of the treatment drug, with expression in CVL218-treated cells being significantly lower than in DSMO-treated cells (Figure 4A). No significant cytopathic effects were observed in infected cells treated with 25 μM CVL218.

[0104] 3.2 Testing the duration of action To systematically evaluate the inhibitory activity of compounds against SARS-CoV-2, time-of-addition assays were also performed to determine at what stage of viral infection the compound inhibited the infection. Duration of action was measured using relatively high doses of the test drug (20 μM for CVL218 and 10 μM for remdesivir). Vero E6 cells at a density of 5 × 10⁴ cells per well were treated with the test drug at different stages of viral infection, or with DMSO as a control. The MOI for infecting cells with the virus was 0.05. The "whole process" treatment was designed to evaluate the maximum antiviral effect, and the test drug in the cell culture medium was the same as described in the viral infection assay throughout the experiment. In the "at viral entry" treatment, the test drug was added to cells 1 hour before viral infection, and the cells were then maintained in the drug-virus mixture for 2 hours during viral infection. The medium containing the virus and test drug was then replaced with fresh medium until the end of the experiment. In the "post-viral entry" experiment, the virus was first added to cells and infected for 2 hours. Then, the virus-containing supernatant was replaced with drug-containing culture medium until the end of the experiment. Fourteen hours after infection, the inhibitory effect of the drug on the virus in the cell supernatant was quantitatively detected by qRT-PCR and calculated using the DMSO group as a reference.

[0105] The results showed that both CVL218 and remdesivir exhibited more potent antiviral activity throughout the entire process of SARS-CoV-2 infection of Vero E6 cells compared to the DMSO control group (Figure 4B). The duration of action results indicated that CVL218 could partially antagonize viral entry and significantly inhibit replication after entry, while remdesivir could only play a role in the post-entry phase (Figures 4B and 4C). In conclusion, CVL218 may be a potentially more advantageous drug for the treatment of COVID-19.

[0106] Example 4: CVL218 inhibits CpG-ODN 1826-induced IL-6 production in PBMCs. Interleukin-6 (IL-6) has recently been identified as one of the most important cytokines during viral infections (L. Velazquez-Salinas, A. Verdugo-Rodriguez, LL Rodriguez, MV Borca, The role of interleukin 6 during viral infections, Frontiers in microbiology 10(2019)1057). New human and animal clinical studies show that IL-6 oversynthesis is associated with human immunodeficiency virus (HIV) (MMMcFarland-Mancini, HMFunk, AMPaluch, M. Zhou, PV Giridhar, CAMercer, SCKozma, AFDrew, Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor, The journal of immunology 184(12)(2010)7219-7228), foot-and-mouth disease virus (GAPalumbo, C. Scisciani, N. Pediconi, L. Lupacchini, D. Alfalate, F. Guerrieri, L. Calvo, D. Salerno, S. Di Cocco, M. Levrero, et al., IL6 inhibits HBV transcription by targeting the epigenetic control of the nuclear cccdna minichromosome,PLoS one 10(11)), and vesicular stomatitis virus (VSV) (L. Velazquez-Salinas, S. J. Auszek, C. Stenfeldt, E. O Harn, J. M. Checo, M. B. Borca, A. Verdugo-Rodriguez, J. Arzt, LLMany studies suggest that IL-6 is associated with the persistence of viruses, such as Rodriguez's "Increased virulence of an epidemic strain of vesicular stomatitis virus is associated with interference of the innate response in pigs," Frontiers in microbiology 9(2018)1891. Furthermore, in vivo studies using the Friend retrovirus (FV) mouse model have shown that IL-6 blockade can reduce viral load and enhance virus-specific CD8+ T cell immunity (W. Wu, K.K. Dietze, K. Gibbert, K. Slang, M. Trilling, H. Yan, J. Wu, D. Yang, M. Lu, M. Roggendorf, et al., "TLR ligand induced IL-6 counter-regulates the anti-viral CD8+ T cell response during an acute retrovirus infection," Scientific reports 5(2015)10501). These findings support the hypothesis that rapid production of IL-6 may be a possible mechanism leading to adverse clinical findings in viral pathogenicity (J. Zheng, Y. Shi, L. Xiong, W. Zhang, Y. Li, PGGibson, JLSimpson, C. Zhang, J. Lu, J. Sai, et al., The expression of IL-6, tNF-α, and MCP-1 in respiratory viral infection in acute exacerbations of chronic obstructive pulmonary disease, Journal of immunology research 2017). A recently published study on the clinical characteristics of severely ill patients with SARS-CoV-2 infection has shown that IL-6 is significantly elevated, particularly in patients treated in the ICU, and triggers an overactivated immune response (Y. Zhou, B. Fu, X. Zheng, D.Wang,C.Zhao,Y.Qi,R.Sun,Z.Tian,X.Xu,H.Wei,Aberrant pathogenic GM-CSF+T cells and inflammatory CD14+CD16+monocytes in severe pulmonary syndrome patients of a new coronavirus,bioRxiv、J.-J.Zhang,X.Dong,Y.-Y.Cao,Y.-D.Yuan,Y.-B.Yang,Y.-Q.Yan,CAAkdis,Y.-D.Gao, Wuhan, China,Allergy、B. Diao, C. Wang, Y. Tan, X. Chen, Y. Liu, L. Ning, L. Chen, M. Li, Y. Liu, G. Wang, et al 2019(COVID-19),medRxiv、XCHuang, Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu, L. Zhang, G. Fan, J. Xu, Gu, et al 395(10223)(2020)497-506、YBLi, F. Feng, G. Yang, A. Liu, N. Yang, Q. Jiang, H. Zhang, T. Wang, P. Li, Mao, et al coronavirus(2019-nCoV)infection、SSRN 3543609 is an IL-6 antibody in the SARS-CoV-2 strain. The IL-6 vaccine has been shown to be specific for this type of COVID-19.

[0107] To test whether CVL218 can modulate IL-6 production in vitro, peripheral blood mononuclear cells (PMBCs) were stimulated to produce IL-6 using CpG-ODN 1826, a potent stimulant of cytokines and chemokines. Incubation of PBMCs with 1 μM CpG-ODN 1826 for 6 hours (Method) induced a 40% increase in IL-6 production compared to untreated cells (Figure 5). The stimulating effect of CpG-ODN 1826 was inhibited in the presence of CVL218. Further studies showed that CVL218 inhibited CpG-induced upregulation of IL-6 in a time- and dose-dependent manner (Figure 5). More specifically, exposure to CVL218 at concentrations of 1 μM and 3 μM for 12 hours reduced CpG-induced IL-6 production by 50% and 72.65%, respectively. These results provide in vitro evidence for the use of CVL218 as a potential therapeutic agent for treating inflammatory responses induced by SARS-CoV-2 infection.

[0108] The experimental steps for CpG-PDN1826-induced PBMC production were as follows: Peripheral blood mononuclear cells (Beijing Yicon) were cultured in 96-well plates in RPMI1640 cell growth medium (Corning, catalog 10-040-CVR) at 37°C in a 5% CO2 atmosphere. For stimulation, PBMC cells were incubated with 1 μM CpG-ODN1826 (InvivoGen, catalog tlrl-1826). To test whether CVL218 could inhibit IL-6 production, CVL218 was added to the cell culture medium at concentrations of 1 μM and 3 μM for 6 and 12 hours, respectively. The concentration of IL-6 was determined by ELISA using a commercially available kit (Dakewe Biotech, catalog 1110602).

[0109] Example 5: Metabolism and safety profile of CVL218 in animals (I) Experimental Steps 5.1. Pharmacokinetic Studies Sprague-Dawley rats were purchased from the Animal Experiment Center in Shanghai, China. The experimental animals were divided into groups of no more than 6 animals per cage and housed in wire cages. Experimental conditions were favorable (temperature 25±2°C, relative humidity 50±20%) with a light-dark cycle (12 hours / 12 hours). 144 Sprague-Dawley rats were randomly divided into four groups (18 rats / sex / group). CVL218 was administered at doses of 20, 40, 60, and 160 mg / kg. From all groups, 20 rats (10 rats / sex / group) were randomly selected, euthanized on day 28, and sections of various tissues and organs were obtained and frozen. Ten animals (5 rats / sex / group) were euthanized after a 28-day drug-free period, and sections of their tissues and organs were collected and frozen. After collecting blood samples, six animals (3 / sex / group) were euthanized. For pharmacokinetic and safety evaluation, the animals' blood concentrations, clinical symptoms, mortality rates, and body weight were examined.

[0110] 5.2. Tissue distribution test Thirty Sprague-Dawley rats were randomized to three time-point groups (3 rats / sex / group). Animals were sacrificed 3, 6, and 8 hours after CVL218 administration, and tissues from the brain, heart, lungs, liver, spleen, stomach, and kidneys were collected. Tissue samples were washed with ice-cold saline, excess fluid was removed with a paper towel, and then weighed. After weighing the tissue sample solutions, they were stored at -20±2°C until the drug concentration was determined by LC-MS-MS.

[0111] 5.3. Safety testing in cynomolgus monkeys Healthy male and female monkeys aged 3-4 years were purchased from Landao Biotechnology, Guangdong, China. The animals were fed according to the Guide for Care and Use of Laboratory Animals. Animals were randomized (5 animals / sex / group) and administered CVL218 via nasogastric administration at dose levels of 0 (control), 5, 20, and 80 mg / kg. The monkeys were observed twice daily for survival / death and any changes in behavior, response to treatment, or health status.

[0112] 5.4.Statistical analysis All data represent the mean ± standard deviation (SD) of the n-value, where n corresponds to the number of data points used. The numerical values ​​were compiled using GraphPad Prism (GraphPad Software, USA). Statistical significance was calculated using SPSS (ver. 12), and two values ​​were considered significantly different if the p-value was less than 0.05.

[0113] (II) Experimental results and conclusions 5.5. CVL218 was most commonly found in rat lung tissue. Figure 8 and Table 5 show the concentrations of CVL218 in different tissues at different time points after oral administration of different doses in rats. Of the seven tissues (i.e., lung, spleen, liver, kidney, stomach, heart, and brain), the highest CVL218 concentration was observed in the lung, which was 188 times higher than that in plasma (Table 6). The observation of the highest concentration of CVL218 in the lung is consistent with the fact that the pathological effects of the SARS-CoV-2 virus are greatest and the viral load is highest in the lung, suggesting the potential use of CVL218 for the indication of lung disease caused by SARS-CoV-2 infection.

[0114] In addition, the results show that the pharmacokinetic parameters of CVL218 and arbidol are equivalent, and that plasma concentrations and drug exposures are similar (Table 7). After administration to rats, arbidol is mainly distributed in the stomach and plasma. In contrast, CVL218 is more readily distributed in tissues, particularly in the lungs rather than in plasma, which is higher than that of arbidol, indicating that CVL218 has a favorable pharmacokinetic profile, making it a potential antiviral treatment for SARS-CoV-2 lung infection. [Table 17] [Table 18] [Table 19]

[0115] 5.6. CVL218 showed good safety in animals. Rats were orally administered CVL218 at doses of 20 / 60 / 160 mg / kg for 28 days, followed by a 28-day drug-free period. No significant differences in body weight were observed between rats and cynomolgus monkeys at different doses and the control group (Figure 6).

[0116] The in vivo data described above suggest that CVL218 has favorable pharmacokinetic and safety profiles in rats and monkeys, and that its high distribution in therapeutic target tissues (i.e., lungs) may be beneficial for the treatment of SARS-CoV-2 infection.

[0117] Example 6: Molecular docking demonstrates the interaction between the PARP1 inhibitor and the N-terminal domain of coronavirus nucleocapsidin. Molecular docking was performed in the examples to investigate possible modes of interaction between the two drugs, olaparib and CVL218, and the SARS-CoV-2 N-NTD.

[0118] Using the docking program AutoDock 4.2, we generated molecular interaction models between the PARP1 inhibitors CVL218 and olaparib and the N-terminal domain of the SARS-CoV-2 N protein (SARS-CoV-2-N-NTD). The structure of SARS-CoV-2-N-NTD for molecular docking was established by homology modeling. Using the AutoGrid program, we generated a grid map with 0.375 Å spacing and 60 × 60 × 60 points, which was used to evaluate the binding energy between the protein and ligand.

[0119] The results showed that both CVL218 and olaparib were able to bind to the N-NTD of SARS-CoV-2 (Figure 7). Regarding hydrogen bond formation, CVL218 showed stronger binding ability than olaparib. Meanwhile, the key residues on the SARS-CoV-2-N-NTD involved in drug binding (i.e., S51, Y109, and Y111) are highly conserved in other viruses such as SARS-CoV, HCoV-OC43, mouse hepatitis virus (MHV), and infectious bronchitis virus (IBV), suggesting that N-NTDs from different viruses are very likely to exhibit similar binding behavior to PARP inhibitors, thereby inhibiting viral replication.

[0120] In summary, PARP1 inhibitors may be understood to have therapeutic potential in the treatment of viral diseases such as COVID-19. Firstly, during the life cycle of the coronavirus, PARP1 inhibitors may inhibit viral replication and prevent nucleocapsid binding to viral RNA, which can also be supported by the inventors' molecular docking results. Secondly, PARP1 inhibitors play a crucial role in controlling the inflammatory response by modulating inflammatory factors such as IL-6, thereby offering clinical potential for mitigating the cytokine storm and inflammatory response induced by SARS-CoV-2 infection. The Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) published by the Chinese government recommends tocilizumab, a monoclonal antibody drug against IL-6, for the treatment of COVID-19, which also highlights the important role of the inflammatory response in current SARS-CoV-2 treatment. CVL218 can effectively inhibit CpG-induced IL-6 production in PBMCs. These findings suggest that CVL218 may also possess IL-6-specific anti-inflammatory effects in patients with severe SARS-CoV-2 infection.

[0121] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these are merely examples and that various modifications or revisions can be made to these embodiments without departing from the principles and essence of the present invention. Accordingly, the scope of the present invention shall be defined by the appended claims.

Claims

1. Antiviral agents or pharmaceuticals for the treatment of diseases caused by viruses: wherein the antiviral agent or pharmaceutical comprises a poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof, and the virus is a β-coronavirus. The aforementioned β-coronavirus is SARS-CoV-2, The poly-ADP-ribose polymerase inhibitor is substance A or a pharmaceutically acceptable salt thereof. The substance A is a compound represented by formula III, and the compound represented by formula III is 【Chemistry 1】 That is the case.

2. The antiviral agent or pharmaceutical product according to claim 1, wherein the poly-ADP-ribose polymerase inhibitor is an inhibitor of PARP 1 and / or PARP 2.

3. The pharmaceutically acceptable salt is a hydrochloride salt, or 【Chemistry 2】 The antiviral agent or pharmaceutical product according to claim 1 or 2.

4. The antiviral agent or pharmaceutical product according to any one of claims 1 to 3, wherein the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof exists in the form of a pharmaceutical composition containing the same.

5. The antiviral agent or pharmaceutical according to claim 4, wherein the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof is the sole active ingredient of the pharmaceutical composition, and / or the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

6. The antiviral agent or pharmaceutical according to any one of claims 1 to 5, wherein the poly-ADP-ribose polymerase inhibitor or a pharmaceutically acceptable salt thereof exists in the form of a kit composition comprising the same, the kit also comprising a drug for treating coronavirus-related illnesses and / or a drug for treating illnesses caused by other viruses.

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