Anti-viral 1,3-dioxo-indene compounds

Abstract

The present disclosure provides a compound of formula (I) as described herein, TIFF2023520819000058.tif23128 Also provided are pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods for using these compounds, salts, and compositions to treat viral infections.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, varicella-booster disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

Description

Technical Field

[0001] The present invention is an inhibitor of picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and thus is useful for treating viral infections including polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, colds, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, rhinitis, or otitis media. The present invention provides novel 1,3-dioxoin den compounds, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of viral diseases.

Background Art

[0002] Picornaviruses are non-enveloped positive-strand single-stranded RNA viruses with an RNA genome 7.2 - 8.5 Kb in length. These viruses are very small spherical, having a size of about 22 - 30 nm, and were first identified a long time ago. Among the viruses belonging to the Picornaviridae family are enteroviruses including rhinovirus, poliovirus, coxsackievirus A, coxsackievirus B, and echovirus, as well as hepatitis A virus.

[0003] Diseases caused by picornaviruses range from respiratory diseases to digestive diseases, cardiovascular diseases, and skin diseases. Examples include polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot, and mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, colds, herpangina, and foot-and-mouth disease. However, there are no therapeutic agents to cure these diseases. Most of the drugs under development are capsid inhibitors. Viruses belonging to the Picornaviridae family cause various diseases, including the aforementioned respiratory diseases, which pose hygienic, social, and economic problems. Picornaviruses are the main causative agents of waterborne infections. RNA viruses are constantly causing related diseases because they are very stable and difficult to disinfect.

[0004] Human rhinovirus (hRV) has recently been associated with most exacerbations of asthma and is known to be present even in the bronchial tissues of many stable asthmatic patients. Comparing the respective bronchial mucosal biopsy materials taken from asthmatic and non-asthmatic patients, it was shown that human rhinovirus was detected at a significantly higher frequency in the lower airways of asthmatic patients compared to non-asthmatic patients. A correlation has also been reported between the presence of human rhinovirus and the clinical severity of asthma. Furthermore, rhinovirus causes chronic obstructive pulmonary disease, pneumonia, rhinitis, and otitis media, as well as asthma.

[0005] Rhinovirus is the main cause of colds, but enterovirus-induced diseases include meningitis, airway infections, etc. Due to extensive efforts to provide vaccination against poliovirus, the incidence of polio has decreased significantly worldwide, but disease cases are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A can now be somewhat controlled thanks to the vaccine for hepatitis A virus. However, no vaccines for coxsackievirus, echovirus, or rhinovirus have been developed so far.

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

[0007] Enviroxime derivatives are considered the most promising candidates with broad anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with plus-strand RNA synthesis by binding to viral protein 3A, which is required to form RNA intermediates in viral replication (Heinz B A and Vance L M: J Virol, 1995, 69(7), 4189-97). However, in clinical studies, the compound has been observed to have only a non-significant or little therapeutic effect, and poor pharmacokinetics and undesirable side effects have been detected (Miller F D 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 an effect against 48 rhinovirus types, as well as coxsackievirus A21, B3, enterovirus 70, and echovirus 11 (Pattick A K et al.: Antimicrobila Agents Chemother, 1999, 43(10), 2444-50).

[0009] Thanks to the elucidation of the molecular structure of the virus capsid, the prerequisite for the intentional design of capsid blockers, the "WIN substances", was obtained (Diana G D: Curr Med Chem 2003, 2, 1-12). They inhibit the adsorption and / or uncoating of rhinoviruses and enteroviruses. Some of the WIN substances have highly specific effects only on individual genera or virus types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. For example, arildone, disoxaril, and pyrodavir are members of the WIN substances. These compounds showed very good antiviral effects in cell cultures. However, due to insufficient solubility (arildone), low bioavailability (arildone and disoxaril), rapid metabolism and excretion (disoxaril and WIN54954), and side effects such as skin rashes (WIN54954), clinical application has become impossible.

[0010] Pleconaril, a WIN substance, has very good oral bioavailability and inhibits the entry of rhinoviruses, echoviruses, and coxsackieviruses after binding to hydrophobic pockets in the viral capsid (Pevear D C et al.: Antimicrob Agents Chemother 1999, 43(9), 2109 - 15; McKinlay M A et al.: Annu Rev Microbiol 1992, 46, 635 - 54). Therefore, pleconaril is potentially effective against a wide range of viral diseases ranging from the common cold to viral meningitis or myocarditis. Resistance has been observed for rhinoviruses, enterovirus 71, and coxsackievirus B3 (Ledford R M et al.: J Virol 2004, 78(7), 3663 - 74; Groarke J M et al.: J Infect Dis 1999, 179(6), 1538 - 41). However, the demonstrated therapeutic effect 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 a too low treatment success rate and observed side effects.

[0011] BTA - 798 has been found to have higher antiviral activity than pleconaril when evaluated against rhinoviruses 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 that have obtained approval for use in the treatment of enteroviruses or rhinoviruses. New treatments and therapies for enteroviruses or rhinoviruses are still needed. As a result of intensive and thorough research on effective viral growth inhibitors against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, the finding that a novel 1,3-dioxoin den derivative exhibits highly inhibitory activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus was obtained, leading to the present invention.

Prior Art Documents

Non-Patent Documents

[0013]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

Means for Solving the Problems

[0014] The present invention provides a compound having antiviral activity. The present invention also provides a pharmaceutical composition containing the compound, and a method of using the compound and the composition to inhibit viral replication or reactivation and to treat a disease state associated with or caused by a virus. 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),

Chemical formula

Best Mode for Carrying Out the Invention

[0016] For the purpose of interpreting this specification, the following definitions apply, and terms used in the singular also include the plural when appropriate and so recognized.

[0017] The terms used in this specification have the following meanings unless the context clearly indicates otherwise.

[0018] As used herein, the term "subject" refers to an animal. In certain embodiments, the 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, the subject is a human. As used herein, the term "patient" refers to a human subject. As used herein, a subject "requires" treatment if such subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0019] As used herein, the term "inhibit" or "inhibiting" refers to a 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, in one embodiment, refers to ameliorating the disease or disorder (i.e., delaying, 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 ameliorating at least one physical parameter, which may or may not be recognizable by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset, development, or progression of the disease or disorder.

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

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

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

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

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

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

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

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

[0029] Embodiment 1. A compound of formula I or a pharmaceutically acceptable salt thereof:

Chemical formula

[0030] Embodiment 2. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein G 1 is selected from linear or branched C1-C5 haloalkyl, linear or branched C1-C5 haloalkyloxy, and 3-7 membered cycloalkyl.

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

[0032] Embodiment 4. The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 3, wherein G 1 is CF3.

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

[0034] Embodiment 6.G 1 The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1, 2, and 5, wherein it is OCF3.

[0035] Embodiment 7.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 2, wherein it is a 3- to 7-membered cycloalkyl.

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

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

[0038] Embodiment 10.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 9, wherein it is methyl.

[0039] Embodiment 11.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 9, wherein it is OCH3.

[0040] Embodiment 12.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 9, wherein it is isopropyl.

[0041] Embodiment 13.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 9, wherein it is halo.

[0042] Embodiment 14.G 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein it is H.

[0043] Embodiment 15.G 2 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein it is methyl.

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

Chemical formula

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

Chemical formula

[0046] Embodiment 17a. The compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IV):

Chemical formula

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

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

[0049] Embodiment 18. The compound according to any one of Embodiments 1 to 17, selected from the following:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0050] A compound, or a pharmaceutically 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-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (19); N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bS,9bS)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide;N-((4bS,9bS)-1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bS,9bS)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide and N-((4bS,9bS)-1-amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)-N-methylacetamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide; or a pharmaceutically acceptable salt thereof.;

[0051] Embodiment 18b.

Chem.

Chem.

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

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

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

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

[0056] Embodiment 23. Use of a compound or a pharmaceutically acceptable salt thereof or an optical isomer thereof according to Embodiment 19, or the pharmaceutical composition according to Embodiment 20, or the 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 viral disease is caused by poliovirus, 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.

[0059] Embodiment 26. The viral disease is caused by echovirus, 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.

[0060] Embodiment 27. The viral disease is caused by enterovirus, 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.

[0061] Embodiment 28. The viral disease is caused by rhinovirus, 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.

[0062] Embodiment 29. The viral disease is caused by picornavirus, 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.

[0063] Embodiment 30. 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, rhinitis, or otitis media, 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.

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

[0065] Another embodiment of the invention provides the above compounds, or pharmaceutically acceptable salts thereof, as a medicament.

[0066] The use of a compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing viral diseases and / or infectious diseases in humans is also within the scope of the invention.

[0067] Pharmaceutical compositions comprising a compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are also included within the scope of the invention.

[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 invention also provides the use of the above-described pharmaceutical composition for treating viral infections in humans having or at risk of having an infectious disease.

[0070] The invention also provides the use of the above-described pharmaceutical composition for treating viral diseases or infectious diseases in humans having or at risk of having a disease.

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

[0072] An additional aspect of the present invention is a product comprising a composition effective for treating a viral disease and / or an infectious disease, and a packaging material containing a label indicating that the composition can be used for treating a disease and / or an infectious disease caused by a virus, 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 present invention is a method of inhibiting viral replication, which comprises exposing a virus to an effective amount of a compound of formula I, II, or III or a salt thereof under conditions where the replication of the virus is inhibited. This method can be carried out in vitro or in vivo.

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

[0075] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent(s). Optionally, the pharmaceutical composition may contain a pharmaceutically 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 viral inhibitor or a vaccine.

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

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

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

[0079] When the composition of the invention comprises a combination of a compound of the invention with one or more additional therapeutic or prophylactic agents, both the compound and the additional agent(s) may be present at dosage levels of about 10 to 100%, for example about 10 to 80% of the dosage normally administered in a monotherapy regimen.

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

[0081] Many of the compounds of the 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 invention are used as a single substantially pure isomer, which means that at least 90% of the 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 single isomer may be selected based on the level of activity against viral replication in cell culture using methods such as those described herein: the isomer with the lower IC50 or EC50 may be selected.

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

[0083] The present invention also provides a method for preparing 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 present invention further includes any variation of the process in which an intermediate product obtainable at any stage of the process is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or optically pure materials.

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

[0086] The terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric configurations that can exist for a given compound of the invention and include geometric isomers. It is understood that substituents can be attached to the chiral centers of carbon atoms. The term "chiral" refers to a molecule having the property of non-superimposability with respect to its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner. Accordingly, the invention includes enantiomers, diastereomers, or racemates of the compounds. "Enantiomers" are a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used, as appropriate, to refer to a racemic mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be assigned as either R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. The specific compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined as (R)- or (S)- with respect to absolute stereochemistry.

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

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

[0089] Any obtained racemate of the final product or intermediate can be resolved into its optical antipodes by known methods, for example by separating the diastereomeric salts obtained using an optically active acid or base and liberating the optically active acidic or basic compound. Thus, in particular, the compounds of the present invention can be resolved into their optical antipodes by fractional crystallization of salts formed using a basic moiety, for example, an optically active acid such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic product 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 containing such salts can be obtained in the form of their hydrates or can also contain other solvents used for their crystallization. The compounds of the present invention may form solvates with pharmaceutically acceptable solvents (including water), either essentially or by design. Accordingly, the present invention is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are known to be harmless to recipients, such as water and ethanol, and are commonly used in the pharmaceutical art. The term "hydrate" refers to a complex in which the solvent molecule is water.

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

[0092] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. The term "salt" includes, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and is typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid salts and / or base salts due to the presence of amino groups and / or carboxyl groups or similar groups.

[0093] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, acetates, aspartates, benzoates, besylates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, chlorotheophyllonates, citrates, ethanedisulfonates, fumarates, gluceptates, gluconates, glucuronates, hippurates, hydroiodides / iodides, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfosalicyclates, tartrates, tosylates, and trifluoroacetates.

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

[0095] Examples of 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, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

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

[0097] Examples of organic bases capable of inducing salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0098] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when feasible. A list of additional suitable salts can be found, for example, in "Remington’s Pharmaceutical Sciences," 20th Edition, Mack 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 shown herein represents the unlabeled form of the compounds of the present invention, as well as up to three atoms having a non-natural isotope distribution, such as deuterium or 13 C or 15It is intended to represent an isotopically labeled form having a site where N is concentrated. The isotopically labeled compound has a structure represented by the formula shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number other than the naturally occurring mass distribution. Examples of isotopes that can be usefully incorporated in excess in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I and the like. The present invention includes various isotopically labeled compounds of the present invention, for example 3 H and 14 C and other radioisotopes, or 2 H and 13 C and other non-radioisotopes that are present at levels substantially exceeding the normal isotope distribution. Such isotopically labeled compounds are useful in metabolic studies (e.g., with 14 C), kinetic studies (e.g., with 2 H or 3 H), detection techniques or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including tissue distribution assays of drugs or substrates, or in radiotherapy of patients. In particular, the 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 a process similar to that described in the appended examples and preparations, using appropriate isotopically labeled reagents in place of conventional techniques known to those skilled in the art or the unlabeled reagents typically used. Labeled samples can be useful with very low isotope incorporation, such as when a radiolabel is used to detect trace amounts of a compound.

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

[0101] Pharmaceutically acceptable solvates according to the present invention are those in which the crystallization solvent is isotopically substituted, such as D2O, d6 - Acetone, d 6 - including those that can be DMSO.

[0102] The compounds of the present invention containing a group capable of acting as a hydrogen bond donor and / or acceptor may be capable of forming a co-crystal with a suitable co-crystallizing agent. These co-crystals can be prepared from the compounds of the present invention by known co-crystallization procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting in solution of the compound of the present invention and the co-crystallizing agent under crystallization conditions, and isolation of the co-crystals thus formed. Suitable co-crystallizing agents include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising the compounds of the present invention.

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

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

[0105] The compounds of the invention may also be used in combination with other agents (combination partners), for example additional antiviral agents which are of formula I or not of formula I, for the treatment of viral infections in a subject.

[0106] The term "combination / co - administration" means either separate dosage forms suitable for use together either simultaneously or sequentially, or as a kit of parts for co - administration, where the compound of the invention and the combination partner can be administered independently simultaneously or separately within a time interval such as to allow the combination partner to exhibit a synergistic, e.g. supra - additive, effect, or any combination thereof, or as a combination fixed in one unit dosage form.

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

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

[0110] The "effective amount" of a compound is the amount necessary or sufficient to treat or prevent the viral infections and / or diseases or conditions described herein. In one example, the effective amount of a viral inhibitor of Formula I is an amount sufficient to treat a viral infection in a subject. The effective amount can vary depending on factors such as the size and weight of the subject, the type of disease, or the particular compound of the invention. For example, the selection of a compound of the invention can affect what constitutes an "effective amount". One of ordinary skill in the art will be able to study the factors included herein and make determinations regarding the effective amount of a compound of the invention without undue experimentation.

[0111] The dosing regimen can affect what constitutes an effective amount. The compounds of the invention can be administered to a subject either before or after the onset of a viral infection. Further, several divided dosages and staggered dosages can be administered daily or sequentially, or the dosage can be administered continuously by infusion or can be a bolus injection. Further, the dosage of the compound(s) of the 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 the conditions, disorders, or diseases described herein, or for the manufacture of a pharmaceutical composition for use in the treatment of these diseases. The present invention provides a method of using a compound of the invention in the treatment of these diseases, or a method of preparing a pharmaceutical composition having a compound of the invention for the treatment of these diseases.

[0113] The term "pharmaceutical composition" includes preparations suitable for administration to a mammal, such as a human. When a compound of the invention is administered as a medicine to a mammal, such as a human, the compound may be administered by itself, or, for example, in combination with at least one compound of Formula (I) or any subgenus thereof as the active ingredient in an amount of 0.1 to 99.5% (sometimes 0.5 to 90%), in a pharmaceutically acceptable carrier, or optionally in combination with two or more pharmaceutically acceptable carriers.

[0114] The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering the compounds of the present invention to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials and is involved in transporting or conveying the subject agent from one organ or part of the body to another organ or to a part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions, and other non-toxic compatible substances used in pharmaceutical formulations. Typically, the pharmaceutically acceptable carrier is sterilized and / or substantially free of pyrogenic substances.

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

[0116] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, 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, and phosphoric acid.

[0117] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage 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 the amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent, sometimes from about 5 percent to about 70 percent, and sometimes from about 10 percent to about 30 percent of the active ingredient.

[0118] The method of preparing these formulations or compositions involves associating a compound of the present invention with a carrier and optionally one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately associating a compound of the present invention with a liquid carrier or a finely divided solid carrier or both, and then shaping the product, if necessary.

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

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

[0121] Tablets can optionally be prepared by compression or molding together with one or more accessory components. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent using a suitable machine.

[0122] Tablets, as well as other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills, and granules, can optionally be prepared using scoring, coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient(s) therein using, for example, various ratios of hydroxypropylmethylcellulose, other polymeric matrices, liposomes, and / or microspheres to provide a desired release profile. They can 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 by some other sterile injectable medium immediately prior to use. These compositions can also optionally contain an opacifying agent and can also be compositions that release the active ingredient(s) optionally in a sustained release manner only in a specific portion of the gastrointestinal tract or, for example, in a specific portion. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient can also optionally be in microencapsulated form having one or more of the excipients described above.

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

[0124] In addition to the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

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

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

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

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

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

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

[0131] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a 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 either by providing a rate-controlling membrane or by dispersing the active compound in a polymeric matrix or gel.

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

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

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

[0135] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid, etc. It may also be desirable to include isotonic agents such as sugar and sodium chloride in the composition. In addition, the long-term 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 the drug from subcutaneous or intramuscular injection in order to extend the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. And the absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

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

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

[0139] As used herein, the terms "parenteral administration" and "administered parenterally" mean a mode of administration, other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intra - arterial, intrathecal, intracapsular, intra - orbital, intracardiac, intradermal, intraperitoneal, trans - tracheal, subcutaneous, sub - epidermal, intra - articular, sub - capsular, sub - arachnoid, intraspinal, and sub - sternal injections and infusions. Sometimes, intravenous infusion is the method of delivering the compounds of the present invention. Infusions may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion at intervals of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once, twice, or up to three times per day.

[0140] The terms "systemic administration", "administered systemically", "peripheral administration", and "administered peripherally" as used herein mean the administration of a compound, drug, or other material that enters the patient's system and thus, for example, corresponds to subcutaneous administration, into the patient's system other than directly into the central nervous system, and is subject to metabolism and other similar processes.

[0141] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal, for example, by spray, rectal, intravaginal, parenteral, intravesical, and topically, by powder, ointment, or drops (including oral and sublingual).

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

[0143] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention is not toxic to the patient and may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic result for a particular patient, composition, and mode of administration.

[0144] The selected dosage level depends on various factors including the activity of the specific compound of the present invention, or its ester, salt, or amide, used, the route of administration, the time of administration, the rate of excretion of the specific compound being used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific 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 pharmaceutical arts.

[0145] A physician or veterinarian having 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 start with a dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

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

[0147] Optionally, an effective daily dose of the active compound can be administered, at the option of the user, as a single dose per day or as two, three, four, five, or six or more sub-doses administered separately at appropriate intervals throughout the day, in unit dosage form. Compounds delivered by oral or inhalation are generally administered in doses 1 to 4 times 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 doses 1 to 3 times 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] It is possible to administer the compound of the present invention alone, but the compound can also be administered as a pharmaceutical composition such as those described herein. Accordingly, a method of using the compound of the present invention includes administering the compound as a pharmaceutical composition, wherein at least one compound of the present invention is mixed with a pharmaceutically acceptable carrier prior to administration. General synthetic procedures

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

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

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

[0152] Within the scope of this specification, only readily removable groups that are not part of a particular desired final 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 such as Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag (Stuttgart, Germany, 2005), page 41627 (URL: http: / / www.science-of-synthesis.com (electronic version, volume 48)); J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press (London and New York, 1973), T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley (New York, 1999), "The Peptides"; Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press (London and New York, 1981), "Methoden der Organischen Chemie" ("Methods of Organic Chemistry"), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag (Stuttgart, 1974), H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" ("Amino Acids, Peptides, Proteins"), 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), and the like.The protecting group may be characterized, for example, in that it can be easily removed (i.e., without the occurrence of unwanted secondary reactions) by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage).

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

[0154] Salts can be converted to the free compound in a conventional manner. Metal salts and ammonium salts can be converted, for example, by treatment with a suitable acid and acid addition salts, or by treatment with a suitable basic agent.

[0155] The mixtures of isomers obtainable according to the invention can be separated in a manner known per se for the individual isomers. Diastereoisomers can be separated, for example, by distribution between multiphase solvent mixtures, recrystallization, and / or by chromatographic separation, for example on silica gel, or by medium pressure liquid chromatography, for example on a reverse phase column, and racemates can be separated, for example, by formation of salts with optically pure salt-forming reagents and separation of the resulting mixtures of diastereoisomers, for example by fractional crystallization, or by chromatography on an optically active column material.

[0156] The intermediates and final products can be worked up and / or purified according to standard methods, for example using chromatography, distribution methods, (re)crystallization, and the like.

Examples

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

[0158] The compounds of the invention can be produced by organic synthesis methods known to those skilled in the art with reference to the following reaction schemes and examples. A general method for synthesizing the compounds of formula (I) is provided in the following scheme. 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 30,000. Drug candidates were injected into the mass spectrometer from the sample probe by UPLC (Acquity, Waters). Separation was performed on an Acquity UPLC BEH C18 1×50 mm column at a flow rate of 0.15 mL / min with a gradient of 5% to 95% over 3 minutes. Solvent A was water containing 0.1% trifluoroacetic acid, and solvent B was 75% methanol and 25% isopropyl alcohol containing 0.1% trifluoroacetic acid. The mass accuracy of the system has been 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-inden[1,2-b]benzofuran-9b-yl)acetamide

Chemical formula

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

[0161] A suspension of anhydride 2 (50 g, 0.26 mol) in dry DCM (260 mL) was added with 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 minutes. This was stirred at the same temperature for an additional 15 minutes and then the DCM was evaporated. The resulting crude product was then dissolved in 2 liters of water and cooled to 0 °C. This was fixed to an overhead stirrer and 300 mL of 2N HCl was added dropwise thereto while maintaining the temperature below 0 °C under vigorous stirring conditions. This was stirred at 0 °C for an additional 15 minutes 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 placed 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 rotary evaporator until approximately 100 mL of the solvent remained. The precipitated solid was then filtered through a Buchner funnel and washed with (1:1) CHCl3:hexane. This gave a solid product and the filtrate was concentrated again to obtain more product in a second crop. [Chemical formula] 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 mol) was taken in 1,4-dioxane (2 L) and AcOH (200 mL). To this, SeO2 (291 g, 2.62 mol) was added at room temperature and the mixture was then refluxed at 110 °C for the next 4 h. This was stirred at room temperature for the next 12 h. Then, 500 g - 600 g of celite was charged thereto. This was carefully stirred and filtered through a celite pad. The residue was washed with ethyl acetate (300 - 500 mL). The resulting filtrate was concentrated to obtain a crude mass, which was then used as such in the next step. 4b,9b-Dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-inden[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), 3-isopropylphenol 6 (196 g, 1.44 mol) was charged, and the mixture was then refluxed for the next 10 h. Then, this was completely concentrated and purified by silica gel column chromatography (30% EA in hexane) to obtain a pure product. 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (8):

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

[0166] 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-inden[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, a 2.0 M solution of NH3 in IPA (100 mL, 0.20 mol) was added using a dropping funnel while maintaining the temperature below -20 °C. The reaction mass was monitored at -20 °C for 1 h and then warmed to room temperature. This 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 × 2) and brine (100 mL). This was dried over anhydrous Na2SO4 and then concentrated to obtain a crude mass which was purified over a short pad of silica to obtain the pure product. 1 1H-NMR (300 MHz, CDCl3) δ 1.18 (d, J = 6.9 Hz, 6H), 2.84 (sept, J = 6.9 Hz, 1H), 3.46 (s, 1H), 6.25 (s, 1H), 6.74 (s, 2H), 6.90 (dd, J = 1.2 Hz, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 8.22 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 8.52 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H). N-(4b-Hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (10):

[0167] 9b-Amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 9 (950 mg, 2.80 mmol) was taken in AcOH (10 mL, 0.1 M), and acetic anhydride (0.263 mL, 2.8 mmol) was added thereto at ambient temperature. This was heated at 80 °C for the next 30 minutes. The reaction mass was concentrated and then 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 obtained crude product was purified by silica gel column chromatography (30 - 40% EA in hexane) to obtain the pure product. N-(1-Amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (11):

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

[0169] N-(1-Amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-inden[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-inden[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), and 246 mg of N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide 13 (peak 1, tR 2.30 min); 1H NMR (400 MHz, METHANOL-d4) δ: 7.39 - 7.46 (m, 1H), 7.35 (br d, J = 7.8 Hz, 1H), 6.97 (br d, J = 7.3 Hz, 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-inden[1,2-b]benzofuran-9b-yl)acetamide (19); N-((4bR,9bR)-1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (20) and N-((4bS,9bS)-1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (21)

Chem.

[0171] N-(1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[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-inden[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-inden[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).

Chemical Structure

[0172] 1,4-Dioxane: 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 was added dropwise 3-(trifluoromethyl)phenol 14 (29 mL, 0.24 mol) and the mixture was stirred at room temperature (30 °C) for the 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). This was dried over anhydrous Na2SO4 and concentrated to the crude. The crude was purified by silica gel column chromatography (10 - 40% EA in hexane containing 5 - 10% DCM) to afford the pure product. 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-indenol[1,2-b]benzofuran-10-one (16):

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

[0174] 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 16 (20.5 g, 53 mmol) was taken 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 minutes. Then, the reaction mixture was stirred at -40 °C for the next 3 hours. Then, this was diluted with EA (~200 - 300 mL) and washed with 10% brine (~200 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. N-(4b-Hydroxy-4-nitro-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (18):

[0175] 9b-Amino-4b-hydroxy-4-nitro-7-(trifluoromethyl)-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 17 (21 g, 50 mmol) was taken in glacial AcOH (250 mL, 0.2 M), and Ac2O (9.5 mL, 0.1 mol) was immediately charged. The reaction mixture was then heated at 80 °C for the next 60 minutes. The reaction mixture was concentrated to obtain a crude product. The crude mass was purified directly by silica gel column chromatography (20 - 40% EA in Hx containing 10% DCM as a co-solvent) to obtain the pure product. N-(1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (19):

[0176] N-(4b-Hydroxy-4-nitro-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[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 Fe powder (3.7 g, 66 mmol) was charged thereto, followed by concentrated HCl (0.5 mL). This was refluxed at 90 °C for the next 3 hours. Using hot EA (~50 - 100 mL), the reaction mass was filtered through celite under warm conditions. 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 × 2). The combined organic layers were washed with water (~300 mL) and brine (~200 mL). This was dried over anhydrous Na2SO4 and concentrated to (~100 - 150 mL). The precipitated solid was then sonicated thoroughly and filtered to obtain the pure product. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (20 - 50% EA in Hx containing DCM as an additive) to obtain an additional amount of the pure product. 11H-NMR (300 MHz, CD3OD) δ 2.0 (s, 3H), 6.74 (s, 1H), 7.00 - 7.02 (m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.43 - 7.48 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H). LCMS: 378.6 [M+H] + 。

Table 3

[0177] N-(1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethyl)-4b,10-dihydro-9bH-inden[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-inden[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-inden[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-inden[1,2-b]benzofuran-9b-yl)acetamide (31)

Chemical Structure

[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). To this was charged SeO2 (12.77 g, 115.1 mmol), and the mixture was refluxed at 105 - 110 °C for 5 h. Then, the reaction mass was filtered through celite under hot conditions and then concentrated to remove volatile substances to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5. Next, this crude product was taken in glacial AcOH (210 mL, 0.25 mmol), and to this was charged 3-bromophenol 22 (9.96 g, 57.5 mmol), and refluxing was continued for the next 12 h. The reaction mass was concentrated and taken in EA (500 - 600 mL). This was filtered through celite, and the residue was washed with EA. The filtrate was washed with water (200 mL × 2) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was purified twice by silica gel column chromatography (35 - 40% EA in hexane) to obtain the pure product. 7-Bromo-9b-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indenol[1,2-b]benzofuran-10-one (24):

[0179] 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 23 (39.5 g, 0.105 mol) was taken in DCM (520 mL, 0.2 M), and oxalyl chloride (11 mL, 0.13 mol) was charged at room temperature. To this, DMF (40 mL, 0.53 mol) was added slowly (0.05 mL / min for 30 minutes, then 0.1 mL / min for 30 minutes, then the rest), and the mixture was kept stirring at ambient temperature (30 °C). Then, the reaction mixture was 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). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude was purified by silica gel column chromatography (10 - 30% EA in hexane) to obtain the pure product. 9b-Amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (25):

[0180] 9b-Chloro-4b-hydroxy-4-nitro-8-(trifluoromethyl)-4b,9b-dihydro-10H-inden[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, 2.0 M NH3 in IPA (54 mL, 0.11 mmol) was charged at the same temperature, and the mixture was kept stirring for the next 3 hours. The reaction mixture was diluted with water (~150 mL) and brine (150 mL). The aqueous layer was extracted with EA (~300 mL×2). The combined organic layers were washed with brine (~100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude was purified by silica gel column chromatography (20 - 30% EA in hexane containing 20% DCM as a co-solvent) to obtain the pure product. Tert-butyl (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[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 a racemic mixture of 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 25 (10.1 g, 31 mmol) in THF (5.0 mL, 5.0 M), and the mixture was stirred at room temperature (30 °C) for the next 72 h. The reaction mass was concentrated and purified. The crude product was purified by silica gel column chromatography (10 - 30% EA in hexane containing 5 - 10% DCM) to obtain the pure product. Tert-butyl (1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl) carbamate (27):

[0182] The racemic mixture of tert-butyl (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[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 Fe powder (3.57 g, 63.9 mmol) was charged thereto, followed by concentrated HCl (0.8 mL, cat.). This was refluxed at 90 °C for the next 3 h. Using hot EA (50 - 100 mL), the reaction mass was filtered through celite under warm conditions. The filtrate was concentrated, taken in EA (~1000 - 1200 mL), and washed with water (~300 - 500 mL) and brine (~300 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10 - 30% EA in hx) to obtain the pure product. Tert-butyl ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[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-inden[1,2-b]benzofuran-9b-yl) carbamate (29):

[0183] Tert-butyl (1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[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-inden[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 = 7.1 Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s, 5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M+H] + And tert-butyl ((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-inden[1,2-b]benzofuran-9b-yl) carbamate (29) was obtained as (peak 1, tR 8.97 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.48 (br t, J = 7.6 Hz, 1H), 7.37 (br s, 1H), 7.11 (br s, 1H), 7.02 (br d, J = 6.9 Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s, 5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M+H] + as obtained. (4bR,9bR)-1,9b-diamino-7-bromo-4b-hydroxy-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (30):

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

[0185] (4bR,9bR)-1,9b-diamino-7-bromo-4b-hydroxy-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 30 (76 mg, 0.22 mmol) was taken in glacial AcOH (2.2 mL, 0.1 M), and Ac2O (0.03 mL, 1.2 mmol) was charged immediately. The reaction mixture was then heated at 80 °C for the next 30 minutes. Then, 10 mL of 2N HCl (aqueous solution) was added and the mixture was stirred at 80 °C for the next 2 hours. The reaction mixture was concentrated to obtain a crude product. The crude mass was purified directly by silica gel column chromatography (20 - 50% EA in Hx containing 1 - 2% MeOH as co-solvent) to obtain the pure product 1Obtained as \(^{1}\)H-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

Chem.

[0186] 3-Bromophenol 22 (2.08 g, 12 mmol) was taken in dry DCM (40 mL, 0.3 M). To this, TBDMS-Cl (2.0 g, 13 mmol) was charged. Then, imidazole (1.37 g, 20 mmol) was charged thereto, and the mixture was stirred at room temperature for the next 15 hours. The reaction mass was filtered as it was, and the residue was washed with DCM. The filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (0 - 5% EA: hexane) to obtain the pure product. 1 \(^{1}\)H-NMR (300 MHz, CDCl\(_3\)) 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). Then, to this were charged PCy3 (42 mg, 0.15 mmol), K3PO4 (1.1 g, 5.24 mmol), and Pd(OAc)2 (17 mg, 0.07 mmol). Then, this was refluxed at 110 °C for the next 3 hours. The reaction mass was passed through celite and washed with ether. The organic layer was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was purified by silica gel column chromatography (0 - 5% EA:hexane) to obtain the pure product. 1 1H-NMR (300 MHz, 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), and 1.0 M TBAF (9.1 mL, 9.1 mmol) was added thereto. This was stirred at room temperature for the next 75 minutes. The reaction mass was concentrated and then taken in EA (200 mL). This was washed with saturated NH4Cl (50 mL), water (50 mL), and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The obtained crude product was purified by silica gel column chromatography (5% EA in hexane) to obtain the pure product. 1H-NMR (500 MHz, 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 = 2.5 Hz, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 7.13 - 7.16 (m, 1H, ArH). 7-Cyclopropyl-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-inden[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). This was washed with water (50 mL) and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was taken in DCM:hexane (approx. 50 mL), and the resulting solid was sonicated. This was filtered to obtain the pure product. The filtrate was concentrated again and purified by silica gel column chromatography (30% EA in hexane) to obtain the remaining product. 1 H-NMR (300 MHz, 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 = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.78 - 7.82 (m, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H). 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (37):

[0190] 7-Cyclopropyl-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 36 (1.70 g, 5.0 mmol) was taken in DCM (20 mL, 0.25 M), and oxalyl chloride (0.52 mL, 6.0 mmol) was charged. Then, DMF (2 mL) was slowly charged thereto. After 3 hours, additional oxalyl chloride (0.08 mL) was added. Then, the reaction mixture was stirred at room temperature for the next 30 minutes. The reaction mass was diluted to 200 mL with DCM. This was washed with water (100 mL × 2). Then, this was washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. This was concentrated to obtain a crude product, which was purified by silica gel column chromatography (10 - 15% EA in Hx) to obtain a pure product. 1 1H-NMR (300 MHz, 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 = 8.1 Hz, 1H, ArH), 7.39 (d, J = 8.1 Hz, 1H), 7.78 - 7.823 (m, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.49 (d, J = 8.1 Hz, 1H). 9b-Amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (38):

[0191] 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 37 (715 mg, 2.0 mmol) was taken in dry THF (20.0 mL, 0.1 M). This was cooled to -40 °C and then 2.0 M NH3 in IPA (2.0 mL, 4.0 mmol) was charged. Then, this was stirred at -40 °C to -30 °C for the next 2 hours. The reaction mass was concentrated at 25 °C until the volume was halved and then quenched with water. This was concentrated again to remove all volatiles and then taken in EA (150 mL). This was washed with water (50 mL × 2) and brine (50 mL). This was dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by silica gel column chromatography pre-inactivated with TEA (1:2 = EA:hexane) to obtain the pure product. 1 1H-NMR (300 MHz, 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 = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.77 - 7.80 (m, 1H), 8.25 (d, J = 7.5 Hz, 1H), 8.58 (d, J = 8.1 Hz, 1H). 9b-Chloro-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[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), and NMM (0.083 mL, 0.75 mmol) was added thereto at 0 °C. Acetyl chloride (0.054 mL, 0.75 mmol) was charged thereto, and the mixture was stirred at 0 °C for the next 30 minutes. Then, 9b-amino-7-cyclopropyl-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 38 (170 mg, 0.5 mmol) was charged in a single lot, and the mixture was stirred at 0 °C for the next 3 hours. The reaction mass was concentrated and then 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 obtained crude product was purified by silica gel column chromatography (1:1 = EA:hexane) to obtain a pure product. 1 1H-NMR (300 MHz, 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 = 7.8 Hz, J = 1.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.71 - 7.76 (m, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H). N-(1-Amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (40):

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

Table 5

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

Table 6

[0195] And N-((4bS,9bS)-1-amino-7-cyclopropyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (42) (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) was obtained as

Table 7

Chem.

Chem.

[0196] 2,2-Dihydroxy-4-nitro-1H-inden-1,3(2H)-dione 5 (1.34 g, 6 mmol) was taken in TFA (24 mL, 0.25 M). To this, 3-(trifluoromethoxy)phenol 43 (1.07, 6 mmol) was charged and this was stirred at room temperature (30 °C) for the next 12 hours. The reaction mass was concentrated. Then, this was taken in EA (200 mL) and washed with water (100 mL × 2) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude mass. Then, the crude product was 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-inden[1,2-b]benzofuran-10-one (45):

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

[0198] 9b-Chloro-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 45 (200 mg, 0.50 mmol) was taken in THF (5.0 mL, 0.1 M). This was cooled to -40 °C, 2.0 M NH3 in IPA (0.5 mL, 1.0 mmol) was added, and then the mixture was warmed to -10 °C for the next 3 hours. 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 obtain a crude product. The crude product was purified by a short pad of silica gel column chromatography (30~40% EA in hexane) to obtain the pure product. N-(4b-Hydroxy-4-nitro-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[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, NMM (0.44 mL, 0.40 mmol) was added, followed by AcCl (0.021 mL, 0.30 mmol). The reaction mass was stirred for 10 minutes and to this, 9b-amino-4b-hydroxy-4-nitro-7-(trifluoromethoxy)-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 46 (76 mg, 0.2 mmol) was added. The reaction mass was stirred at 0 °C for the next 1.5 hours. The reaction mass was concentrated, 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 obtain a crude product. The crude product was purified by silica gel column chromatography (30 - 35% EA in hexane) to obtain the pure product. N-(1-Amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (48):

[0200] N-(4b-Hydroxy-4-nitro-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[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 Fe powder (8.3 mg, 0.15 mmol) was charged. To this, concentrated HCl (1 drop) was charged and refluxed at 90 °C for the next 3 hours. The reaction mass was filtered through celite under hot conditions. The residue was washed with EA (~20 mL). This was concentrated and then taken in EA (~50 mL). This was washed with water (~20 mL) and brine (~20 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude mass. The crude mass was purified directly by reverse phase HPLC (MeCN:water as eluent) to obtain the pure product. 1H-NMR (300 MHz, CD3OD) δ 2.01 (s, 3H), 6.71 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 7.45 - 7.52 (m, 2H).

Table 8

[0201] N-(1-amino-4b-hydroxy-10-oxo-7-(trifluoromethoxy)-4b,10-dihydro-9bH-inden[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-inden[1,2-b]benzofuran-9b-yl)acetamide (49) as (peak 2, tR 7.41 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.37 - 7.55 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.85 (br d, J = 8.3 Hz, 1H), 6.75 (br d, J = 6.9 Hz, 1H), 6.69 (s, 1H), 1.99 (s, 3H),

Table 9

Table 10

Chemical formula

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

[0203] To a mixture of 2,2-dihydroxy-4-nitro-1H-inden-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 bed of celite, washed with ethyl acetate, and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. 7,9b-Dichloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (53):

[0204] To a mixture of 7-chloro-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-inden[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), and 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 give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. 9b-Amino-7-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (54):

[0205] To a mixture of 7,9b-dichloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 53 (220 mg, 0.63 mmol) in THF (3 mL) at -40 °C was added ammonia in IPA (0.8 mL, 1.6 mmol) over 5 minutes, and the reaction mass was stirred at -40 °C for 2 hours. The reaction mass was diluted with ethyl acetate and washed with brine solution (50 mL × 2). Then, the organic layer was dried over Na2SO4 and the solvent was evaporated to give the (crude) product. The crude product was used as such in the next step without purification. N-(7-Chloro-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[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-inden[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 hour. 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 product. The crude product 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-inden[1,2-b]benzofuran-9b-yl)acetamide (56):

[0207] A solution of N-(7-chloro-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (100 mg, 0.26 mmol) in EtOH:H2O (9 mL) was added with 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 a residue, which was dissolved in ethyl acetate (100 mL). The organic layer was washed with water (50 mL × 2), dried over Na2SO4, and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography using (ethyl acetate:hexane) to give the product. 1 H NMR (300 MHz, Methanol-d4) δ 7.62 - 7.24 (m, 2H), 6.99 (t, J = 8.8 Hz, 2H), 6.82 (d, J = 1.9 Hz, 1H), 6.72 (s, 1H), 2.01 (s, 3H).

Table 11

[0208] N-(1-Amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)acetamide (56) (200 mg) was purified by chiral chromatography using an IC column, SFC = 100 mL / min, CO2 / MeOH = 85 / 15, 206 bar to give N-((4bR,9bR)-1-amino-7-chloro-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[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 = 3.8 Hz, 1H), 6.99 (br d, J = 4.5 Hz, 1H), 6.90 - 6.96 (m, 1H), 6.80 (br s, 1H), 6.66 - 6.77 (m, 1H), 1.99 (br s, 3H) as follows,

Table 12

Table 13

[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 hours and then concentrated. The residue was purified by column chromatography (50% EA in hexane containing 50% dichloromethane) and reprecipitated to obtain the pure product. 1 H NMR (300 MHz, CDCl3) δ 8.51 (dd, J = 8.0, 0.8 Hz, 1H), 8.19 (dd, J = 7.7, 0.9 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 48H), 6.67 (s, 1H), 2.31 (s, 3H). 9b-Chloro-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one (61)

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

[0211] 61 (2.29 g, 6.9 mmol) of 9b-chloro-4b-hydroxy-7-methyl-4-nitro-4b,9b-dihydro-10H-inden[1,2-b]benzofuran-10-one 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 containing 3.3% DCM), and reprecipitated (DCM / Hex = 1 / 2) to give the product. 11H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.31 (m, 1H), 6.83 (t, J = 8.6 Hz, 1H), 6.67 (s, 1H), 2.30 (d, J = 6.0 Hz, 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 and then diluted with EA and washed with water. The organic layer was dried over anhydrous MgSO4, concentrated, and then purified by column chromatography (50% EA in hexane containing 5% DCM) and reprecipitated (DCM / Hex = 1 / 2) to give the product. 1 1H NMR (300 MHz, CDCl3) δ 8.47 (dd, J = 8.1, 0.8 Hz, 1H), 8.22 (d, J = 6.9 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.64 (s, 1H), 6.50 (s, 1H), 6.08 (s, 1H), 2.31 (s, 3H), 2.10 (s, 3H). N-(1-Amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (64)

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

Table 14

[0214] N-(1-Amino-4b-hydroxy-7-methyl-10-oxo-4b,10-dihydro-9bH-inden[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-inden[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 = 6.6 Hz, 1H), 6.79 (br d, J = 6.9 Hz, 1H), 6.66 (br d, J = 7.3 Hz, 1H), 6.59 (br s, 1H), 2.27 (s, 3H), 1.99 (s, 3H), and

Table 15

Table 16

Chemical formula

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

[0216] The racemate N-(1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-inden[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 obtain the above product N-((4bR,9bR)-1-amino-4b-hydroxy-8-methyl-10-oxo-4b,10-dihydro-9bH-inden[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-inden[1,2-b]benzofuran-9b-yl)acetamide (peak 1, tR 3.68 min).

Table 18

Chem.

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

Table 19

Chem.

[0218] The procedure for the above compound was carried out according to the same route as described in Examples 16 to 18, except that 3-methoxyphenol was used instead of m-cresol, to obtain the racemate 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 an AD column, HPLC = 20 mL / min, heptane / IPA = 70 / 30, 723 psi) to give the above product N-((4bR,9bR)-1-amino-4b-hydroxy-7-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide (peak 2, tR 24.20 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.39-7.50 (m, 1H), 7.31 (br dd, J = 3.1, 2.4 Hz, 1H), 6.92-7.05 (m, 1H), 6.62-6.74 (m, 1H), 6.44-6.57 (m, 1H), 6.34 (s, 1H), 3.72 (s, 3H), 1.99 (s, 3H) (Example 23), and also 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

[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 at a concentration of 10 - 40 mg / mL in 100% dimethyl sulfoxide (DMSO). The water-soluble reagents were dissolved in PBS(-) solution and stored at -20 °C. On the day of the experiment, they were used at a 3 - 5-fold concentration so that the concentration of dimethyl sulfoxide in each well was 0.5% - 1%.

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

[0221] In HeLa cells, the concentration of the drug that induces a response intermediate between the baseline and the maximum, the EC, was determined using the MTT assay. 50(50% maximum effective concentration), the drug was measured. In RD and MRC-5 cells, CPE was determined using FDA (fluorescein diacetate) or MTT. To determine the effect of drug toxicity on the efficacy results, mock infection was included at the time of virus inoculation. A virus-free medium was added to the cell culture, and then it was subjected to the same treatment as the virus-infected cells inoculated with the virus. That is, after 1 hour of incubation, the medium was removed, and a dilution of the drug in the medium was added again. After incubating for 2 - 3 days, the cells were observed under a microscope, and the number of viable cells in the mock-infected wells containing the drug was compared with the number of viable cells in the control wells without the drug using the MTT assay, and the CC that killed 50% of the cells was determined. 50 (50% cytotoxic concentration), the cells were measured. In the FDA hydrolysis assay, after removing the medium, FDA was added to each well, and after incubating for 20 - 30 minutes, the fluorescence intensity was measured using a spectrofluorometer to determine CPE in the same way as MTT.

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

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

[0224] 100% cell survival means that there is no cytotoxicity of the drug, while 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%. The concentration of this drug is represented as CC 50 and is expressed as. A higher value means lower cytotoxicity.

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

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

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

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

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

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

[0231] The %CPE value for measuring the cytotoxicity of the drug was calculated by the following formula 4: %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)] In the above formulas 3 and 4, OD(CC) represents the OD of the background cell culture that is not induced by the virus and not treated with the chemical substance, OD(VC) represents the OD of the control cell culture induced by the virus but not treated with the chemical substance, OD(virus + compound) represents the OD of the cell culture infected with the virus treated with the concentrated compound, OD(compound) represents the OD of the cell culture treated only with the concentrated compound, and OD(blank) represents the OD of the well to which only the cell culture was added.

[0232] The effective concentration (EC 50 ) represents the concentration of the drug at which 50% of the cells can survive due to the CPE of the induced virus, and the cytotoxic concentration (CC 50 ) represents the concentration of the drug at which the compound killed 50% of the cells, and these were calculated by logarithmic interpolation.

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

Table 21

[0234] As shown in Table 1 above, most of the compounds according to the present invention have a high CC 50Since it shows [the relevant property], it can be seen that the cytotoxicity is low. Furthermore, the novel compounds according to the present invention have been found to have very high antiviral activity against most rhinoviruses (HRV) in most cases. Furthermore, the novel compounds according to the present invention have been found to have high antiviral activity against Coxsackievirus B4 (Cox B4) and poliovirus 1 (PV1) in most cases.

[0235] Therefore, since the compounds according to the present invention show 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 compounds according to the present invention have low cytotoxicity and excellent antiviral activity against picornaviruses to which Coxsackievirus, poliovirus, and rhinovirus belong, they can be effectively used for the prevention or treatment of diseases caused by such viruses, such as poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot, and mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, rhinitis, and otitis media, including respiratory, cardiovascular, and nervous system diseases.

[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 excellent antiviral activity against picornaviruses including Coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus. Therefore, they can be effectively used as pharmaceutical compositions for preventing or treating viral diseases such as poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot, and mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, rhinitis, or otitis media. In one embodiment, for example, the following items are provided. (Item 1) A compound of formula I or a pharmaceutically acceptable salt thereof:

Chem.

Chem.

Chem.

Chem.

Table 22-1

Table 22-2

Table 22-3

Table 22-4

Chem.

Chem.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemical 31】 (wherein, G １ is selected from linear or branched C １ -C ５ haloalkyl, linear or branched C １ -C ５ haloalkyloxy and 3- to 7-membered cycloalkyl; G ２ is H; R １ is selected from H and linear or branched C １ -C ５ alkyl).

2. G １ is a linear or branched C １ -C ５ haloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. G １ is CF ３ The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

4. G １ is a linear or branched C １ -C ５ haloalkyloxy, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. G １ is OCF ３ The compound according to claim 1 or claim 4, or a pharmaceutically acceptable salt thereof.

6. G １ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein G is a 3- to 7-membered cycloalkyl.

7. G １ The compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 6, wherein G is cyclopropyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): 【Chemical 32】

9. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having formula (III): 【Chemical 33】

10. G １ is selected from CF ３ , OCF ３ , and cyclopropyl, the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. A compound selected from the following: 【Table 22-1】 【Table 22-2】 【Table 22-4】 or a pharmaceutically acceptable salt thereof.

12. Structure: 【Chemical Figure 34-2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having

13. Structure: [Chemical 34-3] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having

14. A composition for preventing or treating a viral disease, comprising a compound according to any one of claims 1 to 9, 11 to 13, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

15. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound according to any one of claims 1 to 9, 11 to 13, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

16. A combination comprising a compound according to any one of claims 1 to 9, 11 to 13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, and one or more therapeutic agents.

17. A composition for treating a viral disease, comprising a compound according to any one of claims 1 to 9, 11 to 13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, or the combination according to claim 16.

18. A composition according to claim 14 or claim 15, or the combination according to claim 16, for preventing or treating a viral disease.

19. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by a Coxsackievirus.

20. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by a poliovirus.

21. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by echovirus.

22. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by enterovirus.

23. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by rhinovirus.

24. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is caused by picornavirus.

25. The composition according to claim 14 or claim 15, or the composition or combination according to claim 17 or claim 18, wherein the viral disease is poliomyelitis, 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, rhinitis, or otitis media.

26. A composition for preventing or treating a viral disease, comprising the compound according to claim 10 or claim 11, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

27. A pharmaceutical composition for preventing or treating a viral disease, comprising the compound according to claim 10 or claim 11, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

28. A combination comprising the compound according to claim 10 or claim 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, and one or more therapeutic active agents.

29. A composition for treating a viral disease, comprising the compound according to claim 10 or claim 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, or the combination according to claim 28.

30. A composition comprising the compound according to claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for preventing or treating a viral disease, or the pharmaceutical composition according to claim 27, or the combination according to claim 28.

31. The composition according to claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, for preventing or treating a viral disease caused by one of coxsackievirus, poliovirus, echovirus, enterovirus, rhinovirus, and picornavirus, or the pharmaceutical composition according to claim 27, or the composition or combination according to claim 29 or claim 30.

32. The composition according to claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, for preventing or treating a viral disease which is poliomyelitis, 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, rhinitis, or otitis media, or the pharmaceutical composition according to claim 27, or the composition or combination according to claim 29 or claim 30.

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