Antiviral 1,3-dioxoindene compounds

Abstract

To provide compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections.SOLUTION: The present invention relates to novel 1,3-dioxoindene compounds that are inhibitors of picornaviruses including coxsackie-, entero-, echo-, polio-, and rhinoviruses, and are thus useful to treat viral infections, including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel 1,3-dioxoindene compounds that are inhibitors of picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and are therefore useful for treating viral infections, including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, common cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. The present invention provides novel tetracyclic pyridone compounds disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of viral diseases. [Background technology]

[0002] Picornaviruses are non-enveloped, positive-stranded single-stranded RNA viruses with RNA genomes 7.2–8.5 kb long. These viruses are very small and spherical, about 22–30 nm in size, and were first identified a long time ago. Viruses belonging to the Picornaviridae family include rhinoviruses, polioviruses, coxsackievirus A, coxsackievirus B, enteroviruses including echoviruses, and hepatitis A virus.

[0003] Diseases caused by picornaviruses are diverse, ranging from respiratory to digestive, circulatory, and skin diseases. Examples include polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpangina, and foot-and-mouth disease. However, there are no cures for these diseases. Most drugs under development are descathing inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory diseases, which pose sanitary, social, and economic problems. Picornaviruses are the main causative agents of waterborne diseases. Because they are very stable and difficult to disinfect, RNA viruses continuously cause related diseases.

[0004] Human rhinovirus (hRV) has recently been associated with a large proportion of asthma exacerbations and is known to be present even in the bronchial tissue of many stable asthma patients. Comparison of bronchial mucosal biopsy samples from asthma and non-asthma patients has shown that human rhinovirus is detected at a significantly higher frequency in the lower respiratory tract of asthma patients compared to non-asthma patients. A correlation between the presence of human rhinovirus and the clinical severity of asthma has also been reported. Furthermore, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, and asthma.

[0005] Rhinovirus is the main cause of the common cold, but enterovirus-induced diseases include meningitis and respiratory infections. Extensive efforts to provide poliovirus vaccination have significantly reduced polio incidence worldwide, although cases are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is now controllable to some extent thanks to vaccines for the hepatitis A virus. However, vaccines for coxsackievirus, echovirus, or rhinovirus have not yet been developed.

[0006] In particular, coxsackievirus B is a major cause of myocarditis, which in severe cases can develop into idiopathic dilated cardiomyopathy requiring a heart transplant.

[0007] Enviroxime derivatives are considered the most promising candidates with broad anti-enteroviral and anti-rhinoviral activity. Enviroxime interferes with the synthesis of positive-strand RNA by binding to viral protein 3A, which is necessary for the formation of RNA intermediates in viral replication (Heinz BA and Vance LM: J Virol, 1995, 69(7), 4189-97). However, clinical studies have observed that the compounds have little to no therapeutic effect, accompanied by poor pharmacokinetics and undesirable side effects (Miller FD et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

[0008] The protease inhibitor AG7088 was developed based on knowledge of the ultrastructure and function of viral protease 2C. In cell cultures within the nanomolar concentration range, AG7088 is effective against 48 rhinovirus types, as well as coxsackievirus A21, B3, enterovirus 70, and echovirus 11 (Pattick AK et al.: Antimicrobila Agents Chemother, 1999, 43(10), 2444-50).

[0009] The elucidation of the molecular structure of viral capsids provided the prerequisites for the intentional design of capsid blockers, or "WIN substances" (Diana GD: Curr Med Chem 2003, 2, 1-12). These substances inhibit the adsorption and / or detachment of rhinoviruses and enteroviruses. Some of the WIN substances exhibit highly specific effects only against individual genera or viral types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. For example, allildone, disoxalil, and pirodavir belong to the WIN substance group. These compounds showed very good antiviral effects in cell cultures. However, their clinical application was not possible due to insufficient solubility (allildone), low bioavailability (allildone and disoxalil), rapid metabolism and excretion (disoxalil and WIN54954), and side effects such as skin rash (WIN54954).

[0010] Preconalil, a type of WIN substance, has excellent oral bioavailability and, after binding to the hydrophobic pocket in the viral capsid, inhibits the entry of rhinovirus, echovirus, and coxsackievirus (Pevear DC et al.). al.:Antimicrob Agents Chemother 1999,43(9),2109-15;McKinlay MA et al.:Annu Rev (Microbiol 1992, 46, 635-54). Therefore, preconaril is potentially effective against a wide range of viral diseases, from the common cold to viral meningitis or myocarditis. Resistance was observed against rhinovirus, enterovirus 71, and coxsackievirus B3 (Ledford RM et al.: J Virol 2004, 78(7), 3663-74; Groarke JM et al.: J Infect Dis 1999, 179(6), 1538-41). However, the demonstrated therapeutic efficacy was not sufficient to register preconaril (Picovir, Viropharma, USA) as an agent for the treatment of rhinovirus infections in the United States. In March 2002, the corresponding application was rejected by the Food and Drug Administration (FDA) due to too low a success rate and observed side effects. Ta.

[0011] BTA-798 has been found to have higher antiviral activity than preconalil when evaluated with rhinovirus in vitro and in vivo, and is currently in clinical trials (Ryan, J. et al. Antiviral Res [18th Intl Conf Antiviral Res (April 11-14, Barcelona) 2005] 2005, 65(3): Abst LB-11).

[0012] However, no antiviral drugs have yet been developed that have received approval for use in the treatment of enteroviruses or rhinoviruses. New treatments and therapies for enteroviruses or rhinoviruses remain in need. As a result of intensive and thorough research on effective viral replication inhibitors against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, it was found that a novel 1,3-dioxoindene derivative exhibits high inhibitory activity against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, leading to the present invention. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Heinz BA and Vance LM:J Virol,1995,69(7),4189-97 [Non-Patent Document 2] Miller FD et al.: Antimicrob Agents Chemother,1985,27(1),102-6 [Non-Patent Document 3] Pattick AK et al.: Antimicrobial Agents Chemother,1999,43(10),2444-50 [Non-Patent Document 4] Diana GD:Curr Med Chem 2003,2,1-12 [Non-Patent Document 5] Pevear DC et al.: Antimicrob Agents Chemother 1999,43(9),2109-15 [Non-Patent Document 6] McKinlay MA et al.: Annu Rev Microbiol 1992,46,635-54 [Non-Patent Document 7] Ledford RM et al.:J Virol 2004,78(7),3663-74 [Non-Patent Document 8] Groarke JM et al.:J Infect Dis 1999,179(6),1538-41 [Non-Patent Document 9] Ryan,J.et al.Antiviral Res[18th Intl Conf Antiviral Res(April 11-14,Barcelona)2005]2005,65(3):Abst LB-11 [Overview of the project] [Means for solving the problem]

[0014] The present invention provides compounds having antiviral activity. The present invention also provides pharmaceutical compositions containing these compounds, as well as methods of using the compounds and compositions to inhibit viral replication or reactivation and to treat disease conditions associated with or caused by viruses. Further objects of the present invention are described in the following description and examples.

[0015] In one embodiment, the present invention provides a compound of formula (I), [ka] (In the formula, G 1 and G 2 One of these is selected from linear or branched C1-C5 alkyl, linear or branched C1-C5 alkyloxy, linear or branched C1-C5 haloalkyl, linear or branched C1-C5 haloalkyloxy, halo and 3-7 membered cycloalkyl; G 1 and G 2 The other of these is H; R 1 The compound is optionally selected from H and linear or branched C1-C5 alkyl groups, and is enantiomerically pure. In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers. In another embodiment, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound of the present invention and one or more therapeutic activators. [Modes for carrying out the invention]

[0016] For the purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular form shall also include their plural forms.

[0017] The terms used herein have the following meanings unless the context clearly indicates otherwise:

[0018] As used herein, the term “subject” refers to an animal. In certain embodiments, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In certain embodiments, a subject is a human. As used herein, “patient” refers to a human subject. As used herein, a subject “needs” treatment if such a subject would benefit from such treatment in biological, medical, or quality of life.

[0019] As used herein, the terms “inhibit” or “suppress” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0020] As used herein, the terms “to treat” or “to cure” any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., delaying, preventing, or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, “to treat” or “to cure” means alleviating or improving at least one physical parameter, including one that may not be recognizable by the patient. In yet another embodiment, “to treat” or “to cure” means modulating the disease or disorder by any means, either physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, “to treat” or “to cure” means preventing or delaying the onset, development, or progression of the disease or disorder.

[0021] Where used herein, “a,” “an,” “the,” and similar terms (in particular, in the context of the claims) should be construed to encompass both singular and plural forms unless otherwise specified herein or unless the context clearly contradicts this.

[0022] All methods described herein may be carried out in any preferred order, unless otherwise specified herein or unless the context clearly contradicts it. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to further illustrate the invention and not to limit the scope of the claimed invention.

[0023] As used herein, "halo" or "halogen" may be fluorine, chlorine, bromine, or iodine.

[0024] When used herein, "C 1-6 "Alkyl" or "C1-C6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition should be modified accordingly, for example, "C1-4 "Alkyl" represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0025] As used herein, "C" 1-6 "Alkoxy" indicates a straight-chain or branched-chain alkoxy (-O-alkyl) having 1 to 6 carbon atoms. When different numbers of carbon atoms such as C4 or C3 are specified, the definition should be corrected accordingly. For example, "C" 1-4 "Alkoxy" represents methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0026] As used herein, "C" 1-4 "Haloalkyl" or "C1-C4 haloalkyl" indicates a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, in which at least one hydrogen is substituted by a halogen. The number of halogen substitutions can range from 1 to the number of hydrogen atoms in the unsubstituted alkyl group. When different numbers of carbon atoms such as C6 or C3 are specified, the definition should be corrected accordingly. Thus, "C" 1-4 "Haloalkyl" represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl having at least one hydrogen substituted by a halogen. For example, when the halogen is fluorine, it is CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-.

[0027] As used herein, "C" 3-8 The term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When different numbers of carbon atoms such as C3-C6 are specified, the definition should be corrected accordingly.

[0028] Various embodiments of the present invention are described herein. It will be recognized that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The following listed embodiments are representative of the present invention.

[0029] Embodiment 1. Compound of Formula I or a pharmaceutically acceptable salt thereof: [ka] (In the formula, G 1 and G 2 One of these is selected from linear or branched C1-C5 alkyl, linear or branched C1-C5 alkyloxy, linear or branched C1-C5 haloalkyl, linear or branched C1-C5 haloalkyloxy, halo and 3-7 membered cycloalkyl; G 1 and G 2 The other of these is H; R 1 (Selected from H and linear or branched C1-C5 alkyl groups).

[0030] Embodiment 2.G 1 The compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, selected from linear or branched C1-C5 haloalkyls, linear or branched C1-C5 haloalkyloxys, and 3- to 7-membered cycloalkyls.

[0031] Embodiment 3.G 1 The compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, is a linear or branched C1-C5 haloalkyl compound.

[0032] Embodiment 4.G 1 However, the compound described in any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt thereof is CF3.

[0033] Embodiment 5.G 1 The compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, is a linear or branched C1-C5 haloalkyloxy.

[0034] Embodiment 6.G 1 However, the compound described in any one of Embodiments 1, 2, and 5, or a pharmaceutically acceptable salt thereof, is OCF3.

[0035] Embodiment 7.G 1 However, the compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, is a 3- to 7-membered cycloalkyl group.

[0036] Embodiment 8.G 1 The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1, 2, and 7, wherein the compound is cyclopropyl.

[0037] Embodiment 9.G 2 A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 8, wherein H is present.

[0038] Embodiment 10.G 1 The compound described in Embodiment 1 or 9, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0039] Embodiment 11.G 1 However, the compound described in Embodiment 1 or 9, or a pharmaceutically acceptable salt thereof, is OCH3.

[0040] Embodiment 12.G 1 However, the compound described in Embodiment 1 or 9, or a pharmaceutically acceptable salt thereof, is isopropyl.

[0041] Embodiment 13.G 1 However, the compound described in Embodiment 1 or 9, or a pharmaceutically acceptable salt thereof, is a halo.

[0042] Embodiment 14.G 1 The compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein H is present.

[0043] Embodiment 15.G 2The compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0044] Embodiment 16. The compound described in any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): [ka]

[0045] Embodiment 17. A compound according to any one of Embodiments 1-10 and 12-13, having formula (III), or a pharmaceutically acceptable salt thereof: [ka]

[0046] Embodiment 17a. The compound described in any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IV): [ka] (In the formula, G 1 (Selected from linear or branched C1-C5 haloalkyl groups, linear or branched C1-C5 haloalkyloxy groups, and 3- to 7-membered cycloalkyl groups).

[0047] Embodiment 17b.G 1 However, the compound is selected from CF3, OCF3, and cyclopropyl, as described in any one of Embodiments 1 to 9 and 17a.

[0048] Embodiment 17c.R 1 The compound according to any one of embodiments 1 to 9, 17a, and 17b, selected from H and methyl.

[0049] Embodiment 18. A compound according to any one of Embodiments 1 to 17, selected from the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 18a. A compound, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, selected from the group consisting of the following: N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(19); N-((4bR ,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide;N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide;N-((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH -Indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bS,9bS)-1-amino-7-cyclopropyl-4b-hydro Roxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide;N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b ]benzofuran-9b-yl)acetamide; N-((4bS,9bS)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9b H-Indeno[1,2-b]benzofuran-9b-yl)acetamide and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-8-methyl-10-oxo- 4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N-methylacetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide; or pharmaceutically acceptable salts thereof.

[0051] Embodiment 18b. [ka] or [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0052] Embodiment 19. A compound according to any one of Embodiments 1 to 18, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for the prevention or treatment of a viral disease.

[0053] Embodiment 20. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound described in any one of Embodiments 1 to 18, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

[0054] Embodiment 21. A combination comprising a compound described in any one of Embodiments 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 20, and one or more therapeutic agents.

[0055] Embodiment 22. A method for treating a viral disease, comprising administering a therapeutically effective amount of a compound described in any one of Embodiments 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment 20, or the combination described in Embodiment 21, to the target.

[0056] Embodiment 23. Use of the compound described in Embodiment 19 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, or the pharmaceutical composition described in Embodiment 20, or the combination described in Embodiment 21, for the prevention or treatment of a viral disease.

[0057] Embodiment 24. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the method described in Embodiment 23, in which the viral disease is caused by a coxsackievirus.

[0058] Embodiment 25. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the use described in Embodiment 23, wherein the viral disease is caused by poliovirus.

[0059] Embodiment 26. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the method described in Embodiment 23, in which a viral disease is caused by an echovirus.

[0060] Embodiment 27. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the method described in Embodiment 23, in which the viral disease is caused by an enterovirus.

[0061] Embodiment 28. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the use described in Embodiment 23, wherein the viral disease is caused by a rhinovirus.

[0062] Embodiment 29. The use of the compound described in Embodiment 19, or the pharmaceutical composition described in Embodiment 20, or the method described in Embodiment 21, or the method described in Embodiment 23, in which the viral disease is caused by a picornavirus.

[0063] Embodiment 30. The compound described in Embodiment 19, the pharmaceutical composition described in Embodiment 20, the method described in Embodiment 21, or the use described in Embodiment 23, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0064] The compounds of formulas I, II, or III are novel and useful as intermediates for preparing the compounds of formulas (I) to (III) described herein.

[0065] Another embodiment of the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt thereof, as a pharmaceutical.

[0066] The use of compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, for the manufacture of pharmaceuticals for the treatment or prevention of viral diseases and / or infectious diseases in humans is also within the scope of the present invention.

[0067] A pharmaceutical composition comprising a compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is also included within the scope of the present invention.

[0068] According to a further embodiment of this embodiment, the pharmaceutical composition according to the present invention further comprises at least one other antiviral agent in a therapeutically effective amount.

[0069] The present invention also provides the use of the above-described pharmaceutical composition for treating viral infections in humans who have or are at risk of having an infection.

[0070] The present invention also provides the use of the above-described pharmaceutical compositions for treating viral diseases or infections in humans who have or are at risk of developing the disease.

[0071] Another aspect of the present invention relates to a method for treating or preventing viral diseases and / or infections in humans by administering to humans an antivirally effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or the above composition, alone, together, or in combination with at least one other antiviral agent administered separately.

[0072] An additional aspect of the present invention is a product comprising a composition effective for treating viral diseases and / or infections, and packaging material including a label indicating that the composition may be used to treat viral diseases and / or infections, wherein the composition comprises a compound of formula I, II, or III according to the present invention or a pharmaceutically acceptable salt thereof.

[0073] A further aspect of the present invention relates to a method for inhibiting viral replication, comprising exposing the virus to an effective amount of a compound of formula I, II, or III or a salt thereof under conditions that inhibit viral replication. This method can be carried out in vitro or in vivo.

[0074] Furthermore, the use of compounds of formula I, II, or III, or salts thereof, for inhibiting viral replication is also included within the scope of the present invention.

[0075] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent(s). Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described above. In some embodiments, the compound of formula I, II, or III is administered concurrently with at least one additional agent selected from a viral inhibitor or a vaccine.

[0076] These additional agents may be combined with the compound of the present invention to create a single pharmaceutical dosage form. Alternatively, these additional agents may be administered separately to the patient as part of multiple dosage forms, for example, using a kit. Such additional agents may be administered to the patient before, simultaneously with, or after the administration of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0077] The applicable daily dose range of the compound of the present invention is typically 0.01 to 100 mg / kg (body weight), and sometimes 0.1 to 50 mg / kg (body weight). Each drug dose unit may conveniently contain 5% to 95% (w / w) of the active compound. Sometimes, such preparations contain 20% to 80% of the active compound.

[0078] The actual pharmacokinetic or therapeutic dose will naturally depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In any case, the combination is administered in a dosage and manner that allows for the delivery of a pharmacokinetic dose based on the patient's specific condition.

[0079] When the composition of the present invention comprises a combination of the compound of the present invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents may be present at drug dose levels of about 10-100% of the drug dose typically administered in a monotherapy regimen, for example, about 10-80%.

[0080] Antiviral agents intended for use in such combination therapies include, but are not limited to, agents (compounds or biologics) that are effective in inhibiting the formation and / or replication of viruses in humans, by interfering with either the host or viral mechanism necessary for the formation and / or replication of viruses in humans.

[0081] Many of the compounds of the present invention contain one or more chiral centers. These compounds can be prepared and used as single isomers or as mixtures of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of preferred methods are described herein. In certain embodiments, the compounds of the present invention are used as a single, substantially pure isomer, meaning that at least 90% of a sample of the compound is the designated isomer and less than 10% of the sample is any other isomer or a mixture of isomers. In some embodiments, at least 95% of the sample is a single isomer. If the difference in in vitro activity between isomers is relatively small, for example less than about 4 times, a single isomer may be selected based on the activity level for viral replication in cell cultures using methods such as those described herein: an isomer having a lower IC50 or EC50 may be selected.

[0082] The compounds of the present invention can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the examples.

[0083] The present invention also provides compounds of formula I, II, or III as described herein, and methods for producing intermediates useful for the preparation of compounds of formula I, II, or III.

[0084] The present invention further includes any variation of the process in which an intermediate product that can be obtained at any stage of the process is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reactants are used in the form of their salts or optically pure materials.

[0085] The present invention also relates to a form of process in which a compound that can be obtained as an intermediate at any stage of the process is used as a starting material and the remaining process steps are carried out, or a form of process in which the starting material is formed under reaction conditions or used in the form of a derivative, such as a protected form or a salt, or a form of process in which a compound that can be obtained by the process according to the present invention is produced under process conditions and further processed in situ.

[0086] The terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomer configurations that may exist for a given compound of the present invention, including geometric isomers. Substituents are understood to be bonded to the chiral center of a carbon atom. The term "chiral" refers to a molecule that possesses non-superimposability relative to its enantiomer partner. On the other hand, the term "achiral" refers to molecules that can be superimposed on their enantiomer partners. Therefore, the present invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used as appropriate to refer to a racemic mixture. A "diastereoisomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Absolute stereochemistry is specified according to the Kahn-Ingold-Prelogue RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. A split compound whose absolute configuration is unknown may be designated (+) or (-) depending on the direction in which it rotates plane polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0087] Depending on the selection of starting materials and procedures, compounds may exist in one form of one of the possible isomers, or as a mixture thereof, depending on the number of chiral carbon atoms, for example, as a pure optical isomer, or as an isomer mixture such as a racemic mixture and a diastereoisomer mixture. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or can be divided using the prior art. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomer forms are also intended to be included.

[0088] Any resulting mixture of isomers can be separated into pure or substantially pure geometric isomers, optical isomers, or diastereomers based on the physicochemical differences of their components, for example, by chromatography and / or fractional crystallization.

[0089] Any resulting racemic product or intermediate can be separated into optical counterparts by known methods, for example, by separating its diastereomer salt obtained using an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the compounds of the present invention can be separated into their optical counterparts by fractional crystals of salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using the basic moiety. The racemic products can also be separated by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) with a chiral adsorbent.

[0090] Furthermore, the compounds of the present invention, including those salts, may be obtained in the form of their hydrates or may include other solvents used for their crystallization. The compounds of the present invention may, essentially or by design, form solvates with pharmaceutically acceptable solvents (including water). Thus, the present invention is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are known to be harmless to recipients, such as water and ethanol, and are commonly used in the pharmaceutical art. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0091] The compounds of the present invention (including their salts, hydrates, and solvates) can form polymorphs, either inherently or by design.

[0092] As used herein, the terms "salt" or "salts" are used in accordance with the foregoing. This refers to an acid-addition salt or base-addition salt of the compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the compound of the present invention and is not typically biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid salts and / or base salts in the presence of an amino group and / or a carboxyl group or similar group.

[0093] Pharmacologically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobacillate These include ionates, lauryl sulfates, malates, maleates, malons, mandelates, mesilates, methylsulfates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates, and trifluoroacetates.

[0094] Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0095] Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0096] Examples of inorganic bases that can derive salts include ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts being ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0097] Examples of organic bases that can induce salt formation include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, and pipette. Examples include radin and tromethamine.

[0098] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred when feasible. A list of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th edition, Mack. This information can be found in Publishing Company (Easton, Pa., 1985) and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," and in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0099] Any formula shown herein represents an unlabeled form of the compound of the present invention, as well as up to three atoms having a non-natural isotopic distribution, for example, deuterium or 13 C or 15This is intended to represent an isotopically labeled form having a nitrogen-enriched region. The isotopically labeled compound has the structure represented by the formula shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number other than that of its naturally occurring mass distribution. Examples of isotopes that can be usefully over-incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I is one example. The present invention relates to various isotope-labeled compounds, for example 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 This includes compounds in which non-radioactive isotopes such as 13C are present at levels substantially exceeding the normal isotopic distribution. Such isotope-labeled compounds are used in metabolic studies (e.g., 14 (by C), reaction kinetic studies (for example, 2 H or 3 In detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients It is useful in that regard. In particular, the present invention 18Fluorine-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention can generally be prepared by processes similar to those described in the accompanying examples and preparations, using conventional techniques known to those skilled in the art, or by using appropriate isotope-labeling reagents instead of typically used unlabeled reagents. Labeled samples may be useful in cases of very low isotope uptake, such as when radiolabeling is used to detect trace amounts of compounds.

[0100] Furthermore, heavier isotopes, especially deuterium (i.e., 2 Broader substitutions with H or D may result in certain therapeutic benefits due to greater metabolic stability, such as extended half-life in vivo, reduced drug dose requirements, or improved therapeutic index. In this context, deuterium is considered a substituent of the compounds of the present invention, and typically, a sample of a compound having deuterium as a substituent is understood to have at least 50% deuterium incorporated at the labeled position(s). The concentration of such heavier isotopes, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio of the isotopic abundance to the natural abundance of a particular isotope. When the substituent in the compound of the present invention is deuterium, such compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0101] The pharmaceutically acceptable solvates according to the present invention are those in which the crystallization solvent is isotope-substituted, for example, D2O, d6 -acetone, d 6 -Includes those that may be DMSO.

[0102] Compounds of the present invention containing groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming cocrystals with suitable cocrystal-forming agents. These cocrystals can be prepared from the compounds of the present invention by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contact in solution of the compounds of the present invention and the cocrystal-forming agent under crystallization conditions, and isolation of the cocrystals formed thereby. Suitable cocrystal-forming agents include those described in International Publication No. 2004 / 078163. Accordingly, the present invention further provides cocrystals comprising the compounds of the present invention.

[0103] All methods described herein may be carried out in any preferred order, unless otherwise specified herein or unless the context clearly contradicts it. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to further illustrate the invention and not to limit the scope of the claimed invention.

[0104] The compounds of the present invention can be administered by known methods, including oral, parenteral, and inhalation. In certain embodiments, the compounds of the present invention are administered orally as pills, lozenges, troches, capsules, liquids, or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is typically, often, performed intravenously over a period of about 15 minutes to 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation. Inhalation is particularly useful for the treatment of respiratory infections. Since the compounds of the present invention exhibit oral bioavailability, in some embodiments, the compounds can be administered orally.

[0105] The compounds of the present invention may also be used in combination with other agents (combination partners), such as additional antiviral agents of formula I or not of formula I, for the treatment of viral infections in subjects.

[0106] The term “combination / combination” means any combination fixed in a single unit dosage form, either as separate dosage forms suitable for use together, either simultaneously or sequentially, or as a kit of components for combination administration, in particular, within a time interval that allows the combination partner to exhibit cooperative, for example, synergistic, effective, or any combination thereof.

[0107] In certain embodiments of the present invention, the compounds of the present invention are used in combination with a second antiviral agent, such as those named herein.

[0108] A second antiviral agent may be administered in combination with the compound of the present invention, where the second antiviral agent is administered before, simultaneously with, or after one or more compounds of the present invention. If simultaneous administration of the compound of the present invention and the second agent is desired and the administration route is the same, the compound of the present invention may be formulated in the same dosage form together with the second agent. Examples of dosage forms containing the compound of the present invention and the second agent are tablets or capsules.

[0109] In some embodiments, the combination of the compound of the present invention and a second antiviral agent may provide synergistic activity. The compound of the present invention and the second antiviral agent may be administered together, separately but simultaneously, or sequentially.

[0110] The “effective amount” of a compound is the amount necessary or sufficient to treat or prevent the viral infection and / or disease or condition described herein. For example, the effective amount of the viral inhibitor of formula I is sufficient to treat a viral infection in a subject. The effective amount may vary depending on factors such as the size and weight of the subject, the type of disease, or the specific compound of the present invention. For example, the selection of the compound of the present invention may affect what constitutes the “effective amount.” Those skilled in the art will be able to study the factors described herein and make a determination regarding the effective amount of the compounds of the present invention without excessive experimentation.

[0111] The administration regimen may affect what constitutes the effective dose. The compounds of the present invention can be administered to subjects either before or after the onset of a viral infection. Furthermore, several divided doses and staggered dosages may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. Furthermore, the dosage of the compound(s) of the present invention may be increased or decreased proportionally, as indicated by the urgency of the therapeutic or preventive situation.

[0112] The compounds of the present invention may be used for the treatment of conditions, disorders, or diseases described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The present invention provides methods for using the compounds of the present invention in the treatment of these diseases, or for preparing pharmaceutical compositions having the compounds of the present invention for the treatment of these diseases.

[0113] The term "pharmaceutical composition" includes preparations suitable for administration to mammals, such as humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, such as humans, the compounds may be given as themselves, or as pharmaceutical compositions containing, for example, 0.1 to 99.5% (sometimes 0.5 to 90%) of at least one compound of formula (I) or any subgenus thereof as an active ingredient, in combination with a pharmaceutically acceptable carrier, or optionally two or more pharmaceutically acceptable carriers.

[0114] The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering the compounds of the present invention to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials and is involved in transporting or delivering the drug of interest from one organ or part of the body to another, or to a part of the body. Each carrier must be compatible with the other components of the formulation and "acceptable" in the sense that it is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer, and other non-toxic, suitable substances used in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterile and / or substantially free of pyrogenic substances.

[0115] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition.

[0116] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0117] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage forms and may be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent, sometimes about 5 percent to about 70 percent, and sometimes about 10 percent to about 30 percent of the active ingredient.

[0118] Methods for preparing these formulations or compositions include the step of associating the compounds of the present invention with a carrier and, optionally, one or more minor components. Generally, formulations are prepared by homogeneously and closely associating the compounds of the present invention with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0119] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as liquids or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, lick, or paste.

[0120] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, sugar-coated tablets, powders, and granules), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; humectants such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycol, etc.

[0121] Tablets may be prepared by compression or molding with one or more optional components. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0122] Tablets, as well as other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be prepared with coatings and shells, such as notches, enteric coatings, and other coatings well known in the field of pharmaceutical formulation. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water, or by some other sterile injection medium immediately before use. These compositions may also optionally contain an opaque agent, and may optionally release the active ingredient(s) in a sustained manner only in or in specific parts of the gastrointestinal tract, for example, in specific parts. Examples of implantable compositions that may be used include polymer substances and waxes. The active ingredient may also be in a microencapsulated form having one or more of the above excipients, as needed.

[0123] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsion formulations, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain, for example, water or other solvents, solubilizers, and emulsifiers, such as inert diluents commonly used in the art, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0124] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances, and preservatives.

[0125] In addition to the active compound, the suspension may contain a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyoxide, bentonite, agar, and tragacanth, or mixtures thereof.

[0126] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may also be presented as suppositories that can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the active compound.

[0127] Formulations of the present invention suitable for intravaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or sprays containing such carriers, which are known to be suitable in the art.

[0128] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0129] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0130] The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0131] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or by dispersing the active compounds in a polymer matrix or gel.

[0132] Ophthalmic preparations, eye ointments, powders, and liquids are also conceived as being within the scope of the present invention.

[0133] The pharmaceutical compositions of the present invention, suitable for parenteral administration, may contain one or more compounds of the present invention in combination with one or more pharmaceutically acceptable carriers, such as a sterile isotonic aqueous solution or nonaqueous solution, dispersion, suspension, emulsion, or sterile powder, which can be reconstituted into a sterile injectable solution or dispersion immediately before use, and which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the preparation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0134] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0135] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, long-term absorption of injectable pharmaceutical forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0136] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, and subsequently on the crystal size and morphology. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0137] Injectable depot formulations are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsion formulations compatible with body tissues.

[0138] The preparations of the present invention may be administered orally, parenterally, topically, or rectally. Naturally, they may be administered in a form suitable for each route of administration. For example, they may be administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointment, suppository, etc., by injection, infusion, or inhalation, topically by lotion or ointment, and rectally by suppository.

[0139] As used herein, the terms “parenteral administration” and “administered parenterally” mean, but are not limited to, injections and infusions of a mode of administration other than enteral and topical administration, typically by injection, including intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and substernal injections and infusions. Sometimes, intravenous infusion is the method of delivery of the compounds of the present invention. Infusions may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion over intervals of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once daily, twice daily, or up to three times per day.

[0140] When used herein, the terms “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other material that enters the patient’s system and is therefore administered in a manner other than directly to the central nervous system, such as through metabolism and other similar processes, such as subcutaneous administration.

[0141] These compounds may be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including orally and nasally, for example, by spray, rectally, vaginally, parenterally, intracisionally, and topically, in the form of powder, ointment, or drops (including oral and sublingual).

[0142] Regardless of the selected route of administration, the compounds of the present invention, and / or the pharmaceutical compositions of the present invention, which can be used in a preferred hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0143] The actual drug dose level of the active ingredient in the pharmaceutical composition of the present invention may be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0144] The selected drug dose level depends on a variety of factors, including the activity of the specific compound of the present invention used, or its ester, salt, or amide; the route of administration; the time of administration; the elimination rate of the specific compound used; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health, and prior medical history of the patient being treated; and similar factors well known in the pharmaceutical field.

[0145] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound of the present invention used in the pharmaceutical composition at a level lower than necessary to achieve the desired therapeutic effect and to gradually increase the drug dose until the desired effect is achieved.

[0146] Generally, the preferred daily dose of the compound of the present invention is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. Generally, the intravenous and subcutaneous doses of the compound of the present invention for a patient, when used for the specified effect, range from about 0.0001 to about 100 mg / kg (body weight) per day, sometimes from about 0.01 to about 50 mg / kg per day, and sometimes from about 0.1 to about 20 mg / kg per day. An effective dose is the amount that prevents or treats a viral infection.

[0147] If necessary, the effective daily dose of the active compound may be administered in unit dosage form, either as a single daily dose or as two, three, four, five, or six or more secondary doses administered separately at appropriate intervals throughout the day. Compounds delivered orally or by inhalation are generally administered in doses of one to four times per day. Compounds delivered by injection are typically administered once daily or every other day. Compounds delivered by infusion are typically administered in doses of one to three times per day. If multiple doses are administered within a day, the doses may be administered at intervals of approximately four hours, six hours, eight hours, or twelve hours.

[0148] The compounds of the present invention may be administered alone, but they may also be administered as part of a pharmaceutical composition, such as those described herein. Therefore, a method of using the compounds of the present invention includes administering the compounds as part of a pharmaceutical composition, wherein at least one of the compounds of the present invention is mixed with a pharmaceutically acceptable carrier before administration. General synthesis procedure

[0149] The compounds described herein can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0150] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th edition (1952), Methods of Organic Synthesis, Thieme, Vol. 21). [Table 2-1] [Table 2-2]

[0151] The compounds of the present invention are prepared from commonly available compounds using procedures known to those skilled in the art, taking into consideration the examples and schemes provided herein.

[0152] Within the scope of this specification, only readily removable groups that are not components of a particular desired final product of the compounds of the present invention are referred to as “protecting groups” unless otherwise indicated in the context. Protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in standard references, e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag (Stuttgart, Germany, 2005), p. 41627 (URL: http: / / www.science-of-synthesis.com (electronic edition Vol. 48)); JFWMcOmie, “Protective "Groups in Organic Chemistry," Plenum Press (London and New York, 1973), TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," 3rd edition, Wiley (New York, 1999), "The Peptides are described in "Peptides"; Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press (London and New York, 1981), "Methoden der Organischen Chemie" ("Methoden of Organic Chemistry"), Houben Weyl, 4th edition, Vol. 15 / I, Georg Thieme Verlag (Stuttgart, 1974), H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Protein" ("Amino Acids, Peptides, Proteins"), Verlag Chemie (Weinheim, Deerfield Beach, and Basel, 1982), and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharides and Derivatives" ("Chemistry of Carbohydrates: Monosaccharides and Derivatives"), Georg Thieme Verlag (Stuttgart, 1974), among others. A key feature of protecting groups is that they can be easily removed (i.e., without the occurrence of unwanted secondary reactions) by means of solvolysis, reduction, photolysis, or alternatively, under physiological conditions (e.g., enzymatic cleavage).

[0153] Salts of the compounds of the present invention having at least one salt-forming group can be prepared in known ways. For example, salts of the compounds of the present invention having an acid group can be formed by treating the compound with a metal compound such as an alkali metal salt of a suitable organic carboxylic acid, e.g., the sodium salt of 2-ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound such as a corresponding hydroxide, carbonate, or bicarbonate, e.g., sodium or potassium hydroxide, carbonate, or bicarbonate, with a corresponding calcium compound, or with ammonia or a suitable organic amine, sometimes using a stoichiometric amount or a slightly excess of the salt-forming agent. Acid addition salts of the compounds of the present invention can be obtained in a conventional way, for example, by treating the compound with an acid or a suitable anion exchange reagent. Intramolecular salts of the compounds of the present invention containing acidic and basic salt-forming groups, e.g., free carboxyl groups and free amino groups, can be formed, for example, by treatment with a weak base or an ion exchanger, or by neutralization to the isoelectric point of the salt, such as an acid addition salt.

[0154] Salts can be converted to free compounds in the usual manner. Metal salts and ammonium salts can be converted, for example, by treatment with suitable acids and acid addition salts, or by treatment with suitable basic agents.

[0155] A mixture of isomers that can be obtained according to the present invention can be separated into individual isomers in ways known to themselves. Diastereoisomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization, and / or by chromatographic separation, for example, on silica gel, or by medium-pressure liquid chromatography, for example, on a reversed-phase column, and racemates can be separated, for example, by salt formation with an optically pure salt-forming reagent and separation of the mixture of diastereoisomers thus obtained, for example, by fractional crystallization, or by chromatography on an optically active column material.

[0156] Intermediates and final products can be post-processed and / or purified according to standard methods, such as chromatography, partitioning, and (re)crystallization. [Examples]

[0157] The present invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art. Demonstrations of efficacy in these assays are generally considered to be predictive of efficacy in the subject.

[0158] The compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art, with reference to the following reaction scheme and examples. A general method for synthesizing the compound of formula (I) is provided in the following scheme. High-resolution mass spectrometry using LC-MS

[0159] ESI-MS data was recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The MS system resolution was approximately 30,000. Drug candidates were injected into the mass spectrometer from the sample probe by UPLC (Acquity, Waters). Separation was performed on an Acquity UPLC BEH C18 1×50 mm column at a flow rate of 0.15 mL / min with a gradient of 5% to 95% over 3 minutes. Solvent A was water containing 0.1% trifluoroacetic acid, and solvent B was 75% methanol and 25% isopropyl alcohol containing 0.1% trifluoroacetic acid. The system's mass accuracy was found to be less than 5 ppm. Examples 1 and 2: N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide [ka] 4-Nitroisobenzofuran-1,3-dione(2):

[0160] An initial suspension of 3-nitrophthalic acid 1 (1.0 kg, 4.7 mol) in Ac2O (1 liter) was refluxed at 140°C for 2.5 hours. This was then cooled to 80°C and slowly added to diethyl ether (4 liters) with vigorous stirring. The precipitate was collected by filtration through a Buchner funnel and washed with Et2O to obtain the product as a solid. Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate (3):

[0161] To a suspension of anhydrous 2 (50 g, 0.26 mol) in dry DCM (260 mL), ethyl acetoethyl (42 mL, 0.31 mol) and Ac2O (48.5 mL, 0.52 mol) were added at ambient temperature. To this suspension, Et3N (108 mL, 0.78 mol) was added dropwise over 30 minutes at room temperature. The mixture was stirred at the same temperature for a further 15 minutes, and then the DCM was evaporated. The resulting crude product was then dissolved in 2 liters of water and cooled to 0°C. This was fixed in an overhead stirrer, and 300 mL of 2N HCl was added dropwise under vigorous stirring conditions, maintaining the temperature below 0°C. The mixture was stirred at 0°C for a further 15 minutes, then filtered through a Buchner funnel and washed with ice-cold water (500 mL). The mixture was then air-dried for 3 days to obtain the product. 4-Nitro-1H-Inden-1,3(2H)-Zeon(4):

[0162] Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate 3 (272.5 g, 1.04 mol) was added to 1 liter of MeCN:water (20:1, 1.0 M). To this suspension, TFA (60 mL, 1.14 mol) was slowly charged at room temperature, and the mixture was then heated continuously at 50°C. After 4 hours, the reaction mixture was concentrated in a rotary evaporator until approximately 100 mL of solvent remained. The precipitated solid was then filtered through a Buchner funnel and washed with (1:1)CHCl3:hexane. This yielded a solid product, and the filtrate was concentrated again to obtain a second crop for more product. [ka] 2,2-dihydroxy-4-nitro-1H-idden-1,3(2H)-dione(5):

[0163] 4-nitro-1H-indene-1,3(2H)-dione(4) (250 g, 1.31 mol) was placed in 1,4-dioxane (2 liters) and AcOH (200 mL). SeO2 (291 g, 2.62 mol) was added at room temperature, and the mixture was refluxed at 110°C for the next 4 hours. This mixture was then stirred at room temperature for the next 12 hours. Next, 500 g to 600 g of Celite was added. This mixture was stirred thoroughly and filtered through a Celite pad. The residue was washed with ethyl acetate (300 to 500 mL). The resulting filtrate was concentrated to obtain a crude mass, which was then used directly in the next step. 4b,9b-dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(7):

[0164] Crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (1.31 mol) was placed in 2 liters of ice AcOH, and 3-isopropylphenol 6 (196 g, 1.44 mol) was added. The mixture was refluxed for the next 10 hours. The mixture was then completely concentrated and purified by silica gel column chromatography (30% EA in hexane) to obtain the pure product. 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(8):

[0165] 4b,9b-dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 7 (50 g, 0.147 mol) was placed in DCM (500 mL), and then oxalyl chloride (1.2 equivalents) was charged into this suspension in a single lot. Next, DMF (50 mL) was slowly charged. The reaction mixture was then stirred at room temperature for the next 6 hours. It was quenched with water (500 mL) and the layers were separated. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic layers were washed with water (300 mL) and brine (300 mL). This was dried over sodium sulfate and concentrated to obtain a crude mass, which was then purified over a silica short pad (30% ethyl acetate in hexane) to obtain the pure product. mp: 1 H-NMR(300MHz, CDCl3):δ 1.18(dd,J=3.6Hz,J=6.9Hz,6H),2.84(sept,J=6.9Hz,1H),6.34(s,1H),6.70(s,1H),6.94(d d,J=1.0Hz,J=7.8Hz,1H),7.45(d,J=7.8Hz,1H),7.81-7.83(m,1H),8.21(m,1H),8.52(m,1H). 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(9):

[0166] 36.0 g, 0.1 mol of 9b-chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 8 was placed in 350 mL of THF and cooled to -40°C. A 2.0 M solution of NH3 in 100 mL of IPA (0.20 mol) was added using a dropping funnel, and the temperature was maintained below -20°C. The reaction mixture was monitored at -20°C for 1 hour, and then warmed to room temperature. The mixture was stirred at room temperature until the reaction was complete, and then completely concentrated. The crude product was placed in 500 mL of ethyl acetate and washed with water (200 mL x 2) and brine (100 mL). This was dried over anhydrous Na2SO4, then concentrated to obtain a crude mixture, which was purified over a silica short pad to obtain the pure product. 1 H-NMR(300MHz,CDCl3)δ 1.18(d,J=6.9Hz,6H),2.84(sept,J=6.9Hz,1H),3.46(s,1H),6.25(s,1H),6.74(s,2H),6.90(dd,J=1.2Hz,J=7.8Hz, 1H),7.55(d,J=7.8Hz,1H),7.77(t,J=8.1Hz,1H),8.22(dd,J=1.2Hz,J=8.4Hz,1H),8.52(dd,J=1.2Hz,J=8.1Hz,1H). N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(10):

[0167] 9b-amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 9 (950 mg, 2.80 mmol) was placed in AcOH (10 mL, 0.1 M), and acetic anhydride (0.263 mL, 2.8 mmol) was added at ambient temperature. This was heated at 80°C for the next 30 minutes. The reaction mixture was concentrated and then placed in EA (100 mL). This was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (30-40% EA in hexane) to obtain the pure product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(11):

[0168] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 10 (500 mg, 1.3 mmol) was placed in EtOH:water (10:1, 15 mL, 0.1 M), and Fe powder (0.219 mg, 3.92 mmol) was added. A catalytic amount of concentrated HCl (3 drops) was charged, and the mixture was refluxed at 90°C for the next 3 hours. The reaction mixture was filtered through Celite under thermal conditions, and the residue was washed with EA. This was concentrated and then placed in EA (250 mL). This was washed with water (100 mL) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (1:1=EA:hexane) to obtain the pure product. N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (12) and N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (13):

[0169] N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (560 mg) was purified by chiral chromatography using an AD column (SFC=100 mL / min, CO2 / EtOH=70 / 30, 236 bar) to obtain 243 mg of N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 12 (peak 2, tR 4.33 min); 1H NMR (500 MHz, METHANOL-d4)δ As 7.41-7.50 (m,1H), 7.32-7.40 (m,1H), 6.94-7.03 (m,1H), 6.79-6.91 (m,1H), 6.58-6.74 (m,2H), 2.77-2.94 (m,1H), 1.96-2.05 (m,3H), and 1.12-1.26 (m,6H), and 246 mg of N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 13 (peak 1, tR 2.30 min); 1H NMR(400MHz,METHANOL-d4)δ:7.39-7.46(m,1H),7.35(br d,J=7.8Hz,1H),6.97(br d,J=7.3Hz,1H),6.84(br The values ​​obtained were d, J=7.6Hz, 1H), 6.61-6.69(m, 2H), 2.82(dt, J=13.6, 6.8Hz, 1H), 1.98(s, 3H), and 1.17(dd, J=6.9, 1.6Hz, 6H).

[0170] Examples 3-5: N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (19); N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (20) and N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (21) [ka]

[0171] N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (19) (500 mg) was purified by chiral chromatography using an AD column (SFC = 100 mL / min, CO2 / IPA = 80 / 20, 226 bar) to obtain N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (20) (peak 2, tR 4.50 min); 1H NMR (500 MHz, METHANOL-d4)δ 7.58-7.70 (m, 1H), 7.42-7.53 (m, 1H), 7.26 (br d, J=7.80Hz, 1H), 6.97-7.11 (m, 2H), 6.67-6.83 (m, 1H), 2.02 (s, 3H), and N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (21) (peak 1, tR 2.49 min); 1H NMR (500MHz, METHANOL-d4) δ: -1.13 (br The values ​​obtained were d, J=7.6Hz, 1H), -1.29(br t, J=7.6Hz, 1H), -1.50(br d, J=7.3Hz, 1H), -1.79--1.69(m, 2H), -2.09--1.95(m, 1H), and -6.75(s, 3H). [ka] 4b,9b-dihydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(15):

[0172] To a solution of 4-nitro-1H-indene-1,3(2H)-dione 4 (42.1 g, 0.22 mol) in 1,4-dioxane:AcOH (10:1, 330 mL, 0.6 M), SeO2 (48.8 g, 0.44 mol) was added. The resulting solution was refluxed at 130 °C for 3 hours. Then, it was cooled and filtered through Celite using EA (~200 mL). The filtrate was completely concentrated, and crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 was taken in MeSO3H (350 mL, 0.6 M). 3-(trifluoromethyl)phenol 14 (29 mL, 0.24 mol) was added dropwise, and the mixture was stirred at room temperature (30 °C) for the next 24 hours. The reaction mixture was then quenched with ice water (1500 mL), and the solid was filtered off. The residue was dissolved in EA (500 mL) and washed with water (200 mL) and brine (200 mL). This was dried over anhydrous Na2SO4 and concentrated to a crude product. The crude product was purified by silica gel column chromatography (10-40% EA in hexane containing 5-10% DCM) to obtain a pure product. 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(16):

[0173] 4b,9b-dihydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 15 (25 g, 68 mmol) was placed in DCM (270 mL, 0.25 M), and oxalyl chloride (7.1 mL, 82 mmol) was charged at room temperature. DMF (26 mL, 340 mmol) was slowly added, and the mixture was stirred at ambient temperature (20°C). The reaction mixture was then stirred at room temperature (20°C) for the next 6 hours. Oxalyl chloride (1.8 mL, 0.3 equivalents) was again charged to the reaction mixture, and the mixture was stirred for the next 12 hours. The reaction mixture was diluted with water (~300 mL). The aqueous layer was extracted with DCM (~300 mL x 2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10-25% EA in hexane) to obtain the pure product. 9b-amino-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(17):

[0174] 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 16 (20.5 g, 53 mmol) was placed in THF (350 mL, 0.15 M) and cooled to -40°C. 2.0 M NH3 in IPA (65 mL, 0.13 mol) was added dropwise over 10 minutes. The reaction mixture was then stirred at -40°C for the next 3 hours. This was then diluted with EA (~200~300 mL) and washed with 10% brine (~200 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. N-(4b-hydroxy-4-nitro-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(18):

[0175] 9b-amino-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 17 (21 g, 50 mmol) was placed in ice AcOH (250 mL, 0.2 M), and Ac2O (9.5 mL, 0.1 mol) was immediately added. The reaction mixture was then heated at 80°C for the next 60 minutes. The reaction mixture was concentrated to obtain the crude product. The crude product was purified in its raw state by silica gel column chromatography (20-40% EA in Hx with 10% DCM as cosolvent) to obtain the pure product. N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(19):

[0176] N-(4b-hydroxy-4-nitro-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 18 (9.0 g, 22 mmol) was placed in EtOH:water (10:1, 110 mL, 0.2 M), to which Fe powder (3.7 g, 66 mmol) was added, followed by concentrated HCl (0.5 mL). This was refluxed at 90°C for the next 3 hours. The reaction mixture was filtered through Celite under warm conditions using hot EA (~50~100 mL). The filtrate was concentrated and placed in EA (~600~800 mL), and washed with water (400 mL). The aqueous layer was extracted with EA (~200 mL x 2). The combined organic layers were washed with water (~300 mL) and brine (~200 mL). This was dried over anhydrous Na2SO4 and concentrated to (~100~150 mL). The precipitated solid was then thoroughly sonicated and filtered to obtain the pure product. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (20~50% EA in Hx with DCM as an additive) to obtain an additional amount of pure product. 1H-NMR(300MHz,CD3OD)δ 2.0(s,3H),6.74(s,1H),7.00-7.02(m,2H),7.24(d,J=7.8Hz,1H),7.43-7.48(m,1H),7.61(d,J=7.8Hz,1H). LCMS:378.6[M+H] + . [Table 3] N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(20)

[0177] N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (19) (500 mg) was purified by chiral chromatography using an AD column (SFC=100 mL / min, CO2 / IPA=80 / 20, 226 bar) to obtain 202 mg of N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (20) (peak 2, tR 4.50 min); 1H NMR (500 MHz, METHANOL-d4)δ 7.58-7.70 (m,1H), 7.42-7.53 (m,1H), 7.26 (br d,J=7.80Hz,1H), 6.97-7.11 (m,2H), 6.67-6.83 (m,1H), 2.02 (s,3H), and 205 mg of N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (21) (peak 1, tR 2.49 min); 1H NMR (500MHz, METHANOL-d4) δ: -1.13 (br d,J=7.6Hz,1H), -1.29 (br The values ​​obtained were t, J=7.6Hz, 1H), -1.50(br d, J=7.3Hz, 1H), -1.79--1.69(m, 2H), -2.09--1.95(m, 1H), and -6.75(s, 3H). Example 6: N-((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(31) [ka] 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(23):

[0178] 4-nitro-1H-indene-1,3(2H)-dione 4 (10.0 g, 52.3 mmol) was placed in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added, and the mixture was refluxed at 105-110°C for 5 hours. The reaction mixture was then filtered through Celite under thermal conditions, and then concentrated to remove volatile substances to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5. This crude product was then placed in ice AcOH (210 mL, 0.25 mmol), to which 3-bromophenol 22 (9.96 g, 57.5 mmol) was added, and the mixture was refluxed for another 12 hours. The reaction mixture was concentrated and placed in EA (500-600 mL). This was filtered through Celite, and the residue was washed with EA. The filtrate was washed with water (200 mL x 2) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified twice by silica gel column chromatography (35-40% EA in hexane) to obtain the pure product. 7-Bromo-9b-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(24):

[0179] 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 23 (39.5 g, 0.105 mol) was placed in DCM (520 mL, 0.2 M), and oxalyl chloride (11 mL, 0.13 mol) was charged at room temperature. DMF (40 mL, 0.53 mol) was slowly added (0.05 mL / min over 30 minutes, then 0.1 mL / min over 30 minutes, then the remainder), and the mixture was stirred at ambient temperature (30°C). The reaction mixture was then stirred at room temperature (20°C) for the next 12 hours. The reaction mixture was diluted with water (~300 mL). The aqueous layer was extracted with DCM (~500 mL x 2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10-30% EA in hexane) to obtain the pure product. 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(25):

[0180] 9b-Chloro-4b-hydroxy-4-nitro-8-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 24 (21.2, 53.4 mmol) was placed in THF (530 mL, 0.1 M) and cooled to -40°C. 2.0 M NH3 in IPA (54 mL, 0.11 mmol) was added at the same temperature, and the mixture was stirred for the next 3 hours. The reaction mixture was diluted with water (~150 mL) and brine (150 mL). The aqueous layer was extracted with EA (~300 mL x 2). The combined organic layers were washed with brine (~100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (20-30% EA in hexane containing 20% ​​DCM as cosolvent) to obtain the pure product. Tert-butyl(7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(26):

[0181] Anhydrous Boc (8.74 g, 40 mmol) and molecular I2 (0.69 g, 2.67 mmol) were added to a racemic solution of 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 25 (10.1 g, 31 mmol) in THF (5.0 mL, 5.0 M), and the mixture was stirred at room temperature (30°C) for the following 72 hours. The reaction mixture was concentrated and purified. The crude product was purified by silica gel column chromatography (10-30% EA in hexane containing 5-10% DCM) to obtain the pure product. Tert-butyl(1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(27):

[0182] A racemic mixture of tert-butyl(7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) carbamate 26 (10.3 g, 21.5 mmol) was placed in EtOH:water (10:1, 110.0 mL, 0.20 M), to which Fe powder (3.57 g, 63.9 mmol) was added, followed by concentrated HCl (0.8 mL, cat.). This mixture was refluxed at 90°C for the next 3 hours. The reaction mixture was filtered through Celite under warm conditions using hot EA (50-100 mL). The filtrate was concentrated and placed in EA (~1000-1200 mL), and washed with water (~300-500 mL) and brine (~300 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (10-30% EA in hx) to obtain a pure product. Tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (28) and tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (29):

[0183] Tert-butyl(1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (27) was purified by chiral chromatography using (AD column, HPLC=20mL / min, heptane / EtOH=70 / 30, 724psi) to obtain tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (28) (peak 2, tR 15.59 min); 1H NMR (500MHz, METHANOL-d4) δ:7.48 (br t, J=7.7Hz, 1H), 7.37 (br s,1H),7.11(br s,1H),7.02(br d,J=7.1Hz,1H),6.95(s,1H),6.72(br s,1H),1.42(br s,5H),1.13(br s,4H)LCMS:447.2 / 449.2[M+H] + As such, tert-butyl((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (29) (peak 1, tR 8.97 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.48 (br t, J=7.6 Hz, 1H), 7.37 (br s, 1H), 7.11 (br s, 1H), 7.02 (br d, J=6.9 Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s, 5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M+H] + It was obtained as such. (4bR,9bR)-1,9b-diamino-7-bromo-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(30):

[0184] Tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 28 (112 mg, 0.25 mmol) was placed in DCM (2.5 mL, 0.1 M), and immediately 4.0 M HCl in dioxane (0.63 mL, 2.50 mmol) was charged. The reaction mixture was then stirred at room temperature (20°C) for the next 6 hours. The reaction mixture was diluted with EA (50 mL) and vigorously stirred with saturated NaHCO3 (20 mL) for 5-10 minutes. The layers were separated, and the aqueous layer was extracted with EA (30 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the product. The crude product was used directly in the next process without further refinement. N-((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(31):

[0185] (4bR,9bR)-1,9b-diamino-7-bromo-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 30 (76 mg, 0.22 mmol) was placed in ice AcOH (2.2 mL, 0.1 M), and Ac2O (0.03 mL, 1.2 mmol) was immediately added. The reaction mixture was then heated at 80°C for the next 30 minutes. Next, 10 mL of 2N HCl (aqueous solution) was added, and the mixture was stirred at 80°C for the next 2 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was purified directly by silica gel column chromatography (20-50% EA in Hx containing 1-2% MeOH as cosolvent) to obtain the pure product. 1The 1H-NMR spectrum (300MHz, MeOD) was obtained as follows: δ 7.50-7.40 (br,1H), 7.40-7.25 (br,1H), 7.10 (d,J=7.4Hz,1H), 7.05-6.85 (m,2H), 6.69 (br,1H), and 1.99 (s,3H). [Table 4] Examples 7-9: N-(1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (40); N-((4bR,9bR)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (41) and N-((4bS,9bS)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (42) [ka] (3-bromophenoxy)(tert-butyl)dimethylsilane(32):

[0186] 3-bromophenol 22 (2.08 g, 12 mmol) was placed in dry DCM (40 mL, 0.3 M). TBDMS-Cl (2.0 g, 13 mmol) was added to this. Next, imidazole (1.37 g, 20 mmol) was added, and the mixture was stirred at room temperature for the next 15 hours. The reaction mixture was filtered, and the residue was washed with DCM. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (0-5% EA: hexane) to obtain the pure product. 1 H-NMR (300MHz, CDCl3) δ 0.20 (s, 6H), 0.97 (s, 9H), 6.74-6.78 (m, 1H), 7.00 (s, 1H), 7.07-7.09 (m, 1H). Tert-butyl(3-cyclopropylphenoxy)dimethylsilane(34):

[0187] (3-bromophenoxy)(tert-butyl)dimethylsilane 32 (430 mg, 1.5 mmol) was placed in toluene:water (pre-purged with nitrogen) (7.33 mL, 0.2 M). Cyclopropaneboronic acid 33 (154 mg, 1.8 mmol) was then charged. Next, PCy3 (42 mg, 0.15 mmol), K3PO4 (1.1 g, 5.24 mmol), and Pd(OAc)2 (17 mg, 0.07 mmol) were charged. The mixture was then refluxed at 110°C for the next 3 hours. The reaction mixture was passed through Celite and washed with ether. The organic layer was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product, which was purified by silica gel column chromatography (0-5% EA: hexane) to obtain the pure product. 1 H-NMR(300MHz,CDCl3)δ 0.19(s,6H),0.63-0.68(m,2H),0.89-1.02(m,11H),1.79-1.88(m,1H),6.52-6.54(m,1H),6.59-6.68(m,2H),7.06-7.11(m,1H). 3-Cyclopropylphenol (35)

[0188] Tert-butyl(3-cyclopropylphenoxy)dimethylsilane 34 (1.74 g, 7.0 mmol) was placed in THF (23 mL, 0.3 M), and 1.0 M TBAF (9.1 mL, 9.1 mmol) was added. This was stirred at room temperature for the following 75 minutes. The reaction mixture was concentrated and then placed in EA (200 mL). This was washed with saturated NH4Cl (50 mL), water (50 mL), and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (5% EA in hexane) to obtain the pure product. 1H-NMR(500MHz,CDCl3)δ 0.69-0.73(m,2H),0.95-0.99(m,2H),1.85-1.90(m,1H),4.71(br,1H),6.56-6.57(m ,1H),6.63(dd,J=2.5Hz,J=8.0Hz,1H),6.70(d,J=8.0Hz,1H),7.13-7.16(m,1H,ArH). 7-Cyclopropyl-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(36):

[0189] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (1.80 g, 8.0 mmol) and 3-cyclopropylphenol 35 (1.1 g, 8.0 mmol) were refluxed in ice AcOH (40 mL, 0.2 M) for 2 hours. The reaction mixture was concentrated and dissolved in EA (200 mL). This was washed with water (50 mL) and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was then placed in DCM:hexane (approximately 50 mL), and the resulting solid was sonicated. This was filtered to obtain the pure product. The filtrate was concentrated again and purified by silica gel column chromatography (30% EA in hexane) to obtain the remaining product. 1 H-NMR(300MHz,CD3OD)δ 0.65-0.67(m,2H),0.95-0.99(m,2H),1.81-1.86(m,1H),3.67(br,1H),6.22(br,1H),6.50(s,1H),6.77 (d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.78-7.82(m,1H),8.18(d,J=7.5Hz,1H),8.50(d,J=8.0Hz,1H). 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(37):

[0190] 7-Cyclopropyl-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 36 (1.70 g, 5.0 mmol) was placed in DCM (20 mL, 0.25 M) and oxalyl chloride (0.52 mL, 6.0 mmol) was charged. Then, DMF (2 mL) was slowly charged. After 3 hours, an additional oxalyl chloride (0.08 mL) was added. The reaction mixture was then stirred at room temperature for the next 30 minutes. The reaction mixture was diluted to 200 mL with DCM. This was washed with water (100 mL x 2). This was then washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. This was concentrated to obtain the crude product, which was purified by silica gel column chromatography (10-15% EA in Hx) to obtain the pure product. 1 H-NMR(300MHz,CDCl3)δ 0.61-0.68(m,2H),0.93-0.99(m,2H),1.81-1.87(m,1H),6.28(br,1H),6.49(s,1H),6.78(d,J=8.1H z,1H,ArH),7.39(d,J=8.1Hz,1H),7.78-7.823(m,1H),8.19(d,J=7.5Hz,1H),8.49(d,J=8.1Hz,1H). 9b-amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(38):

[0191] 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (715 mg, 2.0 mmol) was placed in dry THF (20.0 mL, 0.1 M). This was cooled to -40°C, and then 2.0 M NH3 was charged in IPA (2.0 mL, 4.0 mmol). This was then stirred at -40°C to -30°C for the next 2 hours. The reaction mixture was concentrated at 25°C until its volume was halved, and then quenched with water. This was concentrated again to remove all volatile substances, and then placed in EA (150 mL). This was washed with water (50 mL x 2) and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography using TEA (1:2=EA:hexane) pre-inactivated to obtain the pure product. 1 H-NMR(300MHz,CD3OD)δ 0.59-0.64(m,2H),0.85-0.90(m,2H),1.73-1.85(m,1H),6.56(s,1H),6.81(d,J=7.8Hz,1 H),7.46(d,J=7.8Hz,1H),7.77-7.80(m,1H),8.25(d,J=7.5Hz,1H),8.58(d,J=8.1Hz,1H). 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(39):

[0192] 2,4,6-trichlorobenzoic acid (168 mg, 0.75 mmol) was placed in THF (5 mL, 0.1 M), to which NMM (0.083 mL, 0.75 mmol) was added at 0°C. Acetyl chloride (0.054 mL, 0.75 mmol) was then charged, and the mixture was stirred at 0°C for the next 30 minutes. Next, 9b-amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 38 (170 mg, 0.5 mmol) was charged in a single lot, and the mixture was stirred at 0°C for the next 3 hours. The reaction mixture was concentrated and then placed in EA (100 mL). This was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated. The obtained crude product was purified by silica gel column chromatography (1:1=EA:hexane) to obtain the pure product. 1 H-NMR(300MHz,CDCl3)δ 0.59-0.64(m,2H),0.92-0.98(m,2H),1.77-1.85(m,1H),2.07(s,3H),6.06(br,1H),6.46(br,2H),6.76(dd,J =7.8Hz,J=1.2Hz,1H),7.38(d,J=7.8Hz,1H),7.71-7.76(m,1H),8.19(d,J=7.5Hz,1H),8.45(d,J=7.8Hz,1H). N-(1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(40):

[0193] N-(7-Cyclopropyl-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide 39 (150 mg, 0.39 mmol) was taken in EtOH:water (10:1, 8 mL, 0.05 M), to which Fe powder (66 mg, 1.18 mmol) was added. Two drops of concentrated HCl were charged thereto, and then the reaction mixture was refluxed for the next 2 hours. The reaction mass was filtered through celite, and the residue was washed with EA under hot conditions. The filtrate was concentrated, and the crude product was taken in EA (100 mL). This was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated. Then, the obtained crude product was purified by silica gel column chromatography (1:1 = EA in hexane) to obtain the pure product. 1 1H-NMR (300 MHz, CD3OD) δ 0.59 - 0.61 (m, 2H), 0.89 - 0.92 (m, 2H), 1.79 - 1.85 (m, 1H), 2.01 (s, 3H), 6.44 (s, 1H), 6.52 - 6.72 (m, 2H), 6.95 - 7.02 (m, 1H), 7.29 - 7.32 (m, 1H), 7.39 - 7.44 (m, 1H).

Table 5

[0194] N-(1-Amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (40) (500 mg) was purified by chiral chromatography using an AD column, HPLC = 20 mL / min, heptane / EtOH = 70 / 30, 722 psi to give N-((4bR,9bR)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (41) (peak 2, tR 17.95 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.43 (br s, 1H), | 7.30 (br s, 1H), 6.98 (br s, 1H), 6.60 - 6.76 (m, 2H), 6.45 (br s, 1H), 1.99 (s, 3H), 1.84 (br s, 1H), 0.91 (br d, J = 8.0 Hz, 2H), 0.58 - 0.66 (m, 2H) as

Table 6

[0195] And N-((4bS,9bS)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (42) was obtained (peak 1, tR 9.16 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.44 (br d, J = 2.8 Hz, 1H), 7.33 (br d, J = 5.7 Hz, 1H), 7.00 (br d, J = 1.7 Hz, 1H), 6.73 (br d, J = 6.9 Hz, 1H), 6.64 - 6.71 (m, 1H), 6.47 (br s, 1H), 2.00 (s, 3H), 1.79 - 1.92 (m, 1H), 0.86 - 0.99 (m, 2H), 0.57 - 0.70 (m, 2H).

Table 7

[0196] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (1.34 g, 6 mmol) was placed in TFA (24 mL, 0.25 M). 3-(trifluoromethoxy)phenol 43 (1.07 g, 6 mmol) was added, and the mixture was stirred at room temperature (30°C) for the next 12 hours. The reaction mixture was concentrated. This was then placed in EA (200 mL) and washed with water (100 mL x 2) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude mixture. The crude product was then purified by silica gel column chromatography (1:2 = EA in hexane) to obtain a pure product. 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(45):

[0197] 4b,9b-dihydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 44 (385 mg, 1.0 mmol) was placed in DCM (4.0 mL, 0.25 M). Oxalyl chloride (0.103 mL, 1.21 mmol) and then DMF (0.4 mL, 5.0 mmol) were charged to this, and the mixture was stirred at room temperature (30°C) for 3 hours. The reaction mixture was diluted with DCM (~100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10 → 15% EA in hexane) to obtain the pure product. 9b-amino-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(46):

[0198] 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 45 (200 mg, 0.50 mmol) was placed in THF (5.0 mL, 0.1 M). This was cooled to -40°C, 2.0 M NH3 was charged in IPA (0.5 mL, 1.0 mmol), and the mixture was heated at -10°C for the next 3 hours. The reaction mixture was concentrated, quenched with water (50 mL), and extracted with EA (100 mL). The combined organic layers were washed with water (50 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography on a short pad (30-40% EA in hexane) to obtain the pure product. N-(4b-hydroxy-4-nitro-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(47):

[0199] 2,4,6-trichlorobenzoic acid (89 mg, 0.40 mmol) was placed in THF (2.0 mL, 0.1 M) and cooled to 0°C. NMM (0.44 mL, 0.40 mmol) was added, followed by AcCl (0.021 mL, 0.30 mmol). The reaction mixture was stirred for 10 minutes, and then 9b-amino-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 46 (76 mg, 0.2 mmol) was added. The reaction mixture was stirred at 0°C for the next 1.5 hours. The reaction mixture was concentrated, the residue was quenched with water (50 mL), and extracted with EA (50 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (30-35% EA in hexane) to obtain the pure product. N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(48):

[0200] N-(4b-hydroxy-4-nitro-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 47 (21 mg, 0.05 mmol) was placed in EtOH:water (10:1, 2.5 mL, 0.02 M), and Fe powder (8.3 mg, 0.15 mmol) was charged. Concentrated HCl (1 drop) was added, and the mixture was refluxed at 90°C for the next 3 hours. The reaction mixture was filtered through Celite under thermal conditions. The residue was washed with EA (~20 mL). This was concentrated and then placed in EA (~50 mL). This was washed with water (~20 mL) and brine (~20 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude mixture. The crude product was purified directly by reverse-phase HPLC (using MeCN and water as the eluent) to obtain a pure product. 1H-NMR (300MHz, CD3OD) δ 2.01(s,3H),6.71(s,1H),6.77(d,J=8.4Hz,1H),6.87(d,J=8.4Hz,1H),7.02(d,J=7.2Hz,1H),7.45-7.52(m,2H). [Table 8] N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (49) and N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (50):

[0201] N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (48) (200 mg) was purified by chiral chromatography using (AD column, SFC=100 mL / min, CO2 / IPA=85 / 15, 206 bar) to obtain N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (49) (peak 2, tR 7.41 min); 1H As NMR(500MHz,METHANOL-d4)δ:7.37-7.55(m,2H),7.00(d,J=7.3Hz,1H),6.85(br d,J=8.3Hz,1H),6.75(br d,J=6.9Hz,1H),6.69(s,1H),1.99(s,3H), [Table 9] And N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (50) was obtained as (Peak 1, tR 4.10 minutes); 1H NMR (500 MHz, METHANOL-d4) δ: 7.42 - 7.52 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.84 (br d, J = 8.3 Hz, 1H), 6.75 (br d, J = 8.3 Hz, 1H), 6.68 (s, 1H), 1.99 (s, 3H).

Table 10

Chemical formula

[0202] Dioxane: Selenium dioxide (2.7 g, 24 mmol) was added to a mixture of 4-nitro-1H-inden-1,3(2H)-dione 4 (2.3 g, 12 mmol) in AcoH (20 mL / 2 mL). The resulting reaction mass was refluxed at 130 °C for 3 hours. The reaction mass was cooled to ambient temperature, diluted with ethyl acetate, filtered through a celite bed, washed with ethyl acetate, and the solvent was evaporated to obtain a crude product. The residue was used in the next step without purification as it was. 7-Chloro-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(52):

[0203] A mixture of 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (3.7 g, crude) in acetic acid (20 mL) was mixed with 3-chlorophenol 51 (1.6 g, 12 mmol). The resulting reaction mixture was refluxed at 110°C for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through a Celite bed, washed with ethyl acetate, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the product. 7,9b-Dichloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(53):

[0204] To a mixture of 7-chloro-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 52 (400 mg, 1.2 mmol) in DCM (6 mL), oxalyl chloride (0.12 mL, 1.44 mmol) was added. DMF (0.4 mL) was added dropwise to the resulting reaction mixture over 1 hour, and the mixture was then stirred at ambient temperature for 15 hours. The reaction mixture was diluted with DCM, washed with water (50 mL x 2), and the organic layer was washed with brine solution. The mixture was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the product. 9b-amino-7-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(54):

[0205] A mixture of 7,9b-dichloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 53 (220 mg, 0.63 mmol) in THF (3 mL) at -40°C was mixed with ammonia in IPA (0.8 mL, 1.6 mmol) over 5 minutes, and the reaction mixture was stirred at -40°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with brine solution (50 mL x 2). The organic layer was then dried over Na2SO4, and the solvent was evaporated to obtain the (crude) product. The crude product was used directly in the next step without purification. N-(7-chloro-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(55):

[0206] To a solution of 9b-amino-7-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 54 (210 mg, 0.63 mmol) in AcoH (6 mL), acetic anhydride (0.07 mL, 0.76 mmol) was added. The resulting reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (50 mL), the organic layer was washed with water (25 mL x 2), the organic layer was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the product. N-(1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(56):

[0207] To a solution of N-(7-chloro-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (100 mg, 0.26 mmol) in EtOH:H2O (9 mL), Fe powder (45 mg, 0.8 mmol) and concentrated HCl (1 drop) were added. The resulting reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The solvent was evaporated to obtain a residue, which was dissolved in ethyl acetate (100 mL). The organic layer was washed with water (50 mL x 2), dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate:hexane to obtain the product. 1 H NMR(300MHz,Methanol-d4)δ 7.62 - 7.24(m,2H),6.99(t,J=8.8Hz,2H),6.82(d,J=1.9Hz,1H),6.72(s,1H),2.01(s,3H). [Table 11] N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (57) and N-((4bS,9bS)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (58):

[0208] N-(1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (56) (200 mg) was purified by chiral chromatography using an IC column (SFC = 100 mL / min, CO2 / MeOH = 85 / 15, 206 bar) to obtain N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (57) (peak 2, tR 7.20 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.42-7.49 (m, 1H), 7.39 (br Assuming d,J=3.8Hz,1H),6.99(br d,J=4.5Hz,1H),6.90-6.96(m,1H),6.80(br s,1H),6.66-6.77(m,1H),1.99(br s,3H), [Table 12] Then, N-((4bS,9bS)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (58) (peak 1, tR 4.92 min); 1 The 1H NMR (500MHz, METHANOL-d4) was obtained with the following δ values: 7.47 (t, J=7.8Hz, 1H), 7.41 (br d, J=8.3Hz, 1H), 7.01 (d, J=7.3Hz, 1H), 6.97 (br d, J=8.3Hz, 1H), 6.82 (s, 1H), 6.76 (br s, 1H), and 2.01 (s, 3H). [Table 13] Examples 16-18: N-(1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide and N-((4bR,9bR)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide [ka] 4b,9b-dihydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(60)

[0209] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (6.3 g, crude, 26.15 mmol) was suspended in ice AcOH (44 mL). m-Cresol 59 (3.0 mL, 28.77 mmol) was added. The resulting solution was refluxed at 120°C for the next 6 hours and then concentrated. The residue was purified by column chromatography (50% EA in hexane containing 50% dichloromethane) and precipitated again to obtain the pure product. 1 H NMR(300MHz,CDCl3)δ 8.51(dd,J=8.0,0.8Hz,1H),8.19(dd,J=7.7,0.9Hz,1H),7.80(t,J=7.8Hz,1 H),7.45(d,J=7.8Hz,1H),6.85(d,J=7.8Hz,48H),6.67(s,1H),2.31(s,3H). 9b-Chloro-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(61)

[0210] 4b,9b-dihydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 60 (5.3 g, 16.91 mmol) was suspended in DCM (67 mL). Oxalyl chloride (1.7 mL, 20.3 mmol) was slowly added at ambient temperature (5 minutes), followed by the slow addition of dry DMF (5 mL) at ambient temperature. The reaction mixture was stirred overnight at ambient temperature, diluted with DCM, and washed with water. The organic layer was dried over anhydrous Na2SO4, concentrated, and then purified by column chromatography (25% EA in Hex containing 25% DCM), and re-precipitation (DCM / Hex = 1 / 2) to obtain the product. 1 H NMR(300MHz,CDCl3)δ 8.53(dd,J=8.0,0.9Hz,1H),8.23(dd,J=7.7,1.0Hz,1H),7.83(t,J=7.9Hz,1H),7.44(d,J=7 .9Hz,1H),6.89(d,J=7.9Hz,1H),6.68(d,J=7.2Hz,1H),6.34(s,1H),2.32(d,J=6.1Hz,3H). 9b-amino-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(62)

[0211] 9b-Chloro-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 61 (2.29 g, 6.9 mmol) was dissolved in dry THF (69 mL), and then a 2.0 M solution of NH3 in IPA (6.9 mL) was added at -40°C. The reaction mixture was heated to -10°C and stirred for 3 hours. The reaction mixture was diluted with EA and washed with water. The organic layer was dried over anhydrous Na2SO4, concentrated, and then purified by column chromatography (33% EA in Hex containing 3.3% DCM), and re-precipitation (DCM / Hex = 1 / 2) to obtain the product. 1H NMR(300MHz,CDCl3)δ 8.52(d,J=8.0Hz,1H),8.14(d,J=7.6Hz,1H),7.75(t,J=7.8Hz,1H),7.31(m,1H),6.83(t,J=8.6Hz,1H),6.67(s,1H),2.30(d,J=6.0Hz,3H). N-(4b-hydroxy-7-methyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(63)

[0212] 9b-amino-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (310 mg, 1.0 mmol) and acetic anhydride (0.113 mL, 1.2 mmol) were dissolved in acetic acid (10 mL). The resulting solution was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, then diluted with EA, and washed with water. The organic layer was dried over anhydrous MgSO4, concentrated, and then purified by column chromatography (50% EA in hexane containing 5% DCM), and re-precipitation (DCM / Hex = 1 / 2) to obtain the product. 1 H NMR(300MHz,CDCl3)δ 8.47(dd,J=8.1,0.8Hz,1H),8.22(d,J=6.9Hz,1H),7.76(t,J=7.8Hz,1H),7.42(d,J=7.8Hz, 1H),6.85(d,J=7.9Hz,1H),6.64(s,1H),6.50(s,1H),6.08(s,1H),2.31(s,3H),2.10(s,3H). N-(1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide(64)

[0213] N-(4b-hydroxy-7-methyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide 63 (150 mg, 0.4233 mmol) was dissolved in ethanol (8 mL). To this solution, iron powder (70 mg, 1.27 mmol), water (0.8 mL), and concentrated HCl (2 drops) were added. The resulting solution was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated and then purified by column chromatography (50%-150% EA in Hex containing 5% DCM), reprecipitation with EA, and the product was obtained. 1 H NMR(300MHz,CDCl3)δ 8.83(s,0.5H),7.52(m,1.5H),7.23(m,1.6H),7.17(d,J=7.5Hz,0.7H),6.85(m,1H),6.77(d,J=7.8Hz,0.7H),6.66(m,1.5H) ),6.60(d,J=8.1Hz,0.7H),6.54(brs,0.3H),5.76(d,J=8.9Hz,1H),5.55(brs,1H),2.29(s,2H),2.26(s,1H),2.06(s,3H). [Table 14] N-((4bR,9bR)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (65) and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (66)

[0214] N-(1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (64) (200 mg) was purified by chiral chromatography using (AD column, HPLC = 20 mL / min, heptane / IPA = 70 / 30, 759 psi) to obtain N-((4bR,9bR)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (65) (peak 2, tR 12.49 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.38-7.47 (m, 1H), 7.28-7.37 (m, 1H), 6.97 (br Assuming d,J=6.6Hz,1H),6.79(br d,J=6.9Hz,1H),6.66(br d,J=7.3Hz,1H),6.59(br s,1H),2.27(s,3H),1.99(s,3H), [Table 15] Then, N-((4bS,9bS)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (66) (peak 1, tR 7.77 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.44 (br s, 1H), 7.34 (br s,1H),6.99(br d,J=5.7Hz,1H),6.80(br d,J=6.1Hz,1H),6.68(br d,J=4.0Hz,1H),6.61(br The values ​​obtained were s,1H), 2.28(s,3H), and 2.01(s,3H). [Table 16] Example 19: N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide. [ka]

[0215] The procedure for the above compound followed the same route as described in Examples 16-18, except that p-cresol was used instead of m-cresol, to obtain the product N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide. 1 H NMR(500MHz,METHANOL-d4)δ:7.44(br t,J=7.2Hz,1H),7.30(br s,1H),7.09(br d,J=7.8Hz,1H),6.99(br d,J=6.9Hz,1H),6.67(br t,J=9.2Hz,2H),2.30(br s,3H),2.01(s,3H). [Table 17] Example 20: N-((4bR,9bR)-1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide. [ka]

[0216] Racemic N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (200 mg) was purified by chiral chromatography using an AD column (SFC=100 mL / min, CO2 / EtOH=75 / 25, 226 bar) to obtain the product N-((4bR,9bR)-1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (peak 2, tR 5.43 min); 1H NMR (400 MHz, METHANOL-d4) δ: 7.42 (br t, J=7.1 Hz, 1H), 7.27 (br The compounds obtained were s,1H), 7.06(br d,J=7.9Hz,1H), 6.97(br d,J=6.8Hz,1H), 6.64(br d,J=8.1Hz,2H), 2.28(s,3H), and 1.98(s,3H), as well as N-((4bS,9bS)-1-amino-4b-hydroxy-8-methyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (peak 1, tR 3.68 min). [Table 18] Example 21: N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N-methylacetamide [ka]

[0217] The procedure for the above compound followed the same route as described in Examples 3-5, except that 2.0 M methylamine in THF was used instead of 2.0 M ammonia in IPA, to obtain the product N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N-methylacetamide. 1H NMR(500MHz,METHANOL-d4)δ:7.63(br d,J=7.6Hz,1H),7.44(br t,J=7.8Hz,1H),7.31(br d,J=8.0Hz,1H),7.10(s,1H),6.99(br d,J=7.3Hz,1H),6.70(br d,J=7.3Hz,1H),2.88(s,3H),2.19(s,3H). [Table 19] Examples 22-24: N-(1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (Example 22), N-((4bR,9bR)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (Example 23), and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (Example 24) [ka]

[0218] The procedure for the above compound followed the same route as described in Examples 16-18, except that 3-methoxyphenol was used instead of m-cresol, to obtain racemic N-(1-amino-4b-hydroxy-7-methoxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (Example 22) (200 mg). This was purified by chiral chromatography using (AD column, HPLC = 20 mL / min, heptane / IPA = 70 / 30, 723 psi) to obtain the above product N-((4bR,9bR)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (peak 2, tR 24.20 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.39-7.50 (m, 1H), 7.31 (br dd, J=3.1, 2.4 Hz, 1H), 6.92-7.05 (m, 1H), 6.62-6.74 (m, 1H), 6.44-6.57 (m, 1H), 6.34 (s, 1H), 3.72 (s, 3H), 1.99 (s, 3H) (Example 23), and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methoxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)acetamide was obtained (peak 1, tR 9.78 min) (Example 24). [Table 20] The biological activity of the compounds of the present invention was determined using the following method. Determining drug efficacy against picornaviruses using cytopathic effects (CPE) Inhibition assay

[0219] This assay used HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblasts), and RD cells (derived from human rhabdomyosarcoma). For comparison, ribavirin (Riv), preconalil (pleco), and BTA-798 (BTA) were used as controls. Reagents were dissolved in 100% dimethyl sulfoxide (DMSO) at concentrations of 10–40 mg / mL. Water-soluble reagents were dissolved in PBS(-) solution and stored at -20°C. On the day of the experiment, they were used at 3–5 times the concentration so that the dimethyl sulfoxide concentration in each well was 0.5–1%.

[0220] The pharmacokinetic efficacy was determined using a virus-induced cytopathic effect (CPE) inhibition assay. For this assay, virus-compatible cells were grown in 96-well plates, and the virus was diluted in either DME (DME / 2%FBS) or MEM (MEM / 2%FBS) supplemented with 2%FBS. 50 100 μL of the drug (50% cell culture infectious dose) was inoculated into each well of the plate at the corresponding concentration, and the cells were incubated at 33°C or 37°C for 30 minutes to 1 hour to allow the virus to adsorb onto the cells. After removing the culture medium, aliquots of various concentrations of drug dilutions were added to each well at 100 μL. HRV (human rhinovirus) was grown at 33°C, while other viruses were incubated in a 37°C CO2 incubator for 2-3 days. Alternatively, 50 μL of each drug dilution at twice the concentration was added, followed by 50 μL of a virus dilution, after which the cells were cultured for 2-3 days without removing the medium. The viruses were incubated in host HeLa cells at 37°C for 2-3 days in DME / 2% or MEM / 2% FBS.

[0221] In HeLa cells, the MTT assay is used to determine the drug concentration that induces an intermediate response between baseline and maximum, which is called the EC (Energy Control). 50The drug was measured at the 50% maximum effective concentration. In RD and MRC-5 cells, CPE was determined using FDA (fluorescein diacetate) or MTT. To determine the effect of drug toxicity on efficacy results, simulated infection was included at the time of viral inoculation. Virus-free medium was added to the cell culture and then subjected to the same treatment as virus-infected cells inoculated with the virus. That is, after 1 hour of incubation, the medium was removed and a diluted drug solution in the medium was added again. After incubation for 2-3 days, cells were observed under a microscope, and the number of surviving cells in the drug-containing simulated infection wells was compared to the number of surviving cells in the drug-free control wells. 50% of the cells were killed using the MTT assay in CC cells. 50 Cells were measured at a 50% cytotoxic concentration. In the FDA hydrolysis assay, after removing the culture medium, FDA was added to each well and incubated for 20-30 minutes. The fluorescence intensity was then measured using a spectrofluorometer to determine CPE, similar to the MTT assay.

[0222] Specifically, the survival rate (% survival rate) of simulated infected cells for cytotoxicity measurement was calculated using the following formula 1:

[0223] Cellular drug = Survival × [A (drug) - A (background solution) / A (cell control) - (background × 100% solution)]

[0224] 100% cell viability means that the drug has no cytotoxicity, but the highest level of cytotoxicity is reflected by 0% cell viability. The 50% cytotoxic concentration was defined as the concentration required to reduce the cell number by 50%. This drug concentration is CC 50 It is expressed as follows. A higher value means lower cytotoxicity.

[0225] Furthermore, the antiviral effect can be calculated using the following formula 2: Antiviral effect = [A (drug / virus) - A (virus control) / A (cell control) - A (virus control)]

[0226] When the survival rate is 100%, the antiviral effect is 100%, but when the survival rate is 0%, there is no antiviral effect. The concentration of the drug at which the cells in the well infected with the virus can show a 50% survival rate is EC 50 which is calculated as, and the lower this value, the better the antiviral effect.

[0227] In Table 1 below, the CC 50 concentration showing cytotoxicity to the compound, and the EC 50 concentration showing activity against a number of rhinoviruses belonging to picornavirus are listed. Determination of the drug effect against picornavirus using a multi-cycle cytopathic effect (CPE) reduction assay

[0228] The drug effectiveness against picornavirus was determined using a multi-cycle CPE reduction assay. First, the antiviral activity of the compound was determined by a CPE reduction assay based on MIS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].

[0229] Specifically, cells grown to confluence in a 96-well plate were infected with a virus having a 50% tissue culture infective dose (CCID 50 ) of 100. After a 2-hour adsorption period at 37°C, the virus was removed and serial dilutions of the compound were added. The cultures were further incubated at 37°C for 3 days until complete CPE was observed in the infected and untreated virus controls (VC). After removing the medium, 90 μL of culture medium and 10 μL of MTS-phenazine methosulfate (Promega, Leiden, The Netherlands) were added to each well. After a 2-hour incubation period at 37°C, the optical density (OD) of each well was read at 498 nm in a microplate reader.

[0230] The %CPE value for evaluating antiviral activity was calculated using the following Equation 3: %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(VC)]

[0231] The %CPE value for measuring the cytotoxicity of a drug was calculated using the following formula 4: %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)] In formulas 3 and 4 above, OD(CC) represents the OD of background cell cultures that have not been induced by viruses or treated with chemicals. OD(VC) represents the OD of a control cell culture that was induced by a virus but not treated with chemicals. OD (virus + compound) represents the OD of virus-infected cell cultures treated with a concentrated compound. OD(compound) represents the OD of cell cultures treated with concentrated compounds only, while OD(blank) represents the OD of wells to which only cell cultures were added.

[0232] Effective concentration (EC 50 ) represents the concentration of a drug at which 50% of cells can survive due to CPE of the induced virus, and the cytotoxic concentration (CC) 50 The values ​​represent the concentration of the drug that killed 50% of the cells, and these were calculated using logarithmic interpolation.

[0233] In Table 1 below, the toxicity concentrations (CC) of several compounds in the examples against various viruses are shown. 50 ) and effective concentration (EC 50 List them. [Table 21]

[0234] As shown in Table 1 above, most of the compounds according to the present invention have high CC 50This indicates low cytotoxicity. Furthermore, it was found that the novel compounds according to the present invention have very high antiviral activity against a large number of rhinoviruses (HRV) in most cases. Moreover, it was found that the novel compounds according to the present invention have high antiviral activity against coxsackievirus B4 (Cox B4) and poliovirus 1 (PV1) in most cases.

[0235] Therefore, since the compounds according to the present invention exhibit low cytotoxicity and high antiviral activity against various rhinoviruses, they can be usefully used in pharmacological compositions for preventing or treating diseases caused by picornaviruses, to which rhinoviruses belong.

[0236] Therefore, the compounds according to the present invention have low cytotoxicity and exhibit excellent antiviral activity against picornaviruses, including coxsackievirus, poliovirus, and rhinovirus. Thus, they can be effectively used to prevent or treat diseases of the respiratory, cardiovascular, and nervous systems caused by such viruses, such as polio, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media.

[0237] The compounds represented by the formula according to the present invention, which are in equilibrium with each other, not only have low cytotoxicity but also possess excellent antiviral activity against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus. Therefore, they can be effectively used as pharmaceutical compositions for preventing or treating viral diseases such as polio, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. In one embodiment, for example, the following items are provided. (Item 1) A compound of formula I or a pharmaceutically acceptable salt thereof: [Chemical formula] (wherein, G 1 and G 2 one of them is selected from straight-chain or branched C1-C5 alkyl, straight-chain or branched C1-C5 alkyloxy, straight-chain or branched C1-C5 haloalkyl, straight-chain or branched C1-C5 haloalkyloxy, halo and 3-7 member cycloalkyl; G 1 and G 2 the other of them is H; R 1 is selected from H and straight-chain or branched C1-C5 alkyl). (Item 2) G 1 is selected from straight-chain or branched C1-C5 haloalkyl, straight-chain or branched C1-C5 haloalkyloxy, and 3-7 member cycloalkyl, the compound or a pharmaceutically acceptable salt thereof according to Item 1. (Item 3) G 1 is straight-chain or branched C1-C5 haloalkyl, the compound or a pharmaceutically acceptable salt thereof according to Item 1 or 2. (Item 4) G 1 is CF3, the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3. (Item 5) G 1 is straight-chain or branched C1-C5 haloalkyloxy, the compound or a pharmaceutically acceptable salt thereof according to Item 1 or 2. (Item 6) G 1 is OCF3, the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1, 2, and 5. (Item 7) G 1 is 3-7 member cycloalkyl, the compound or a pharmaceutically acceptable salt thereof according to Item 1 or 2. (Item 8) G1 A compound or pharmaceutically acceptable salt thereof described in any one of items 1, 2, and 7, which is cyclopropyl. (Item 9) G 2 A compound or a pharmaceutically acceptable salt thereof, which is H, as described in any one of items 1 to 8. (Item 10) G 1 However, the compounds listed in item 1 or 9, or their pharmaceutically acceptable salts, are methyl. (Item 11) G 1 However, the compound described in item 1 or 9, or a pharmaceutically acceptable salt thereof, is OCH3. (Item 12) G 1 However, the compounds listed in item 1 or 9, or their pharmaceutically acceptable salts, are isopropyl. (Item 13) G 1 However, a compound listed in item 1 or 9, or a pharmaceutically acceptable salt thereof, that is a halo. (Item 14) G 1 The compound listed in item 1 or a pharmaceutically acceptable salt thereof, wherein H is present. (Item 15) G 2 However, the compounds listed in item 1 or their pharmaceutically acceptable salts are methyl. (Item 16) The compound is a compound of formula (II) as described in any one of items 1 to 15, or a pharmaceutically acceptable salt thereof: [ka] (Item 17) Compounds having formula (III) as described in any one of items 1 to 15, or pharmaceutically acceptable salts thereof: [ka] (Item 18) The compound is a compound of formula (IV) as described in any one of items 1 to 9, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, G 1 (Selected from linear or branched C1-C5 haloalkyl groups, linear or branched C1-C5 haloalkyloxy groups, and 3- to 7-membered cycloalkyl groups). (Item 19) G 1 However, a compound selected from CF3, OCF3, and cyclopropyl, as described in any one of items 1-9 and 18. (Item 20) R 1 A compound selected from H and methyl, as described in any one of items 1-15, 18, and 19. (Item 21) A compound selected from the following, listed in any one of items 1-17: [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] or a pharmaceutically acceptable salt thereof. (Item 22) Compounds described in any one of items 1-17 and 21, pharmaceutically acceptable salts thereof, or optical isomers thereof, for the prevention or treatment of viral diseases. (Item 23) A pharmaceutical composition for the prevention or treatment of a viral disease comprising a compound described in any one of items 1 to 17 and 21, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient. (Item 24) A combination comprising a compound described in any one of items 1 to 17 and 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 23, and one or more therapeutic agents. (Item 25) A method for treating a viral disease, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 1 to 17 and 21, or a pharmaceutical composition described in item 23, or a combination described in item 24. (Item 26) Use of the compounds described in item 22, or pharmaceutically acceptable salts thereof, or optical isomers thereof, or the pharmaceutical compositions described in item 23, or the combinations described in item 24, for the prevention or treatment of viral diseases. (Item 27) The aforementioned viral disease is caused by a coxsackievirus, and the compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26. (Item 28) The aforementioned viral disease is caused by the poliovirus, and the compounds described in item 22, or the pharmaceutical compositions described in item 23, or the methods described in item 24, or the uses described in item 26. (Item 29) The aforementioned viral disease is caused by an echovirus, and the compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26. (Item 30) The aforementioned viral disease is caused by an enterovirus, and the compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26. (Item 31) The aforementioned viral disease is caused by a rhinovirus, and the compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26. (Item 32) The aforementioned viral disease is caused by a picornavirus, and the compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26. (Item 33) The compound described in item 22, or the pharmaceutical composition described in item 23, or the method described in item 24, or the use described in item 26, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. (Item 34) [ka] or [ka] The compounds listed in item 1, or their pharmaceutically acceptable salts. (Item 35) Compounds described in any one of items 18-21 and 34, pharmaceutically acceptable salts thereof, or optical isomers thereof, for the prevention or treatment of viral diseases. (Item 36) A pharmaceutical composition for the prevention or treatment of a viral disease comprising a compound described in any one of items 18-21 and 34, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient. (Item 37) A combination comprising a compound described in any one of items 18-21 and 34, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 36, and one or more therapeutic agents. (Item 38) A method for treating a viral disease, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 18-21 and 34, or a pharmaceutical composition described in item 36, or a combination described in item 37, to the target. (Item 39) Use of any one of the compounds described in items 18-21 and 34, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition described in item 36, or a combination described in item 37, for the prevention or treatment of a viral disease. (Item 40) The aforementioned viral disease is caused by one of the following: coxsackievirus, poliovirus, echovirus, enterovirus, rhinovirus, and picornavirus, and the compounds described in any one of items 18-21 and 34, or the pharmaceutical compositions described in item 36, or the methods described in item 38, or the uses described in item 39. (Item 41) The aforementioned viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, bullous disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media, and the compound described in any one of items 18-21 and 34, or the pharmaceutical composition described in item 36, or the method described in item 38, or the use described in item 39.

Claims

1. Compounds of formula I or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, G １ C is a straight or branched chain. １ -C ５ Selected from alkyloxy and halo; G ２ is H; or G ２ is selected from linear or branched C １ -C ５ alkyl, linear or branched C １ -C ５ alkyloxy, linear or branched C １ -C ５ haloalkyl, linear or branched C １ -C ５ haloalkyloxy, halo, and 3- to 7-membered cycloalkyl; G1 is H; R １ H and linear or branched C １ -C ５ (Selected from alkyl groups).

2. G １ However, linear or branched chain C １ -C ５ Selected from alkyloxy and halo; G ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is H.

3. G １ is bromo, G ２ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

4. G １ ga OCH ３ G ２ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

5. G ２ However, linear or branched chain C １ -C ５ Alkyl, linear, or branched C １ -C ５ Alkyloxy, linear, or branched C １ -C ５ Haloalkyl, linear, or branched C13 １ -C ５ Selected from haloalkyloxy, halo, and 3- to 7-membered cycloalkyl; G １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is H.

6. G ２ is a straight chain or branched chain C １ -C ５ Selected from alkyl groups; G １ A compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

7. G ２ is a straight chain C １ -C ５ It is alkyl, G １ A compound according to any one of claims 1 and 5 to 6, or a pharmaceutically acceptable salt thereof, wherein is H.

8. G ２ is methyl, G １ A compound according to any one of claims 1 and 5 to 7, or a pharmaceutically acceptable salt thereof, wherein is H.

9. R １ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is H.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): 【Chemistry 2】 。

11. A compound according to any one of claims 1 to 9 having formula (III), or a pharmaceutically acceptable salt thereof: 【Transformation 3】 。

12. The following compounds can be selected: 【Chemistry 4-1】 【Chemistry 4-2】 or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound, 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound, 【Transformation 6】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound, 【Transformation 7】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. A composition comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for the prevention or treatment of a viral disease.

17. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

18. A combination comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, and one or more therapeutic agents.

19. A composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, or a combination according to claim 18, for treating a viral disease.

20. A composition according to claim 16 or 17, or a combination according to claim 18, for preventing or treating a viral disease.

21. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by a coxsackievirus.

22. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by poliovirus.

23. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by an echovirus.

24. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by an enterovirus.

25. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by a rhinovirus.

26. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is caused by a picornavirus.

27. The composition according to claim 16 or 17, or the composition or combination according to claim 19 or 20, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

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