Antiviral 1,3-di-oxo-indene 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 coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses, and are therefore useful in treating viral infections, including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, 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] Picornaviridae are non-enveloped, positive-sense, single-stranded RNA viruses whose RNA genome is 7.2-8.5 Kb long. These viruses are very small, spherical, with a size of about 22-30 nm, and were first identified a long time ago. Among the viruses that belong to the Picornaviridae family are rhinoviruses, polioviruses, enteroviruses including coxsackievirus A, coxsackievirus B, and echoviruses, and hepatitis A virus.

[0003] Picornaviruses cause a wide range of diseases, from respiratory to digestive, circulatory, and skin diseases, including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot, and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, common cold, herpangina, and foot and mouth disease. However, there are no drugs to cure these diseases. Most of the drugs under development are shedding inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory diseases, which cause sanitary, social, and economic problems. Picornaviruses are the main causative agents of water-borne diseases. Being very stable and difficult to disinfect, RNA viruses cause related diseases incessantly.

[0004] Human rhinovirus (hRV) has recently been associated with a large proportion of asthma exacerbations and is even known to be present in the bronchial tissues of many stable asthmatic patients. Comparison of bronchial mucosa biopsies from asthmatic and nonasthmatic patients showed that human rhinovirus was detected significantly more frequently in the lower airways of asthmatic patients than in nonasthmatic 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, and otitis media, as well as asthma.

[0005] Rhinoviruses are the main cause of the common cold, while enterovirus-induced diseases include meningitis, respiratory tract infections, etc. Extensive efforts to provide vaccination against poliovirus have significantly reduced the incidence of polio worldwide, although cases of the disease are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A can now be controlled to some extent thanks to a vaccine for hepatitis A virus. However, no vaccines for coxsackievirus, echovirus, or rhinovirus have been developed to date.

[0006] In particular, Coxsackievirus B is a major cause of myocarditis that, in severe cases, can progress to idiopathic dilated cardiomyopathy requiring heart transplantation.

[0007] Enviroxime derivatives are considered to be the most promising candidates with broad anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with the synthesis of positive-stranded 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, in clinical studies, the compounds were observed to have only insignificant or almost no therapeutic effect, and were 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 fine structure and function of viral protease 2C. In cell cultures within the nanomolar concentration range, AG7088 has activity against 48 rhinovirus types, as well as coxsackieviruses A21, B3, enterovirus 70, and echovirus 11 (Pattick AK et al.: Antimicrobial Agents Chemother, 1999, 43(10), 2444-50).

[0009] Thanks to the elucidation of the molecular structure of the viral capsid, the prerequisites were obtained for the purposeful design of capsid blockers "WIN substances" (Diana GD: Curr Med Chem 2003,2,1-12). They inhibit the adsorption and / or uncoating of rhinoviruses and enteroviruses. Some of the WIN substances have a highly specific effect only on individual genera or virus types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. For example, aryldone, disoxalyl, and pirodavir belong to the WIN substances. These compounds showed very good antiviral effects in cell cultures. However, poor solubility (aryldone), low bioavailability (aryldone and disoxalyl), rapid metabolism and excretion (disoxalyl and WIN54954), as well as side effects such as skin rash (WIN54954) preclude clinical application.

[0010] Pleconaril, a type of WIN substance, has very good oral bioavailability and inhibits the entry of rhinoviruses, echoviruses, and coxsackieviruses after binding to a hydrophobic pocket in the viral capsid (Pevear DC et al. al.:Antimicrob Agents Chemother 1999,43(9),2109-15;McKinlay MA et al.:Annu Rev Microbiol 1992,46,635-54). Thus, Pleconaril is potentially effective against a wide range of viral diseases, from the common cold to viral meningitis or myocarditis. Resistance was observed for 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 proven therapeutic efficacy was not sufficient to register Pleconaril (Picovir, Viropharma,USA) as an agent for treating 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 therapeutic success rate and observed side effects. Ta.

[0011] BTA-798 has been found to have greater antiviral activity than pleconaril 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 been developed to date that have received approval for use in the treatment of enteroviruses or rhinoviruses. There remains a need for new treatments and therapies against enteroviruses and rhinoviruses. As a result of intensive and thorough research into effective viral growth inhibitors against picornaviruses, including coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses, it was discovered that novel 1,3-dioxoindene derivatives exhibit high inhibitory activity against picornaviruses, including coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses, which led 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 Summary of the Invention [Means for solving the problem]

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

[0015] In one aspect, the present invention provides a compound of formula (I): [ka] (In the formula, G 1 and G 2 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- to 7-membered cycloalkyl; 1 and G 2 The other of the two is H; 1 is selected from H and straight or branched C1-C5 alkyl), optionally the compound is in enantiomerically pure form. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and one or more pharma- ceutically acceptable carriers. In another aspect, the invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the invention and one or more therapeutically active agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0017] As used herein, terms have the following meanings, unless the context clearly indicates otherwise.

[0018] As used herein, the term "subject" refers to an animal. In certain aspects, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In certain embodiments, a subject is a human. As used herein, a "patient" refers to a human subject. As used herein, a subject is "in need" of a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0019] As used herein, the term "inhibit" or "inhibition" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0020] As used herein, the term "treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or onset or progression of the disease or disorder.

[0021] As used herein, "a," "an," "the," and similar terms as used in the context of the invention (particularly in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise specified in the specification or clearly contradicted by context.

[0022] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention, and does not limit the scope of the invention as claimed.

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

[0024] As used herein, "C 1-6 "Alkyl" or "C1-C6 alkyl" refers to a straight or branched chain alkyl having 1 to 6 carbon atoms. When a different number of carbon atoms, such as C4 or C3, is specified, the definition should be amended accordingly, e.g., "C1-4 "Alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0025] As used herein, "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy (-O-alkyl) having 1 to 6 carbon atoms. When a different number of carbon atoms is specified, such as C4 or C3, the definition should be amended accordingly, e.g., "C 1-4 "Alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0026] As used herein, "C 1-4 "Haloalkyl" or "C1-C4 haloalkyl" refers to a straight or branched alkyl having from 1 to 4 carbon atoms in which at least one hydrogen is replaced with a halogen. The number of halogen substitutions can be from 1 to the number of hydrogen atoms in the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C6 or C3, the definition should be amended accordingly. Thus, "C 1-4 "Haloalkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl having at least one hydrogen replaced with a halogen, for example, CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-, where the halogen is fluorine.

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

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

[0029] Embodiment 1. A compound of formula I or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 and G 2 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- to 7-membered cycloalkyl; 1 and G 2 The other of the two is H; 1 is selected from H and straight or branched C1-C5 alkyl.

[0030] Embodiment 2.G 1 or a pharma- ceutically acceptable salt thereof, of the compound of embodiment 1, wherein is selected from straight or branched chain C1-C5 haloalkyl, straight or branched chain C1-C5 haloalkyloxy, and 3- to 7-membered cycloalkyl.

[0031] Embodiment 3.G 1 is a straight or branched chain C1-C5 haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0032] Embodiment 4.G 1 or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1-3, wherein

[0033] Embodiment 5.G 1 is a straight or branched chain C1-C5 haloalkyloxy; or a pharma- ceutically acceptable salt thereof.

[0034] Embodiment 6.G 1 or a pharma- ceutically acceptable salt thereof.

[0035] Embodiment 7.G 1 is 3-7 membered cycloalkyl; or a pharma- ceutically acceptable salt thereof.

[0036] Embodiment 8.G 1 or a pharma- ceutically acceptable salt thereof. The compound according to any one of embodiments 1, 2, and 7, wherein:

[0037] Embodiment 9.G 2 is H; or a pharma- ceutically acceptable salt thereof.

[0038] Embodiment 10.G 1 is methyl; or a pharma- ceutically acceptable salt thereof.

[0039] Embodiment 11.G 1 is OCH3; or a pharma- ceutically acceptable salt thereof.

[0040] Embodiment 12.G 1 is isopropyl; or a pharma- ceutically acceptable salt thereof.

[0041] Embodiment 13.G 1 is halo; or a pharma- ceutically acceptable salt thereof.

[0042] Embodiment 14.G 1 is H; or a pharma- ceutically acceptable salt thereof.

[0043] Embodiment 15.G 2is methyl; or a pharma- ceutically acceptable salt thereof.

[0044] Embodiment 16. The compound according to any one of embodiments 1 to 15, wherein the compound is a compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka]

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

[0046] Embodiment 17a. The compound of any one of embodiments 1-9, wherein the compound is a compound of formula (IV) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 is selected from straight or branched chain C1-C5 haloalkyl, straight or branched chain C1-C5 haloalkyloxy, and 3- to 7-membered cycloalkyl.

[0047] Embodiment 17b.G 1 The compound according to any one of embodiments 1-9 and 17a, wherein is selected from CF3, OCF3, and cyclopropyl.

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

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

[0050] Embodiment 18a. A compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, selected from the group consisting of: 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 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 a pharma-ceutically acceptable salt thereof.

[0051] Embodiment 18b. [ka] or [ka] or a pharma- ceutically acceptable salt thereof.

[0052] Embodiment 19. A compound according to any one of embodiments 1 to 18, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, for preventing or treating a viral disease.

[0053] Embodiment 20. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound according to any one of embodiments 1 to 18, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient.

[0054] Embodiment 21. A combination comprising a compound according to any one of embodiments 1 to 18 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 20, and one or more therapeutically active agents.

[0055] Embodiment 22. A method for treating a viral disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 18 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 20, or a combination according to embodiment 21.

[0056] Embodiment 23. Use of a compound according to embodiment 19 or a pharma- ceutically acceptable salt or an optical isomer thereof, or a pharmaceutical composition according to embodiment 20, or a combination according to embodiment 21, for preventing or treating a viral disease.

[0057] Embodiment 24. The compound according to embodiment 19, or the pharmaceutical composition according to embodiment 20, or the method according to embodiment 21, or the use according to embodiment 23, wherein the viral disease is caused by a Coxsackievirus.

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

[0059] Embodiment 26. The compound according to embodiment 19, or the pharmaceutical composition according to embodiment 20, or the method according to embodiment 21, or the use according to embodiment 23, wherein the viral disease is caused by an echovirus.

[0060] Embodiment 27. The compound according to embodiment 19, or the pharmaceutical composition according to embodiment 20, or the method according to embodiment 21, or the use according to embodiment 23, wherein the viral disease is caused by an enterovirus.

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

[0062] Embodiment 29. The compound according to embodiment 19, or the pharmaceutical composition according to embodiment 20, or the method according to embodiment 21, or the use according to embodiment 23, wherein the viral disease is caused by a picornavirus.

[0063] Embodiment 30. The compound according to embodiment 19, or the pharmaceutical composition according to embodiment 20, or the method according to embodiment 21, or the use according to 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, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

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

[0065] Another embodiment of the present invention provides a compound as described above, or a pharma- ceutically acceptable salt thereof, as a medicament.

[0066] Also within the scope of the invention is the use of a compound of Formula I, II, or III, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of viral and / or infectious diseases in humans.

[0067] Also within the scope of the present invention is a pharmaceutical composition comprising a compound of Formula I, II, or III, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

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

[0069] The present invention also provides the use of a pharmaceutical composition as described above for the treatment of a viral infection in a human having or at risk of having an infection.

[0070] The invention also provides the use of a pharmaceutical composition as described above for the treatment of a viral or infectious disease in a human having or at risk of having the disease.

[0071] Another aspect of the invention relates to a method of treating or preventing viral and / or infectious diseases in a human by administering to the human an antivirally effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a composition as described above, either alone or in combination with at least one other antiviral agent administered together or separately.

[0072] An additional embodiment of the present invention refers to an article of manufacture comprising a composition effective for treating a viral disease and / or infectious disease and packaging material comprising a label indicating that the composition may be used to treat a viral disease and / or infectious disease, wherein the composition comprises a compound of Formula I, II, or III according to the present invention or a pharmaceutically acceptable salt thereof.

[0073] Yet another aspect of the invention relates to a method of 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 in which replication of the virus is inhibited. The method can be performed in vitro or in vivo.

[0074] Additionally, within the scope of the invention is the use of a compound of Formula I, II, or III, or a salt thereof, to inhibit viral replication.

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

[0076] These additional agents may be combined with the compounds of the invention to produce a single pharmaceutical dosage form. Alternatively, these additional agents may be administered separately to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, simultaneously with, or following administration of the compounds of the invention or a pharma- ceutically acceptable salt thereof.

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

[0078] The actual pharmacologic effective amount or therapeutic dose will, of course, depend on factors known by those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination will be administered in a dosage and manner that allows for the delivery of a pharmacologic effective amount based on the patient's unique condition.

[0079] When the compositions of the invention comprise a combination of a compound of the invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents may be present at dosage levels that are about 10-100%, for example, about 10-80%, of the dosage normally administered in a monotherapy regimen.

[0080] Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologics) effective to inhibit virus formation and / or replication in humans, including, but not limited to, agents that interfere with either the host or viral mechanisms necessary for virus formation and / or replication in humans.

[0081] Many compounds of the present invention contain one or more chiral centers. These compounds can be made and used as a single isomer or as a mixture of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable 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 mixture of isomers. In some embodiments, at least 95% of the sample is a single isomer. When the difference in in vitro activity between isomers is relatively small, for example less than about 4-fold, a method such as that described herein may be used to select a single isomer based on its activity level against virus replication in cell culture: the isomer with the lower IC50 or EC50 may be selected.

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

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

[0084] The invention further includes any variant of this process in which intermediate products obtainable at any stage of the process are used as starting materials and the remaining steps are carried out, or the starting materials are formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or optically pure materials.

[0085] The invention also relates to forms of the process in which compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or in which starting materials are formed under the reaction conditions or are used in the form of derivatives, for example in protected form or in the form of a salt, or in which compounds obtainable by the process according to the invention are produced under process conditions and further processed in situ.

[0086] The term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, including geometric isomers. It is understood that substituents may be attached to chiral centers of carbon atoms. The term "chiral" refers to molecules that possess the property of non-superimposability with respect to their mirror image partners; The term "achiral," on the other hand, refers to molecules that are superimposable relative to their mirror image partners. Thus, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to refer to racemic mixtures where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be designated by either R or S. Resolved compounds of unknown absolute configuration may be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0087] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible isomers, or as mixtures thereof, depending on the number of asymmetric carbon atoms, for example as pure optical isomers or as isomeric mixtures, such as racemic and diastereomeric mixtures. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have cis or trans configuration. All tautomeric forms are also intended to be included.

[0088] Any resulting mixture of isomers can be separated on the basis of the physical chemical differences of the constituents, into pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and / or fractional crystallization.

[0089] Any resulting racemates of the final products or intermediates can be resolved into their optical antipodes by known methods, for example by separation of their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. Thus, in particular, the compounds of the present invention can be resolved into their optical antipodes by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using basic moieties. Racemic products can also be separated by chiral chromatography, for example high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0090] Furthermore, the compounds of the present invention, including their salts, can be obtained in the form of their hydrates or can include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharma- ceutically 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 compounds of the present invention (including its pharma-ceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are known to be harmless to the recipient, e.g., water and ethanol, and are commonly used in the pharmaceutical arts. 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) may inherently or by design form polymorphs.

[0092] As used herein, the term "salt" or "salts" refers to any compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0093] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobisulfate, and the like. The salts are: ionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0094] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0095] Organic acids from which salts can be derived include, for example, 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, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0096] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0097] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, pipetamine, tetrahydrofuran ... Examples include arazine, and tromethamine.

[0098] The pharma- ceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxides, carbonates, or bicarbonates), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences" 20th Edition, Mack, et al., "Pharmaceuticals and Biotechnology", vol. 1, no. 1, pp. 111-115, 19 ... Publishing Company, Easton, Pa. (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0099] Any formula depicted herein represents unlabeled forms of the compounds of the invention, as well as up to three atoms having non-natural isotope distributions, such as deuterium or 13 C or 15It is intended to represent an isotopically labeled form having N-enriched sites. Isotopically labeled compounds have structures represented by the formulas shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number outside the natural abundance distribution. Examples of isotopes that can be usefully overincorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 The present invention relates to various isotopically labeled compounds of the present invention, e.g. 3 H and 14 Radioisotopes such as C, or 2 H and 13 These include those in which non-radioactive isotopes, such as C, are present at levels substantially above the normal isotopic distribution. Such isotopically labeled compounds are useful for metabolic studies (e.g., 14 C), reaction kinetic studies (e.g. 2 H or 3 in detection or imaging techniques such as 3H, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients; In particular, the present invention is useful in 18F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using suitable isotopically labeled reagents instead of typically used non-labeled reagents. Labeled samples can be useful with very low isotope incorporation, such as when radioactive labels are used to detect trace amounts of compounds.

[0100] Additionally, heavier isotopes, particularly deuterium (i.e. 2 More extensive substitution with H or D) may result in certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo, or reduced dosage requirements, or improved therapeutic index. Deuterium in this context is considered a substituent of the compounds of the present invention, and it is understood that a sample of a compound having deuterium as a substituent typically incorporates at least 50% deuterium at the labeled position(s). The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When substituents in the compounds of the invention are designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at 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).

[0101] Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization is isotopically substituted, e.g. D2O, d6 -Acetone, d 6 -Including what may be DMSO.

[0102] Compounds of the present invention that contain groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting in solution the compounds of the present invention with the co-crystal formers under crystallization conditions, and isolating the co-crystals formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. Thus, the present invention further provides co-crystals comprising compounds of the present invention.

[0103] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention, and does not limit the scope of the invention as claimed.

[0104] The compounds of the present invention can be administered by known methods, including orally, parenterally, and by 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. Infusions are typically administered intravenously, often 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 methods are particularly useful for treating respiratory infections. Since the compounds of the present invention exhibit oral bioavailability, in some embodiments, the compounds may be administered orally.

[0105] The compounds of the invention may also be used in combination with other agents (combination partners), such as additional antiviral agents, either of Formula I or not, for the treatment of a viral infection in a subject.

[0106] The term "combination" means either a combination fixed in one unit dosage form, either as separate dosage forms suitable for use together, either simultaneously or sequentially, or as a kit of parts for combined administration, where the compound of the present invention and the combination partner(s) may be administered independently simultaneously or separately, particularly within a time interval that allows the combination partners to exhibit a cooperative, e.g., synergistic, effect, or any combination thereof.

[0107] In certain embodiments of the invention, the compounds of the 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, at the same time, or after the compound or compounds of the present invention.When 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 with the second agent.Examples of dosage forms that contain the compound of the present invention and the second agent are tablets or capsules.

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

[0110] An "effective amount" of a compound is an amount necessary or sufficient to treat or prevent a viral infection and / or disease or condition described herein. In one example, an effective amount of a viral inhibitor of formula I is an amount sufficient to treat a viral infection in a subject. An effective amount may vary depending on factors such as the size and weight of the subject, the type of illness, or the particular compound of the present invention. For example, the selection of a compound of the present invention may affect what constitutes an "effective amount". One of ordinary skill in the art would be able to study the factors contained herein and make a determination regarding the effective amount of a compound of the present invention without undue experimentation.

[0111] Dosage regimes can affect what constitutes an effective amount. The compounds of the present invention can be administered to a subject either before or after the onset of viral infection. Furthermore, several divided doses and staggered dosages can be administered daily or sequentially, or the doses can be continuously infused or bolus injected. Furthermore, the dosage of the compound(s) of the present invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0112] The compounds of the 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 invention provides methods of using the compounds of the invention in the treatment of these diseases, or methods of preparing pharmaceutical compositions having the compounds of the invention for the treatment of these diseases.

[0113] The term "pharmaceutical composition" includes preparations suitable for administration to a mammal, e.g., a human. When a compound of the present invention is administered as a medicine to a mammal, e.g., a human, the compound may be given per se or as a pharmaceutical composition containing, for example, 0.1-99.5% (sometimes 0.5-90%) 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 phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharma-ceutically acceptable materials, compositions, or vehicles suitable for administering a compound of the invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and 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; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, 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 buffers, and other non-toxic compatible materials used in pharmaceutical preparations. Typically, pharmaceutically acceptable carriers are sterile and / or substantially pyrogen-free.

[0115] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0116] Examples of pharma- ceutically 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, α-tocopherol, and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[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 form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of the active ingredient, sometimes from about 5 percent to about 70 percent, and sometimes from about 10 percent to about 30 percent.

[0118] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, 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 (with a flavored base, typically sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (with an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0120] In solid dosage forms of the invention for oral administration (such as capsules, tablets, pills, dragees, powders, and granules), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; humectants, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers for soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0121] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0122] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, with various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only in a certain part of the gastrointestinal tract, or, for example, in a specific part, optionally in a sustained manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, optionally with one or more of the above-mentioned excipients.

[0123] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion preparation, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0124] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0125] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

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

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

[0128] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutical acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

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

[0130] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

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

[0132] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0133] Pharmaceutical compositions of the invention suitable for parenteral administration can contain one or more compounds of the invention in combination with one or more pharma- ceutically acceptable carriers, such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders, which can be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0134] Examples of 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, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0135] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, 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 the effect of the drug. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0137] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsion formulations that are compatible with body tissues.

[0138] The preparations of the present invention can be given orally, parenterally, topically or rectally. They are, of course, given in a form suitable for each administration route. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion or inhalation, topically by lotion or ointment, and rectally by suppositories.

[0139] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and substernal injection and infusion. Sometimes, intravenous infusion is the method of delivery of the compounds of the invention. Infusion may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the 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 a day, twice a day, or up to three times per day.

[0140] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to the administration of a compound, drug, or other material other than directly to the central nervous system, such that it enters the patient's system and is thus subject to metabolic and other similar processes, e.g., corresponding to subcutaneous administration.

[0141] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, for example, by spray, rectally, vaginally, parenterally, intracisternally, and topically, by powders, ointments, or drops (including buccal and sublingual).

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

[0143] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0144] The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention being used, or an ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound being used, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0145] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can begin doses of the compounds of the invention used in the pharmaceutical composition at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

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

[0147] If desired, the effective daily dose of the active compound may be administered as a single dose per day or as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. Compounds delivered orally or by inhalation are generally administered in one to four doses per day. Compounds delivered by injection are typically administered once a day or once every other day. Compounds delivered by infusion are typically administered in one to three doses per day. When multiple doses are administered within a day, the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours, or about 12 hours.

[0148] While the compounds of the invention can be administered alone, they can also be administered as a pharmaceutical composition, such as those described herein. Thus, methods of using the compounds of the invention include administering the compound as a pharmaceutical composition, where at least one compound of the invention is mixed with a pharma- ceutically acceptable carrier prior to administration. General synthetic 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, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th ed. (1952), Methods of Organic Synthesis, Thieme, Vol. 21). [Table 2-1] [Table 2-2]

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

[0152] Within the scope of this specification, only easily removable groups that are not constituents of a particular desired end product of the compounds of the invention are referred to as "protecting groups", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in standard references, for example, Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag (Stuttgart, Germany, 2005) p. 41627 (URL: http: / / www.science-of-synthesis.com (vol. 48 of the electronic version)); JFW MacOmie, "Protective "Protective Groups in Organic Synthesis," 3rd ed., Wiley (New York, 1999); "The Peptides"; vol. 3 (E. Gross and J. Meienhofer, eds.), Academic Press (London and New York, 1981), "Methoden der Organischen Chemie" ("Methods of Organic Chemistry"), Houben Weyl, 4th ed., vol. 15 / I, Georg Thieme Verlag (Stuttgart, 1974), H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Protein" ("Aminosauren, Peptide, Protein"), Verlag Chemie, (Weinheim, Deerfield Beach and Basel, 1982), and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccha-ride und Derivate" ("Chemistry of Carbohydrates: Monosaccharides and Derivatives"), Georg Thieme Verlag (Stuttgart, 1974). A characteristic of a protecting group may be that it is easily removable (i.e. without the occurrence of undesired secondary reactions), for example by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g. by enzymatic cleavage).

[0153] The salts of the compounds of the present invention having at least one salt-forming group can be prepared in a manner known per se. For example, the salts of the compounds of the present invention having an acid group can be formed by treating the compounds with metal compounds such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogencarbonates, for example the hydroxides, carbonates or hydrogencarbonates of sodium or potassium, with the corresponding calcium compounds, or with ammonia or suitable organic amines, sometimes using a stoichiometric amount or a slight excess of the salt former. The acid addition salts of the compounds of the present invention can be obtained in a conventional manner, for example by treating the compounds with an acid or a suitable anion exchange reagent. The internal salts of the compounds of the present invention containing acid and basic salt-forming groups, for example free carboxyl groups and free amino groups, can be formed by neutralizing the salts, for example acid addition salts, to their isoelectric points, for example by treating with a weak base or ion exchanger.

[0154] Salts can be converted into the free compounds in the usual manner: metal salts and ammonium salts can be converted, for example, by treatment with a suitable acid and acid-addition salts, for example by treatment with a suitable basic agent.

[0155] The mixtures of isomers obtainable according to the invention can be separated into the individual isomers in a manner known per se: diastereoisomers can be separated, for example, by partition between multiphase solvent mixtures, recrystallization and / or chromatographic separation, for example on silica gel, or for example by medium pressure liquid chromatography on reversed phase columns, and racemates can be separated, for example, by salt formation with optically pure salt-forming agents and separation of the mixtures of diastereoisomers thus obtainable, for example by fractional crystallization, or by chromatography on optically active column materials.

[0156] Intermediates and final products can be worked up and / or purified according to standard methods, eg using chromatographic methods, distribution methods, (re-)crystallization, and the like. EXAMPLES

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

[0158] The compounds of the invention can be prepared by organic synthesis methods known to those skilled in the art with reference to the following reaction schemes and examples. General methods for the synthesis of compounds of formula (I) are provided in the following schemes. High-resolution mass spectrometry by LC-MS

[0159] ESI-MS data were recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The resolution of the MS system was approximately 30000. Drug candidates were infused into the mass spectrometer by UPLC (Acquity, Waters) from the sample probe. Separation was performed on an Acquity UPLC BEH C18 1 x 50 mm column at a flow rate of 0.15 mL / min with a gradient of 5% to 95% in 3 min. Solvent A was water with 0.1% trifluoroacetic acid and solvent B was 75% methanol and 25% isopropyl alcohol with 0.1% trifluoroacetic acid. The mass accuracy of the system 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 L) was refluxed at 140° C. for 2.5 h. It was then cooled to 80° C. and slowly added to diethyl ether (4 L) with vigorous stirring. The precipitate was collected by filtration through a Büchner funnel, which was washed with Et2O to give the product as a solid. Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate (3):

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

[0162] Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate 3 (272.5 g, 1.04 mol) was taken in 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 then heating was continued at 50° C. After 4 hours, the reaction mass was concentrated on a rotavapour until approximately 100 mL of solvent remained. The precipitated solid was then filtered on a Buchner funnel and washed with (1:1) CHCl3:hexane. This gave a solid product and the filtrate was concentrated again to give more product in a second crop. [ka] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione (5):

[0163] 4-Nitro-1H-indene-1,3(2H)-dione (4) (250 g, 1.31 moles) was taken in 1,4-dioxane (2 liters) and AcOH (200 mL). To this, SeO2 (291 g, 2.62 moles) was added at room temperature and kept refluxing at 110°C for next 4 hours. It was stirred at room temperature for next 12 hours. To this was then charged with 500 g-600 g of Celite. It was thoroughly stirred and filtered through Celite pad. The residue was washed with ethyl acetate (300-500 mL). The filtrate obtained was concentrated to get a crude mass which was then used as such in the next step. 4b,9b-Dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (7):

[0164] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude, 1.31 mol) was taken in glacial AcOH (2 L) and charged with 3-isopropylphenol 6 (196 g, 1.44 mol) and kept refluxing for next 10 h, which was then concentrated completely and purified by silica gel column chromatography (30% EA in hexane) to give 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 moles) was taken in DCM (500 mL) and then this suspension was charged with oxalyl chloride (1.2 eq) in a single lot. This was then slowly charged with DMF (50 mL). The reaction mass was then left stirring at room temperature for next 6 hours. This 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 get a crude mass which was then purified on a short pad of silica (30% ethyl acetate in hexane) to get 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] 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 8 (36.0 g, 0.1 mol) was taken in THF (350 mL) and cooled to -40°C. To this, 2.0 M solution of NH3 in IPA (100 mL, 0.20 mol) was added using a dropping funnel and the temperature was maintained below -20°C. The reaction mass was monitored at -20°C for 1 hour and then warmed to room temperature. It was stirred at room temperature until the reaction was complete and then concentrated completely. The crude was taken in ethyl acetate (500 mL) and washed with water (200 mL x 2) and brine (100 mL). It was dried over anhydrous Na2SO4 and then concentrated to get a crude mass which was purified on a short pad of silica to get 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 taken in AcOH (10 mL, 0.1 M) to which acetic anhydride (0.263 mL, 2.8 mmol) was added at ambient temperature. It was heated at 80° C. for next 30 min. The reaction mass was concentrated and then taken in EA (100 mL). It was washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated. The obtained crude was purified by silica gel column chromatography (30-40% EA in hexane) to give 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 taken in EtOH:water (10:1, 15 mL, 0.1 M) to which was added Fe powder (0.219 mg, 3.92 mmol). It was charged with catalytic amount of concentrated HCl (3 drops) and refluxed at 90° C. for next 3 h. The reaction mass was filtered through Celite under hot condition and EA was used to wash the residue. It was concentrated and then taken in EA (250 mL). It was washed with water (100 mL) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated. The obtained crude was purified by silica gel column chromatography (1:1=EA:Hexane) to give 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 (AD column, SFC=100 mL / min, CO2 / EtOH=70 / 30, 236 bar) to give 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 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), 1.12-1.26(m,6H) as well as 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 d, J = 7.6 Hz, 1H), 6.61-6.69 (m, 2H), 2.82 (dt, J = 13.6, 6.8 Hz, 1H), 1.98 (s, 3H), 1.17 (dd, J = 6.9, 1.6 Hz, 6H).

[0170] Examples 3 to 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 (AD column, SFC=100 mL / min, CO2 / IPA=80 / 20, 226 bar) to give 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 = 7.80 Hz, 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 (500 MHz, METHANOL-d4) δ: -1.13 (br t,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), -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) was added SeO2 (48.8 g, 0.44 mol). The resulting solution was refluxed at 130° C. for 3 h. It was then cooled and filtered through Celite using EA (~200 mL). The filtrate was concentrated completely and the crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 was taken up in MeSO3H (350 mL, 0.6 M). To this, 3-(trifluoromethyl)phenol 14 (29 mL, 0.24 mol) was added dropwise and left stirring at room temperature (30° C.) for next 24 h. The reaction mass was then quenched with ice water (1500 mL) and the solid was filtered. The residue was dissolved in EA (500 mL) and washed with water (200 mL) and brine (200 mL), which was dried over anhydrous Na2SO4 and concentrated to a crude product, which was purified by silica gel column chromatography (10-40% EA in hexanes with 5-10% DCM) to give the 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 taken in DCM (270 mL, 0.25 M) and charged with oxalyl chloride (7.1 mL, 82 mmol) at room temperature. To this, DMF (26 mL, 340 mmol) was added slowly and left to stir at ambient temperature (20° C.). The reaction mixture was then stirred at room temperature (20° C.) for the next 6 hours. The reaction was recharged with oxalyl chloride (1.8 mL, 0.3 equiv.) and left to stir for the next 12 hours. The reaction mixture was diluted with water (~300 mL). The aqueous layer was extracted with DCM (~300 mL×2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (10-25% EA in hexane) to give 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 taken up in THF (350 mL, 0.15 M) and cooled to -40 °C. To this, 2.0 M NH3 in IPA (65 mL, 0.13 mol) was added dropwise over 10 min. The reaction mixture was then left stirring at -40 °C for next 3 h. It 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 give 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 taken in glacial AcOH (250 mL, 0.2 M) and immediately charged with Ac2O (9.5 mL, 0.1 mol). The reaction mixture was then heated at 80 °C for next 60 min. The reaction mixture was concentrated to give the crude product. The crude mass was directly purified by silica gel column chromatography (20-40% EA in Hx with 10% DCM as co-solvent) to give 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 taken in EtOH:water (10:1, 110 mL, 0.2 M) and charged with Fe powder (3.7 g, 66 mmol) followed by concentrated HCl (0.5 mL). This was refluxed at 90 °C for next 3 h. The reaction mass was filtered through Celite under warm conditions using hot EA (~50-100 mL). The filtrate was concentrated, taken 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). It was dried over anhydrous Na2SO4 and concentrated to (~100-150 mL). The precipitated solid was then thoroughly sonicated and filtered to give the pure product. The filtrate was concentrated to give the crude. The crude was purified by silica gel column chromatography (20-50% EA in Hx with DCM as additive) to give 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 (AD column, SFC=100 mL / min, CO2 / IPA=80 / 20, 226 bar) to give 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 = 7.80 Hz, 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 (500 MHz, METHANOL-d4) δ: -1.13 (br d, J = 7.6 Hz, 1H), -1.29 (br t, J = 7.6 Hz, 1H), -1.50 (br d, J = 7.3 Hz, 1H), -1.79--1.69 (m, 2H), -2.09--1.95 (m, 1H), -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 taken in AcOH:dioxane (1:10, 105 mL, 0.5 M). It was charged with SeO2 (12.77 g, 115.1 mmol) and refluxed at 105-110 °C for 5 h. The reaction mass was then filtered through Celite under hot conditions and then concentrated to remove volatiles to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5. This crude product was then taken in glacial AcOH (210 mL, 0.25 mmol) which was charged with 3-bromophenol 22 (9.96 g, 57.5 mmol) and kept refluxing for next 12 h. The reaction mass was concentrated and taken in EA (500-600 mL). It was filtered through Celite and the residue was washed with EA. The filtrate was washed with water (200 mL×2) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified twice by silica gel column chromatography (35-40% EA in hexane) to give 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 taken in DCM (520 mL, 0.2 M) and charged with oxalyl chloride (11 mL, 0.13 mol) at room temperature. To this, DMF (40 mL, 0.53 mol) was added slowly (0.05 mL / min for 30 min, then 0.1 mL / min for 30 min, then the remainder) and left to stir 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×2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (10-30% EA in hexane) to give 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 taken in THF (530 mL, 0.1 M) and cooled to -40 °C. To this was charged 2.0 M NH3 in IPA (54 mL, 0.11 mmol) at the same temperature and left stirring for next 3 h. 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). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified by silica gel column chromatography (20-30% EA in hexane with 20% DCM as co-solvent) to give 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] Boc anhydride (8.74 g, 40 mmol) and molecular I2 (0.69 g, 2.67 mmol) were added to a solution of racemic mixture 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 stirred at room temperature (30 °C) for next 72 h. The reaction mass was concentrated and purified. The crude was purified by silica gel column chromatography (10-30% EA in hexane with 5-10% DCM) to give 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] The mixture racemic 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 taken in EtOH:water (10:1, 110.0 mL, 0.20 M) and charged with Fe powder (3.57 g, 63.9 mmol) followed by concentrated HCl (0.8 mL, cat.). It was refluxed at 90 °C for next 3 h. The reaction mass was filtered through Celite under warm conditions using hot EA (50-100 mL). The filtrate was concentrated, taken in EA (~1000-1200 mL) and washed with water (~300-500 mL) and brine (~300 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (10-30% EA in hx) to give the 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 = 20 mL / min, heptane / EtOH = 70 / 30, 724 psi) to give 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 (500 MHz, METHANOL-d4) δ: 7.48 (br t, J = 7.7 Hz, 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] + and 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 (500MHz, METHANOL-d4) δ: 7.48 (br t,J=7.6Hz,1H), 7.37 (br s,1H), 7.11 (br s,1H), 7.02 (br d,J=6.9Hz,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] + Obtained as. (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 taken in DCM (2.5 mL, 0.1 M) and immediately charged with 4.0 M HCl in dioxane (0.63 mL, 2.50 mmol). The reaction mixture was then stirred at room temperature (20 °C) for next 6 h. The reaction mixture was diluted with EA (50 mL) and stirred vigorously with saturated NaHCO3 (20 mL) for 5-10 min. 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). It was dried over anhydrous Na2SO4 and concentrated to give the product. The crude material was used directly in the next step without further purification. 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 taken in glacial AcOH (2.2 mL, 0.1 M) and immediately charged with Ac2O (0.03 mL, 1.2 mmol). The reaction mixture was then heated at 80 °C for next 30 min. Then 10 mL of 2N HCl (aq) was added and stirred at 80 °C for next 2 h. The reaction mixture was concentrated to obtain the crude product. The crude mass was directly purified by silica gel column chromatography (20-50% EA in Hx with 1-2% MeOH as co-solvent) to obtain the pure product. 1H-NMR (300 MHz, MeOD) δ 7.50-7.40 (br, 1H), 7.40-7.25 (br, 1H), 7.10 (d, J = 7.4 Hz, 1H), 7.05-6.85 (m, 2H), 6.69 (br, 1H), 1.99 (s, 3H). [Table 4] Examples 7 to 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 taken in dry DCM (40 mL, 0.3 M). To this was charged TBDMS-Cl (2.0 g, 13 mmol). This was then charged with imidazole (1.37 g, 20 mmol) and stirred at room temperature for next 15 h. The reaction mass was directly filtered and the residue was washed with DCM. The filtrate was concentrated and the crude obtained was purified by silica gel column chromatography (0-5% EA:Hexane) to give 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 taken in toluene:water (previously purged with nitrogen) (7.33 mL, 0.2 M). To this was charged cyclopropaneboronic acid 33 (154 mg, 1.8 mmol). To this was then charged PCy3 (42 mg, 0.15 mmol), K3PO4 (1.1 g, 5.24 mmol), and Pd(OAc)2 (17 mg, 0.07 mmol). This was then refluxed at 110 °C for next 3 h. The reaction mass was passed through Celite and washed with ether. The organic layer was washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude material which was purified by silica gel column chromatography (0-5% EA:Hexane) to give 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 taken in THF (23 mL, 0.3 M) to which was added 1.0 M TBAF (9.1 mL, 9.1 mmol). It was stirred for next 75 min at room temperature. The reaction mass was concentrated and then taken in EA (200 mL). It was washed with saturated NH4Cl (50 mL), water (50 mL) and brine (50 mL). It was dried over anhydrous Na2SO4 and concentrated. The resulting crude was purified by silica gel column chromatography (5% EA in hexane) to give 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 glacial AcOH (40 mL, 0.2 M) for 2 h. The reaction mass was concentrated and dissolved in EA (200 mL). It was washed with water (50 mL) and brine (50 mL). It was dried over anhydrous Na2SO4 and concentrated. The crude obtained was then taken in DCM:Hexane (approximately 50 mL) and the solid obtained was sonicated. It 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 taken in DCM (20 mL, 0.25 M) and charged with oxalyl chloride (0.52 mL, 6.0 mmol). This was then slowly charged with DMF (2 mL). After 3 hours, additional oxalyl chloride (0.08 mL) was added. The reaction was then stirred at room temperature for next 30 minutes. The reaction mass 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 give the crude product which was purified by silica gel column chromatography (10-15% EA in Hx) to give 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 taken in dry THF (20.0 mL, 0.1 M). It was cooled to -40°C and then charged with 2.0 M NH3 in IPA (2.0 mL, 4.0 mmol). It was then stirred for next 2 h at -40°C to -30°C. The reaction mass was concentrated to half the volume at 25°C and then quenched with water. It was concentrated again to remove all volatiles and then taken in EA (150 mL). It was washed with water (50 mL x 2) and brine (50 mL). It was dried over anhydrous Na2SO4 and concentrated. The resulting crude material was purified by silica gel column chromatography, which had been pre-deactivated with TEA (1:2=EA:hexane), to give 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 taken in THF (5 mL, 0.1 M) to which was added NMM (0.083 mL, 0.75 mmol) at 0° C. This was charged with acetyl chloride (0.054 mL, 0.75 mmol) and stirred for next 30 min at 0° C. This was then charged with 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) in a single lot and stirred for next 3 h at 0° C. The reaction mass was concentrated and then taken in EA (100 mL). It was washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (1:1=EA:hexane) to give 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-indeno[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 was added Fe powder (66 mg, 1.18 mmol). This was charged with 2 drops of concentrated HCl and then the reaction was refluxed for next 2 h. The reaction mass was filtered through Celite and the residue was washed with EA under hot condition. The filtrate was concentrated and the crude 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. The resulting crude was then purified by silica gel column chromatography (1:1=EA in hexane) to give the pure product. 1 H-NMR(300MHz,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,1) H),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] 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).

[0194] N-(1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (40) (500 mg) was purified by chiral chromatography using (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-indeno[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 As, [Table 6]

[0195] 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) (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] Examples 10 to 12: N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (48); 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) [ka] [ka] 4b,9b-Dihydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (44):

[0196] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (1.34 g, 6 mmol) was taken in TFA (24 mL, 0.25 M). To this was charged 3-(trifluoromethoxy)phenol 43 (1.07, 6 mmol) and this was stirred for next 12 h at room temperature (30° C.). The reaction mass was concentrated. It was then taken in EA (200 mL) and washed with water (100 mL×2) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated to obtain a crude mass. The crude product was then purified by silica gel column chromatography (1:2=EA in hexane) to obtain the 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 taken in DCM (4.0 mL, 0.25 M). To this was charged oxalyl chloride (0.103 mL, 1.21 mmol) followed by DMF (0.4 mL, 5.0 mmol) and stirred at room temperature (30 °C) for 3 h. The reaction mass was diluted with DCM (~100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified by silica gel column chromatography (10 -> 15% EA in hexane) to give 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 taken in THF (5.0 mL, 0.1 M). It was cooled to -40 °C and charged with 2.0 M NH3 in IPA (0.5 mL, 1.0 mmol) and warmed at -10 °C for next 3 h. The reaction mass 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 give the crude product. The crude was purified by a short pad of silica gel column chromatography (30-40% EA in hexanes) to give 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 taken in THF (2.0 mL, 0.1 M) and cooled to 0° C. To this was added NMM (0.44 mL, 0.40 mmol) followed by AcCl (0.021 mL, 0.30 mmol). The reaction mass was stirred for 10 min and to this was added 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). The reaction mass was stirred for next 1.5 h at 0° C. The reaction mass was concentrated and the residue was quenched with water (50 mL) and extracted with EA (50 mL×2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (30-35% EA in hexanes) to give 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 taken in EtOH:water (10:1, 2.5 mL, 0.02 M) and charged with Fe powder (8.3 mg, 0.15 mmol). This was charged with concentrated HCl (1 drop) and refluxed at 90 °C for next 3 h. The reaction mass was filtered through Celite under hot condition. The residue was washed with EA (~20 mL). It was concentrated and then taken in EA (~50 mL). It was washed with water (~20 mL) and brine (~20 mL). It was dried over anhydrous Na2SO4 and concentrated to get crude mass. The crude mass was directly purified by reverse phase HPLC (MeCN:water as eluent) to give the 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 give 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-indeno[1,2-b]benzofuran-9b-yl)acetamide (50) was obtained as (peak 1, tR 4.10 min); 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] Examples 13 to 15: N-(1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide and N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide and N-((4bS,9bS)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide [ka] 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione (5):

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

[0203] To 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 added 3-chlorophenol 51 (1.6 g, 12 mmol). The resulting reaction mass was refluxed at 110° C. for 12 h. 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 the crude. The crude 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) was added oxalyl chloride (0.12 mL, 1.44 mmol), DMF (0.4 mL) was added dropwise to the resulting reaction mass over 1 h, and then the reaction mass was stirred at ambient temperature for 15 h. The reaction mass was diluted with DCM, washed with water (50 mL×2), then the organic layer was washed with brine solution, dried over Na2SO4, and the solvent was evaporated to obtain the crude. The crude 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] To 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, ammonia in IPA (0.8 mL, 1.6 mmol) was added over 5 min and the reaction mass was stirred at -40°C for 2 h. The reaction mass 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 give the (crude) product. The crude 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) was added acetic anhydride (0.07 mL, 0.76 mmol). The resulting reaction mass was stirred at 80° C. for 1 h. The reaction mass was evaporated to dryness, the residue was dissolved in ethyl acetate (50 mL), the organic layer was washed with water (25 mL×2), the organic layer was dried over Na2SO4, and the solvent was evaporated to give the crude. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) to give 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) was added Fe powder (45 mg 0.8 mmol) and concentrated HCl (1 drop). The resulting reaction mass was stirred at 90°C for 3 h. The reaction mass was filtered through a celite bed and washed with ethyl acetate. The solvent was evaporated to give the residue and the residue 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 give the crude. The crude was purified by silica gel column chromatography using (ethyl acetate:hexane) to give 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 (IC column, SFC=100 mL / min, CO2 / MeOH=85 / 15, 206 bar) to give 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 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] 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) (peak 1, tR 4.92 min); 1 H NMR (500 MHz, METHANOL-d4) δ: 7.47 (t, J = 7.8 Hz, 1H), 7.41 (br d, J = 8.3 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.97 (br d, J = 8.3 Hz, 1H), 6.82 (s, 1H), 6.76 (br s, 1H), 2.01 (s, 3H). [Table 13] Examples 16 to 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 glacial 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 h and then concentrated. The residue was purified by column chromatography (50% EA in hexane with 50% dichloromethane) and precipitated again to give 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 added slowly (5 min) at ambient temperature, followed by 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 with 25% DCM) and precipitated again (DCM / Hex=1 / 2) to give 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 warmed to -10°C and then stirred for 3 h, 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 with 3.3% DCM) and precipitated again (DCM / Hex=1 / 2) to give 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 h. 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 with 5% DCM) and precipitated again (DCM / Hex=1 / 2) to give 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 h. 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% to 150% EA in Hex with 5% DCM) and reprecipitated with EA to give the product. 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 give 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 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] 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) (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 s,1H), 2.28(s,3H), 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 a similar route as described in Examples 16-18, except that p-cresol was used instead of m-cresol to give 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 (AD column, SFC=100 mL / min, CO2 / EtOH=75 / 25, 226 bar) to give 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 s,1H), 7.06 (br d,J=7.9 Hz,1H), 6.97 (br d,J=6.8 Hz,1H), 6.64 (br d,J=8.1 Hz,2H), 2.28 (s,3H), 1.98 (s,3H) and 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 a similar 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 give 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 to 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), which 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 (500MHz, METHANOL-d4) δ: 7.39-7.50 (m, 1H), 7.31 (br dd, J = 3.1, 2.4Hz, 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 (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 methods. Determining drug efficacy against picornaviruses using cytopathic effect (CPE) Inhibition assay

[0219] In this assay, HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblasts), and RD cells (derived from human rhabdomyosarcoma) were used. For comparison, ribavirin (Riv), pleconaril (pleco), and BTA-798 (BTA) were used as controls. The 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 3-5x concentrations so that the concentration of dimethyl sulfoxide in each well was 0.5%-1%.

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

[0221] In HeLa cells, the MTT assay was used to determine the EC 50Drugs were measured for CPE (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, mock infection was also included at the time of inoculation of the virus. Virus-free medium was added to the cell cultures and then subjected to the same treatment as the virus-infected cells inoculated with the virus. That is, the medium was removed after 1 hour of incubation and another dilution of the drug in medium was added. After 2-3 days of incubation, the cells were observed under a microscope and the number of viable cells in the mock-infected wells containing the drug was compared to the number of viable cells in the control wells not containing the drug, using an MTT assay to determine which CC cells had killed 50% of the cells. 50 (50% cytotoxicity concentration). For the FDA hydrolysis assay, FDA was added to each well after removal of the medium and incubated for 20–30 min, after which the fluorescence intensity was measured using a spectrofluorometer to determine CPE in the same way as for MTT.

[0222] That is, the viability (% viability) of mock-infected cells for cytotoxicity measurements was calculated using the following formula 1:

[0223] Cell-drug = Viability x [A(drug)-A(background solution) / A(cell control)-(background x 100% solution)]

[0224] 100% cell survival means no cytotoxicity of the drug, whereas the highest cytotoxicity is reflected by 0% cell survival. The 50% cytotoxic concentration was defined as the concentration required to reduce the cell number by 50%. This drug concentration was used in the CC study. 50 The toxicity is expressed as a function of time. A higher value means less cytotoxicity.

[0225] Furthermore, the antiviral efficacy can be calculated using the following Equation 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%, the antiviral effect is not present. The concentration of the drug at which the cells in the virus-infected well can show 50% survival rate is called the EC 50 The lower this value, the better the antiviral effect.

[0227] Table 1 below shows CCs that show cytotoxicity for some compounds. 50 and EC2 concentrations showing activity against many rhinoviruses belonging to the picornavirus family 50 Concentrations are listed. Determining drug efficacy against picornaviruses using a multicycle cytopathic effect (CPE) reduction assay

[0228] A multi-cycle CPE reduction assay was used to determine drug efficacy against picornaviruses. First, the antiviral activity of compounds 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 96-well plates were incubated at 50% cell culture infectious dose (CCID 50 ) were infected with 100 virus. After a 2-h adsorption period at 37°C, the virus was removed and serial dilutions of compound were added. Cultures were further incubated at 37°C for 3 days until complete CPE was observed in 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-h 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 formula 3: %CPE = 100 × [OD(CC)-OD(virus + compound) / OD(CC)-OD(VC)]

[0231] The %CPE value for measuring the cytotoxicity of the drug was calculated according to the following formula 4: %CPE = 100 x [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)] In the above formula 3 and formula 4, OD(CC) represents the OD of background cell cultures that were neither induced by viruses nor treated with chemicals; OD(VC) represents the OD of the control cell culture induced by the virus but not treated with chemicals; OD (virus + compound) represents the OD of virus-infected cell cultures treated with concentrated compound; OD(compound) represents the OD of cell cultures treated with concentrated compound only, and OD(blank) represents the OD of wells to which only cell culture was added.

[0232] Effective concentration (EC 50 ) represents the drug concentration at which 50% of cells remain viable due to induced viral CPE, and the cytotoxic concentration (CC 50 ) represent the drug concentration at which the compound killed 50% of the cells and were calculated by logarithmic interpolation.

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

[0234] As shown in Table 1 above, most of the compounds according to the present invention have high CC 50Since the compounds show a high antiviral activity against many rhinoviruses (HRV), it is found that the compounds have low cytotoxicity. Furthermore, the compounds according to the present invention have been found to have a very high antiviral activity against many rhinoviruses (HRV) in most cases. Furthermore, the compounds according to the present invention have been found to have a 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, since the compound according to the present invention has low cytotoxicity and exhibits excellent antiviral activity against picornaviruses, which include coxsackieviruses, polioviruses and rhinoviruses, it can be effectively used for the prevention or treatment of diseases caused by such viruses, such as respiratory system, cardiocirculatory system and nervous system diseases, including polio, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, 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 have very good antiviral activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and can therefore 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 disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, 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 pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 and G 2 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- to 7-membered cycloalkyl; 1 and G 2 The other of the two is H; 1 is selected from H and straight or branched C1-C5 alkyl. (Item 2) G 1 is selected from linear or branched C1-C5 haloalkyl, linear or branched C1-C5 haloalkyloxy, and 3- to 7-membered cycloalkyl, or a pharma- ceutically acceptable salt thereof according to item 1. (Item 3) G 1 is a straight or branched chain C1-C5 haloalkyl, or a pharma- ceutically acceptable salt thereof. (Item 4) G 1 or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 3, wherein (Item 5) G 1 is a straight or branched chain C1-C5 haloalkyloxy, or a pharma- ceutically acceptable salt thereof. (Item 6) G 1 or a pharma- ceutically acceptable salt thereof according to any one of items 1, 2, and 5, wherein (Item 7) G 1 is 3- to 7-membered cycloalkyl, or a pharma- ceutically acceptable salt thereof. (Item 8) G1 or a pharma- ceutically acceptable salt thereof according to any one of items 1, 2, and 7, wherein R is cyclopropyl; (Item 9) G 2 or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 8, wherein (Item 10) G 1 10. The compound according to item 1 or 9, wherein is methyl, or a pharma- ceutically acceptable salt thereof. (Item 11) G 1 10. The compound according to item 1 or 9, or a pharma- ceutically acceptable salt thereof, wherein: (Item 12) G 1 10. The compound according to item 1 or 9, wherein is isopropyl, or a pharma- ceutically acceptable salt thereof. (Item 13) G 1 10. The compound according to item 1 or 9, wherein is halo, or a pharma- ceutically acceptable salt thereof. (Item 14) G 1 is H, or a pharma- ceutically acceptable salt thereof. (Item 15) G 2 is methyl, or a pharma- ceutically acceptable salt thereof. (Item 16) 16. The compound according to any one of items 1 to 15, wherein the compound is a compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka] (Item 17) The compound according to any one of items 1 to 15, having the formula (III) or a pharma- ceutically acceptable salt thereof: [ka] (Item 18) The compound according to any one of items 1 to 9, wherein the compound is a compound of formula (IV) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 is selected from straight or branched chain C1-C5 haloalkyl, straight or branched chain C1-C5 haloalkyloxy, and 3- to 7-membered cycloalkyl. (Item 19) G 1 is selected from CF3, OCF3, and cyclopropyl. (Item 20) R 1 is selected from H and methyl. (Item 21) A compound according to any one of items 1 to 17, selected from the following: [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] or a pharma- ceutically acceptable salt thereof. (Item 22) The compound according to any one of items 1 to 17 and 21, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof for preventing or treating a viral disease. (Item 23) A pharmaceutical composition for preventing or treating a viral disease, comprising the compound according to any one of items 1 to 17 and 21, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient. (Item 24) A combination comprising a compound according to any one of items 1 to 17 and 21 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 23, and one or more therapeutically active agents. (Item 25) A method for treating a viral disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of items 1 to 17 and 21 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 23, or a combination according to item 24. (Item 26) Use of the compound according to item 22 or a pharma- ceutically acceptable salt or an optical isomer thereof, or the pharmaceutical composition according to item 23, or the combination according to item 24, for preventing or treating a viral disease. (Item 27) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by a Coxsackievirus. (Item 28) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by poliovirus. (Item 29) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by an echovirus. (Item 30) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by an enterovirus. (Item 31) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by a rhinovirus. (Item 32) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to item 26, wherein the viral disease is caused by a picornavirus. (Item 33) 27. The compound according to item 22, or the pharmaceutical composition according to item 23, or the method according to item 24, or the use according to 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, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. (Item 34) [ka] Or [ka] 2. The compound according to item 1, wherein: (Item 35) The compound according to any one of items 18 to 21 and 34, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof for preventing or treating a viral disease. (Item 36) A pharmaceutical composition for preventing or treating a viral disease, comprising the compound according to any one of items 18 to 21 and 34, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient. (Item 37) A combination comprising a compound according to any one of items 18 to 21 and 34 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 36, and one or more therapeutically active agents. (Item 38) A method for treating a viral disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of items 18 to 21 and 34 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 36, or a combination according to item 37. (Item 39) Use of the compound according to any one of items 18 to 21 and 34, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or the pharmaceutical composition according to item 36, or the combination according to item 37, for preventing or treating a viral disease. (Item 40) The compound according to any one of items 18 to 21 and 34, or the pharmaceutical composition according to item 36, or the method according to item 38, or the use according to item 39, wherein the viral disease is caused by one of coxsackievirus, poliovirus, echovirus, enterovirus, rhinovirus, and picornavirus. (Item 41) The compound according to any one of items 18 to 21 and 34, or the pharmaceutical composition according to item 36, or the method according to item 38, or the use according to item 39, 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, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

Claims

[Claim 1] The invention described in this specification.

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