Antiviral 1,3-di-oxo-indene compounds

Abstract

To provide antiviral 1,3-di-oxo-indene compounds.SOLUTION: Compounds of Formula (I) as described herein are provided along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections. The present invention provides novel compounds with potent antiviral activity in vitro. The invention also provides pharmaceutical compositions containing the novel compounds as well as methods to use the compounds and compositions to inhibit virus replication or reactivation, and to treat disease conditions associated with or caused by viruses.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Picornaviridae are non-enveloped, positive-sense, single-stranded RNA viruses whose RNA genome is 7.2-8.5 Kb long. These viruses are very small, spherical, with a size of about 22-30 nm, and were first identified a long time ago. Among the viruses that belong to the Picornaviridae family are rhinoviruses, polioviruses, enteroviruses including coxsackievirus A, coxsackievirus B, and echoviruses, and hepatitis A virus.

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

[0004] Human rhinovirus (hRV) has recently been associated with a large proportion of asthma exacerbations and is even known to be present in the bronchial tissues of many stable asthmatic patients. Comparison of bronchial mucosa biopsies from asthmatic and nonasthmatic patients showed that human rhinovirus was detected significantly more frequently in the lower airways of asthmatic patients than in nonasthmatic patients. A correlation between the presence of human rhinovirus and the clinical severity of asthma has also been reported. Furthermore, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media, as well as asthma.

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

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

[0007] Enviroxime derivatives are considered to be the most promising candidates with broad anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with the synthesis of positive-stranded RNA by binding to viral protein 3A, which is necessary for the formation of RNA intermediates in viral replication (Heinz BA and Vance LM: J Virol, 1995, 69(7), 4189-97). However, in clinical trials, the compounds were observed to have insignificant or little therapeutic effect, and were accompanied by poor pharmacokinetics and undesirable side effects (Miller FD et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

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

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

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

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

[0012] However, no antiviral drugs have been developed to date that have received approval for use in the treatment of enteroviruses or rhinoviruses. There remains a need for new treatments and therapies against enteroviruses and rhinoviruses. As a result of intensive and thorough research into effective viral growth inhibitors against picornaviruses, including coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses, it was discovered that novel 1,3-dioxoindene derivatives exhibit high inhibitory activity against picornaviruses, including coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses, which led to the present invention. [Prior art documents] [Non-patent literature]

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

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

[0015] In one aspect, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 is selected from linear or branched C1-C4 alkyl, C3-C4 cycloalkyl, or linear or branched C1-C4 alkoxy; said C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy may be substituted with 1, 2, or 3 substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl; L is a bond or CH; E is a) -CH(CHOHCH3)(NMe2); or b) a monocyclic 4- to 6-membered heterocyclyl containing one or two nitrogen atoms or a 5- to 6-membered heteroaryl containing one nitrogen atom, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl being optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, SO2R; each R is independently selected from linear or branched C1-C3 alkyl, monocyclic 5- to 6-membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 the monocyclic 5- to 6-membered heterocyclyl is optionally selected from C1-C3 alkyl or NR 3 R 4 Replaced with; Each R 1 and R 2 is independently selected from H and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally selected from NR 3 R 4 Replaced with; Each R 3 and R 4 are independently selected from H or methyl. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and one or more pharma- ceutically acceptable carriers. In another aspect, the invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the invention and one or more therapeutically active agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

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

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

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

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

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

[0023] "Optionally substituted" means that the referred group may be substituted at one or more positions with any one or any combination of the groups listed thereafter. The number, arrangement, and selection of substituents are understood to encompass only those substitutions that a chemist of ordinary skill in the art would expect to be reasonably stable, thus "oxo" is, for example, not a substituent on an aryl or heteroaryl ring, and a single carbon atom does not have three hydroxy or amino substituents. Unless otherwise specified, optional substituents are typically halo, oxo, CN, amino, hydroxy, -C 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * , and -CONR * 2 (in the formula, each R * are independently H or C 1-3 and up to four groups selected from the group consisting of alkyl, aryl, aryl and aryl groups.

[0024] As used herein, unless otherwise specified, "aryl" refers to a phenyl or naphthyl group. Aryl groups, unless otherwise specified, are optionally substituted with halo, CN, amino, hydroxy, C 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * , and -CONR * 2 (in the formula, each R * are independently H or C 1-3 and alkyl.

[0025] As used herein, "halo" or "halogen" may be fluorine, chlorine, bromine, or iodine.

[0026] As used herein, "C 1-6 "C1-C6 alkyl" or "C1-C6 alkyl" refers to a straight or branched chain alkyl having 1 to 6 carbon atoms. When a different number of carbon atoms, such as C4 or C3, is specified, the definition should be amended accordingly, e.g., "C 1-4 "Alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0027] As used herein, "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy (-O-alkyl) having 1 to 6 carbon atoms. When a different number of carbon atoms is specified, such as C4 or C3, the definition should be amended accordingly, e.g., "C 1-4 "Alkoxy" means methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso It represents butoxy, sec-butoxy, and tert-butoxy.

[0028] As used herein, "C 1-4 "Haloalkyl" or "C1-C4 haloalkyl" refers to a straight or branched alkyl having from 1 to 4 carbon atoms in which at least one hydrogen is replaced with a halogen. The number of halogen substitutions can be from 1 to the number of hydrogen atoms in the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C6 or C3, the definition should be amended accordingly. Thus, "C 1-4"Haloalkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl having at least one hydrogen replaced with a halogen, for example, CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-, where the halogen is fluorine.

[0029] As used herein, "C 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When a different number of carbon atoms, such as C3-C6, is specified, the definition should be amended accordingly.

[0030] "4-8 membered heterocyclyl", "5-6 membered heterocyclyl", "3-10 membered heterocyclyl", "3-14 membered heterocyclyl", "4-14 membered heterocyclyl", and "5-14 membered heterocyclyl" refer to 4-8 membered, 5-6 membered, 3-10 membered, 3-14 membered, 4-14 membered, and 5-14 membered heterocycles, respectively, and unless otherwise specified, such rings contain 1-7, 1-5, or 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the rings may be saturated or partially saturated, but are not aromatic. Heterocyclic groups can be attached to another group at a nitrogen or carbon atom. The term "heterocyclyl" includes single ring groups, fused ring groups, and bridging groups. Examples of such heterocyclyls include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-aza-bicyclo[3.2.1]octane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 2-oxa-5-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, azetidine, ethylenedioxo, oxetane, or thiazole. In certain embodiments, unless otherwise specified, heterocyclic groups have 1-2 heteroatoms selected from N, O, and S as ring members, and 4-7 ring atoms, and are optionally selected from halo, oxo, CN, amino, hydroxy, C 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * , and -CONR * 2 (in the formula, each R * are independently H or C 1-3 In particular, heterocyclic groups containing a sulfur atom are optionally substituted at the sulfur with one or two oxo groups.

[0031] A "heteroaryl" is a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or tricyclic aromatic ring system having 1-8 heteroatoms selected from N, O, or S. Typically, a heteroaryl is a 5-10 membered ring or ring system (e.g., a 5-7 membered monocyclic group or an 8-10 membered bicyclic group), often a 5-6 membered ring containing up to four heteroatoms selected from N, O, and S, although often a heteroaryl ring contains no more than one divalent O or S in the ring. Exemplary heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, and the like. Heteroaryl groups are optionally selected from halo, CN, amino, hydroxy, C, C-, C-alkyl, C-alkyl- ... 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * , and -CONR * 2 (in the formula, each R * are independently H or C 1-3 and alkyl.

[0032] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0033] Various embodiments of the invention are described herein. It is recognized that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The following listed embodiments are representative of the invention.

[0034] Embodiment 1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 is selected from linear or branched C1-C4 alkyl, C3-C4 cycloalkyl, or linear or branched C1-C4 alkoxy; the C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy may be substituted with 1, 2, or 3 substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl; L is a bond or a C1-C4 straight or branched alkylene linker; E is a) -CH(CHOHCH3)(NMe2); or b) a monocyclic 4- to 6-membered heterocyclyl containing one or two nitrogen atoms or a 5- to 6-membered heteroaryl containing one nitrogen atom, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl being optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, -SO2R; each R is independently selected from linear or branched C1-C3 alkyl, monocyclic 5- to 6-membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 the monocyclic 5- to 6-membered heterocyclyl is optionally selected from C1-C3 alkyl or NR 3 R 4 Replaced with; Each R 1 and R 2 is independently selected from H and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally selected from NR 3 R 4 Replaced with; Each R 3 and R 4 are independently selected from H or methyl.

[0035] Embodiment 2. A compound according to embodiment 1 having formula (II), or a pharma- ceutically acceptable salt thereof: [ka]

[0036] Embodiment 3. A compound according to embodiment 1 having formula (III), or a pharma- ceutically acceptable salt thereof: [ka]

[0037] Embodiment 4.G 1 is a straight or branched chain C1-C4 alkyl; or a pharma- ceutically acceptable salt thereof.

[0038] Embodiment 5.G 1 is C3-C4 cycloalkyl; or a pharma- ceutically acceptable salt thereof.

[0039] Embodiment 6.G 1 is straight or branched chain C1-C4 alkoxy; or a pharma- ceutically acceptable salt thereof.

[0040] Embodiment 7. A compound according to any one of embodiments 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy can be substituted with one, two, or three substituents.

[0041] Embodiment 8. A compound according to any one of embodiments 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein the substituents are independently selected from cyclopropyl and straight or branched C1-C3 alkyl.

[0042] Embodiment 9. A compound according to any one of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein L is a bond. A compound according to any one of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein L is a C1-C4 straight or branched alkylene linker. A compound according to any one of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein L is CH2.

[0043] Embodiment 10. A compound according to any one of embodiments 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein E is -C(CHOHCH3)(NMe2).

[0044] Embodiment 11. A compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein E is monocyclic 4-6 membered heterocyclyl.

[0045] Embodiment 12. Any of embodiments 1 to 11, wherein E is a monocyclic 4- to 6-membered heteroaryl. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

[0046] Embodiment 13. A compound according to any one of embodiments 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein the monocyclic 4-6 membered heterocyclyl contains 1 or 2 nitrogen atoms.

[0047] Embodiment 14. A compound according to any one of embodiments 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein the 5-6 membered heteroaryl contains one nitrogen atom.

[0048] Embodiment 15. A compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with 1, 2, or 3 substituents.

[0049] Embodiment 16. A compound according to any one of embodiments 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein the substituents are independently selected from the group consisting of straight or branched C1-C3 alkyl, -OH, =O, -SO2R.

[0050] Embodiment 17. R is independently selected from linear or branched C1-C3 alkyl, monocyclic 5-6 membered heterocyclyl, and NR 1 R 2 17. The compound according to any one of embodiments 1 to 16, selected from:

[0051] Embodiment 18. The monocyclic 5-6 membered heterocyclyl is optionally C1-C3 alkyl or NR 3 R 4 18. The compound of any one of embodiments 1-17, substituted with:

[0052] Embodiment 19.R 1 and R 2 is independently selected from H and C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof. 3 R 4 19. The compound of any one of embodiments 1-18, substituted with:

[0053] Embodiment 20. Each R 3 and R 4 is independently selected from H or methyl; or a pharma- ceutically acceptable salt thereof.

[0054] Embodiment 21.G 1 is a straight or branched chain C1-C4 alkyl optionally substituted with one, two, or three substituents independently selected from cyclopropyl and straight or branched chain C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof.

[0055] Embodiment 22.G 1 is optionally substituted with 1, 2, or 3 substituents independently selected from straight or branched chain C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof.

[0056] Embodiment 23.G 1 is a straight or branched chain C1-C4 alkoxy optionally substituted with one, two, or three substituents independently selected from cyclopropyl and straight or branched chain C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof.

[0057] Embodiment 24. A compound according to embodiment 1 having the formula (Ia), or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 is selected from the group consisting of H, linear or branched C1-C3 alkyl, and SO2R; A 2 is selected from the group consisting of H and SO2R.

[0058] Embodiment 25.A 1 is methyl or SO2CH3.

[0059] Embodiment 26.A 2 is SO2R, and R is CH3; monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms and substituted with CH3 or N(CH3)2; and NR 1 R 2 25. The compound according to embodiment 23 or 24, selected from the group consisting of:

[0060] Embodiment 27. A compound according to embodiment 1 having the formula (Ib), or a pharma- ceutically acceptable salt thereof: [ka] (wherein Y is H or CH3).

[0061] Embodiment 28. A compound according to embodiment 1 having the formula (Ic), or a pharma- ceutically acceptable salt thereof: [ka] wherein X is selected from the group consisting of methyl, ethyl, and cyclopropyl.

[0062] Embodiment 29. A compound of any of the preceding embodiments of any of the Examples, selected from the group consisting of: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-( 1S,2R)-2-Methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide;N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide;N-(1-amino-7-((1R, 2S)-1,2-Dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-(2-methylcyclobutyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide;N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pi (2S,3S)-N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide;N-(1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(((S)-3-(dimethylamino)-3-hydroxybutanamide) N-((4bR,9bR)-1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b, 10-Dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;(2S,3S)-N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-y; N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro -9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide;N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide;N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro Hydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-((1 S,2R)-2-Methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide;N-(1-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b ]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b ]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide and N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide. This embodiment includes each of the examples presented in the Bioactivity Data Tables herein;

[0063] Embodiment 30. A compound comprising each or any of the examples presented in the Bioactivity Data Tables herein.

[0064] Embodiment 31. A compound according to formula I-III or the present invention for preventing or treating a viral disease. 2. A compound according to any one of the preceding claims, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof.

[0065] Embodiment 32. A pharmaceutical composition for preventing or treating a viral disease comprising a compound according to any one of formulas I-III or embodiments herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient.

[0066] Embodiment 33. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by a coxsackievirus. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by a poliovirus. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by an echovirus. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by an enterovirus. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by a rhinovirus. A compound as described in an embodiment herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition as described in an embodiment herein, wherein the viral disease is caused by a picornavirus. The compound as described in the embodiments herein, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, or the pharmaceutical composition as described in the embodiments herein, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0067] Embodiment 34. Use of a compound according to any one of Formulas 1-III or embodiments herein, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, for preventing or treating a viral disease.

[0068] Embodiment 35 The use described in embodiments herein, wherein the viral disease is caused by a Coxsackievirus.

[0069] Embodiment 36 The use according to embodiments herein, wherein the viral disease is caused by poliovirus.

[0070] Embodiment 37 The use described in embodiments herein, wherein the viral disease is caused by an echovirus.

[0071] Embodiment 38 The use described in embodiments herein, wherein the viral disease is caused by an enterovirus.

[0072] Embodiment 39 The use described in embodiments herein, wherein the viral disease is caused by a rhinovirus.

[0073] Embodiment 40 The use described in embodiments herein, wherein the viral disease is caused by a picornavirus.

[0074] Embodiment 41. The use according to embodiments herein, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0075] These compounds are novel and are useful as intermediates for preparing the compounds of formulae (I)-(III) described herein.

[0076] Another embodiment of the present invention provides a compound as described above, or a pharma- ceutically acceptable salt thereof, as a medicament.

[0077] Also within the scope of the present invention are

[0078] There is also the use of a compound according to formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of viral and / or infectious diseases in humans.

[0079] Included within the scope of the present invention is a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0080] 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.

[0081] The present invention also provides the use of a pharmaceutical composition as described above for treating a viral infection or other viruses in a human having or at risk of having a viral infection.

[0082] The invention also provides the use of the pharmaceutical composition described above for treating a viral disease or other viral infection in a human having or at risk of having a viral disease.

[0083] Another aspect of the invention relates to a method of treating or preventing viral and / or infectious diseases in a human by administering to the human an antivirally effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a composition as described above, either alone or in combination with at least one other antiviral agent administered together or separately.

[0084] An additional aspect of the present invention is directed to an article of manufacture comprising a composition effective to treat a herpes virus disease and / or infection and packaging material comprising a label indicating that the composition can be used to treat a viral disease and / or infection, the composition comprising a compound of formula (I) according to the present invention or a pharma- ceutical acceptable salt thereof.

[0085] Yet another aspect of the present invention relates to a method of inhibiting viral replication, comprising exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions in which replication of the virus is inhibited. The method can be carried out in vitro or in vivo.

[0086] Further included within the scope of the present invention is the use of a compound of formula (I) or a salt thereof for inhibiting viral replication.

[0087] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharma- ceutically acceptable carrier, as described above. In some embodiments, the compound of formula (I) is co-administered with at least one additional agent selected from, including another viral inhibitor.

[0088] These additional agents may be combined with the compounds of the invention to produce a single pharmaceutical dosage form. Alternatively, these additional agents may be administered separately to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following administration of the compounds of the invention or a pharma- ceutically acceptable salt thereof.

[0089] The daily applicable dose range of the compound of the present invention is usually 0.01-100 mg / kg body weight, for example 0.1-50 mg / kg body weight. Each dosage unit may conveniently contain 5%-95% active compound (w / w). Sometimes such preparations contain 20%-80% active compound.

[0090] The actual pharmacologic effective amount or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination will be administered in an amount and manner that allows for the delivery of a pharmacologic effective amount based on the patient's unique condition.

[0091] When the compositions of the invention comprise a combination of a compound of the invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels that are about 10-100%, and sometimes about 10-80%, of the dosage normally administered in a monotherapy regimen.

[0092] Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologics) effective to inhibit virus formation and / or replication in humans, including, but not limited to, agents that interfere with either the host or viral mechanisms necessary for virus formation and / or replication in humans.

[0093] Many compounds of the present invention contain one or more chiral centers. These compounds can be made and used as a single isomer or as a mixture of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the present invention are used as a single substantially pure isomer, meaning that at least 90% of a sample of the compound is a specific 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. Since typically one isomer will be more active in the herpesvirus DNA polymerase in vitro assay described herein, resulting in a single isomer, the selection of a suitable isomer is within the ordinary skill level. When the difference in in vitro activity between isomers is relatively small, e.g., less than about 4-fold, a method such as that described herein may be used to select a single isomer based on the activity level against virus replication in cell culture, e.g., the isomer with a lower IC50 or EC50.

[0094] The compounds of the invention may be synthesised by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0095] The present invention also provides methods for making the compounds of formula I as described herein, and intermediates useful in the preparation of the compounds of formula (I). Thus, the present invention also includes methods for making the compounds of formula (I). The present invention relates to a method for making the compounds of formula (I), in which intermediate products obtainable at any stage thereof are used as starting materials for carrying out the remaining steps, or in which starting materials are formed in situ under reaction conditions, or in which the reaction components are salts or optically pure materials thereof. The present invention further includes any variation of this process, wherein the

[0096] The invention also relates to forms of the process in which compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or in which starting materials are formed under the reaction conditions or are used in the form of derivatives, for example in protected form or in the form of a salt, or in which compounds obtainable by the process according to the invention are produced under the process conditions and further treated in situ.

[0097] The term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, including geometric isomers. It is understood that substituents may be attached to chiral centers of carbon atoms. The term "chiral" refers to molecules that possess the property of non-superimposability with respect to their mirror image partners; The term "achiral," on the other hand, refers to molecules that are superimposable relative to their mirror image partners. Thus, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to refer to racemic mixtures where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be designated by either R or S. Resolved compounds of unknown absolute configuration may be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0098] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible isomers, or in mixtures thereof, depending on the number of asymmetric carbon atoms, e.g., as pure optical isomers or as isomeric mixtures, such as racemic and diastereomeric mixtures. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have cis or trans configuration. All tautomeric forms are also intended to be included.

[0099] Any resulting mixture of isomers can be separated on the basis of the physical chemical differences of the constituents, into pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and / or fractional crystallization.

[0100] Any resulting racemates of the final products or intermediates can be resolved into their optical antipodes by known methods, for example by separation of their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. Thus, in particular, the compounds of the present invention can be resolved into their optical antipodes using basic moieties, for example by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor 10-sulfonic acid. Racemic products can also be resolved into their optical antipodes by chiral chromatography, for example by high pressure liquid chromatography using a chiral adsorbent. It can also be resolved by pressure liquid chromatography (HPLC).

[0101] Furthermore, the compounds of the present invention, including their salts, can be obtained in the form of their hydrates or can include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharma- ceutically acceptable solvents, including water. Thus, the present invention is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including its pharma-ceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are known to be harmless to the recipient, e.g., water and ethanol, and are commonly used in the pharmaceutical arts. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0102] The compounds of the present invention (including their salts, hydrates and solvates) may inherently or by design form polymorphs.

[0103] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of a compound of the invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0104] Pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurate ... The salts may be formed as salts of the following acids: disodium sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0105] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0106] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0107] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0108] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, pipetamine, etc. Examples include arazine, and tromethamine.

[0109] The pharma- ceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxides, carbonates, or bicarbonates), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences" 20th Edition, Mack, et al., "Pharmaceuticals and Biotechnology", vol. 1, no. 1, pp. 111-115, 19 ... Publishing Company, Easton, Pa. (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0110] Any formula given herein includes unlabeled forms of the compounds of the invention having up to three atoms, as well as non-natural isotope distributions, such as deuterium or 13 C or 15 It is intended to represent an isotopically labeled form having N-enriched sites. Isotopically labeled compounds have structures as shown by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number outside the natural abundance mass distribution. Examples of isotopes that can be usefully incorporated in excess into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 The present invention relates to various isotopically labeled compounds of the present invention, e.g. 3 H and 14 Radioisotopes such as C, or 2 H and 13 These include those in which non-radioactive isotopes, such as C, are present at levels substantially above the normal isotopic distribution. Such isotopically labeled compounds may be used in metabolic studies (e.g., 14 C), reaction kinetics studies (e.g. 2 H or 3H), positron emission tomography (PET), or single-photon emission computed tomography (SCT), including drug or substrate tissue distribution assays. In particular, the present invention is useful in detection or imaging techniques such as SPECT (Spectral Tomography), or in radiation therapy of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using suitable isotopically labeled reagents instead of typically used non-labeled reagents. Labeled samples can be useful with very low isotope incorporation, such as when radioactive labels are used to detect trace amounts of compounds.

[0111] Additionally, heavier isotopes, particularly deuterium (i.e. 2 More extensive substitution with deuterium (H or D) may result in certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in vivo, or reduced dosage requirements, or improved therapeutic index. Deuterium in this context is considered a substituent of the compounds of the invention, and it is understood that typically, a sample of a compound having deuterium as a substituent will have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes, specifically deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated deuterium, such a compound will have at least 3500 (each designated deuterium) for each designated deuterium atom. in the elementary atoms), 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).

[0112] Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization is isotopically substituted, e.g. D2O, d 6 -Acetone, d 6 -Including what may be DMSO.

[0113] Compounds of the present invention that contain groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting in solution the compounds of the present invention with the co-crystal formers under crystallization conditions, and isolating the co-crystals formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. Thus, the present invention further provides co-crystals comprising compounds of the present invention.

[0114] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention, and does not limit the scope of the invention as claimed.

[0115] The compounds of the present invention can be administered by known methods, including orally, parenterally, and by inhalation. In certain embodiments, the compounds of the present invention are administered orally as pills, lozenges, troches, capsules, liquids, or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusions are typically administered intravenously, often over a period of about 15 minutes to 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation. Inhalation methods are particularly useful for treating respiratory infections. Since the compounds of the present invention exhibit oral bioavailability, in some embodiments, the compounds may be administered orally.

[0116] The compounds of the invention may also be used in combination with other agents (combination partners), such as additional antiviral agents, whether of Formula I or not, for the treatment of a viral infection in a subject.

[0117] The term "combination / combination / concomitant" means either a combination fixed in one unit dosage form, either as separate dosage forms suitable for use together, either simultaneously or sequentially, or as a kit of parts for combined administration, where the compound of the present invention and the combination partner(s) may be administered independently simultaneously or separately, particularly within a time interval that allows the combination partners to exhibit a cooperative, e.g., synergistic, effect, or any combination thereof.

[0118] 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.

[0119] A second anti-viral agent may be administered in combination with a compound of the invention, where the second anti-viral agent is administered before, simultaneously with, or after the compound or compounds of the invention. When simultaneous administration of the compound of the present invention and the second drug is desired and the routes of administration are the same, the compound of the present invention may be formulated in the same dosage form with the second drug. An example of a dosage form containing the compound of the present invention and the second drug is a tablet or capsule.

[0120] In some embodiments, the combination of a compound of the invention with a second antiviral agent may provide synergistic activity. The compound of the invention and the second antiviral agent may be administered together, separately but simultaneously, or sequentially.

[0121] An "effective amount" of a compound is an amount necessary or sufficient to treat or prevent a viral infection and / or a disease or condition described herein. In one example, an effective amount of a viral inhibitor of formula I is an amount sufficient to treat a viral infection in a subject. In another example, an effective amount of an inhibitor is an amount sufficient to treat a viral infection in a subject in need of such treatment. An effective amount can vary depending on factors such as the size and weight of the subject, the type of illness, or the particular compound of the present invention. For example, the selection of a compound of the present invention can affect what constitutes an "effective amount". One of ordinary skill in the art can study the factors contained herein and make a determination regarding the effective amount of a compound of the present invention without undue experimentation.

[0122] Dosage regimen may affect what constitutes an effective amount. The compound of the present invention may be administered to a subject either before or after the onset of viral infection. Furthermore, several divided doses and staggered dosages may be administered daily or sequentially, or the dose may be continuously infused or bolus injected. Furthermore, the dosage of the compound of the present invention may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0123] The compounds of the invention may be used for the treatment of conditions, disorders, or diseases described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The invention provides methods of using the compounds of the invention in the treatment of these diseases, or methods of preparing pharmaceutical compositions having the compounds of the invention for the treatment of these diseases.

[0124] The term "pharmaceutical composition" includes preparations suitable for administration to a mammal, e.g., a human. When a compound of the present invention is administered as a medicine to a mammal, e.g., a human, the compound may be given per se or as a pharmaceutical composition containing, e.g., 0.1-99.5% (e.g., 0.5-90%) of at least one compound of formula (I) or any subgenus thereof as an active ingredient in combination with a pharmaceutically acceptable carrier or, optionally, two or more pharmaceutically acceptable carriers.

[0125] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharma-ceutically acceptable materials, compositions, or vehicles suitable for administering a compound of the invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; magnesium hydroxide and aluminum hydroxide. Examples of suitable carriers include, but are not limited to, any buffer; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer, and other non-toxic compatible substances used in pharmaceutical formulations. Typically, pharma- ceutically acceptable carriers are sterile and / or substantially pyrogen-free.

[0126] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0127] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0128] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of the active ingredient, sometimes from about 5 percent to about 70 percent, and sometimes from about 10 percent to about 30 percent.

[0129] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0130] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (with an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0131] In solid dosage forms of the invention for oral administration (such as capsules, tablets, pills, dragees, powders, and granules), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; humectants, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; talc, calcium stearate, or the like. lubricants, such as calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0132] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0133] Tablets and other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, with various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient only in the gastrointestinal tract, or, for example, in a specific part of the gastrointestinal tract, optionally in a sustained manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

[0134] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion preparation, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0135] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0136] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0137] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature, and It therefore melts in the rectum or vaginal cavity and releases the active compound.

[0138] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known in the art to be appropriate.

[0139] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0140] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0141] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0142] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention into the body.Such dosage forms can be prepared by dissolving or dispersing the compound in suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.

[0143] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0144] Pharmaceutical compositions of the invention suitable for parenteral administration can contain one or more compounds of the invention in combination with one or more pharma- ceutically acceptable carriers, such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders, which can be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0145] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0146] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents in the compositions, such as sugars and sodium chloride. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by the use of aluminum monostearate. and gelatin, which delays absorption.

[0147] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0148] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsion formulations that are compatible with body tissues.

[0149] The preparations of the present invention can be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for each administration route. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppositories.

[0150] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and substernal injection and infusion. Sometimes, intravenous infusion is the method of delivery of the compounds of the invention. Infusion may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the invention are administered by infusion over intervals of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once a day, twice a day, or up to three times per day.

[0151] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to the administration of a compound, drug, or other material other than directly to the central nervous system, such that it enters the patient's system and is thus subject to metabolic and other similar processes, e.g., corresponding to subcutaneous administration.

[0152] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, for example, by spray, rectally, vaginally, parenterally, intracisternally, and topically, by powders, ointments, or drops (including buccal and sublingual).

[0153] Regardless of the selected route of administration, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0154] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0155] The dosage level selected will depend on the activity of the particular compound of the invention, or an ester, salt, or amide thereof, being used, the route of administration, the time of administration, and the excretion rate of the particular compound being used. It will depend on a variety of factors, including the rate, duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound being used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0156] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can begin doses of the compounds of the invention used in the pharmaceutical composition at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0157] In general, a suitable daily dose of the compound of the present invention is that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. In general, the intravenous and subcutaneous dose of the compound of the present invention for a patient, when used for the indicated effect, ranges from about 0.0001 to about 100 mg / kilogram (body weight) per day, sometimes from about 0.01 to about 50 mg / kg per day, sometimes from about 0.1 to about 20 mg / kg per day. An effective amount is an amount that prevents or treats a viral infection.

[0158] If desired, the effective daily dose of the active compound may be administered as a single dose per day or as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. Compounds delivered orally or by inhalation are generally administered in one to four doses per day. Compounds delivered by injection are typically administered once a day or once every other day. Compounds delivered by infusion are typically administered in one to three doses per day. When multiple doses are administered within a day, the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours, or about 12 hours.

[0159] While it is possible for the compounds of the invention to be administered alone, sometimes the compounds can be administered as a pharmaceutical composition, such as those described herein. Thus, methods of using the compounds of the invention include administering the compound as a pharmaceutical composition, in which at least one compound of the invention is mixed with a pharma- ceutically acceptable carrier prior to administration. General synthetic procedure

[0160] 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.

[0161] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th Edition (1952), Methods of Organic Synthesis, Thieme, Vol. 21). [Table 1-1] [Table 1-2]

[0162] The compounds of the invention are prepared from commonly available compounds using procedures known to those skilled in the art in light of the examples and schemes provided herein.

[0163] Within the scope of this specification, only easily removable groups that are not constituents of a particular desired end product of the compounds of the invention are referred to as "protecting groups", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves and their cleavage reactions are described in standard references, for example in "Science of Synthesis: Houben-Weyl Methods of Molecular Transformation." Georg Thieme Verlag (Stuttgart, Germany, 2005. p. 41627 (URL: http: / / www.science-of-synthesis.com (vol. 48 of the electronic version)); JFW MacOmie, "Protective Groups in Organic Chemistry", Plenum Press (London and New York, 1973); TW Greene and PG M Huts, "Protective Groups in Organic Chemistry", Plenum Press (London and New York, 1973); Synthesis", 3rd ed., Wiley (New York, 1999), The Peptides, Vol. 3 (eds. E. Gross and J. Meienhofer ), Academic Press (London and New York, 1981), "Methoden der Organischen Chemie" ("Methods of Organic Chemistry"), Houben Weyl, 4th ed., Vol. 15 / I, Georg Thieme Verlag (Stuttgart, 1974), H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Protein" ("Amino acids, Peptides, Proteins"), Verlag Chemie, (Weinheim, Deerfield Beach, and Basel, 1982), and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" ("Chemistry of Carbohydrates: Monosaccharides and Derivatives"), Georg Thieme Verlag (Stuttgart, 1974). A characteristic of a protecting group is that it can be easily removed (i.e. without the occurrence of undesired secondary reactions), for example by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g. by enzymatic cleavage).

[0164] 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 formed by treating the compounds with metal compounds such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogencarbonates, for example the hydroxides, carbonates or hydrogencarbonates of sodium or potassium, with the corresponding calcium compounds, or with ammonia or suitable organic amines, sometimes using a stoichiometric amount or a slight excess of salt former. Acid addition salts of the compounds of the present invention can be obtained in a conventional manner, for example by treating the compounds with an acid or a suitable anion exchange reagent. Intramolecular salts of the compounds of the present invention containing acid and basic salt-forming groups, for example free carboxyl groups and free amino groups, can be formed by neutralizing the salts, for example acid addition salts, to their isoelectric points, for example by treating with a weak base or ion exchanger.

[0165] Salts can be converted into the free compounds in the usual manner: metal salts and ammonium salts can be converted, for example, by treatment with a suitable acid and acid-addition salts, for example by treatment with a suitable basic agent.

[0166] The mixtures of isomers obtainable according to the invention can be separated into the individual isomers in a manner known per se: diastereoisomers can be separated, for example, by partition between multiphase solvent mixtures, recrystallization and / or chromatographic separation, for example on silica gel, or for example by medium pressure liquid chromatography on reversed phase columns, and racemates can be separated, for example, by salt formation with optically pure salt-forming agents and separation of the mixtures of diastereoisomers thus obtainable, for example by fractional crystallization, or by chromatography on optically active column materials.

[0167] Intermediates and final products can be worked up and / or purified according to standard methods, eg using chromatographic methods, distribution methods, (re-)crystallization, and the like. High-resolution mass spectrometry by LC-MS

[0168] ESI-MS data were recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The resolution of the MS system was approximately 30000. Drug candidates were infused into the mass spectrometer by UPLC (Acquity, Waters) through the sample probe. The Acquity UPLC BE was run at a flow rate of 0.15 mL / min with a gradient of 5% to 95% in 3 min. Separation was performed on an H C18 1×50 mm column. Solvent A was water with 0.1% trifluoroacetic acid and solvent B was 75% methanol and 25% isopropyl alcohol with 0.1% trifluoroacetic acid. The mass accuracy of the system was found to be less than 5 ppm. EXAMPLES

[0169] The present invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art. Demonstration of efficacy in these assays is generally considered predictive of efficacy in subjects.

[0170] The compounds of the invention can be prepared by organic synthesis methods known to those skilled in the art with reference to the following reaction schemes and examples. General methods for the synthesis of compounds of formula (I) are provided in the following schemes. Example 1: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide (33): [ka] [ka] 4-Nitroisobenzofuran-1,3-dione (2):

[0171] An initial suspension of 3-nitrophthalic acid 1 (1.0 kg, 4.7 mol) in Ac2O (1 L) was refluxed at 140° C. for 2.5 h. It was then cooled to 80° C. and slowly added to diethyl ether (4 L) with vigorous stirring. The precipitate was collected by filtration through a Büchner funnel and washed with Et2O to give the product. Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate (3):

[0172] To a suspension of anhydride 2 (50 g, 0.26 mol) in dry DCM (260 mL) was added ethyl acetoacetate (42 mL, 0.31 mol) and Ac2O (48.5 mL, 0.52 mol) at ambient temperature. To this suspension was charged Et3N (108 mL, 0.78 mol) dropwise over 30 min at room temperature (exothermic). A few mL of TEA was added. It was stirred at the same temperature for another 15 min and then DCM was evaporated. The crude obtained was then dissolved in 2 liters of water and cooled to 0° C. It was fixed on an overhead stirrer and 300 mL of 2N HCl was added dropwise to it under vigorous stirring conditions while maintaining the temperature below 0° C. A precipitate started to form slowly. It was stirred at 0° C. for another 15 min and then filtered through a Buchner funnel and washed with ice-cold water (500 mL). It was then air-dried for 3 days to give a solid product. 4-Nitro-1H-indene-1,3(2H)-dione (4):

[0173] Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate 3 (272.5 g, 1.04 mol) was taken in 1 liter of MeCN:water (20:1, 1.0 M). To this suspension, TFA (60 mL, 1.14 mol) was slowly charged at room temperature and then heating was maintained at 50° C. After 4 hours, the reaction mass was concentrated on a rotavapour until approximately 100 mL of solvent remained. The precipitated solid was then filtered on a Buchner funnel and washed with (1:1) CHCl3:hexane. This gave the product and the filtrate was concentrated again to obtain a second crop. p) gave more product. 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione (5):

[0174] 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 refluxed at 105-110 °C for 5 h. The reaction mass was then filtered through Celite under hot conditions and then concentrated to remove volatiles to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione. 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (7):

[0175] The crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 was then taken in glacial AcOH (210 mL, 0.25 mmol) which was charged with 3-bromophenol 6 (9.96 g, 57.5 mmol) and maintained at reflux for next 12 h. The reaction mass was concentrated and taken in EA (500-600 mL). It was filtered through Celite and the residue was washed with EA. The filtrate was washed with water (200 mL×2) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified twice by silica gel column chromatography (35→40% EA in hexane) to give the pure product. 7-Bromo-9b-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (8):

[0176] 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 7 (39.5 g, 0.105 mol) was taken in DCM (520 mL, 0.2 M) and charged with oxalyl chloride (11 mL, 0.13 mol) at room temperature. To this, DMF (40 mL, 0.53 mol) was added slowly (0.05 mL / min for 30 min, 0.1 mL / min for 30 min, then rapidly) and left to stir at ambient temperature (30° C.). The reaction mixture was then stirred at room temperature (20° C.) for the next 12 hours. The reaction mixture was diluted with water (~300 mL). The aqueous layer was extracted with DCM (~500 mL×2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (10→30% EA in hexane) to give the pure product. 9b-Amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (9):

[0177] 9b-Chloro-4b-hydroxy-4-nitro-8-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 8 (21.2, 53.4 mmol) was taken in THF (530 mL, 0.1 M) and cooled to -40 °C. To this was charged 2.0 M NH3 in IPA (54 mL, 0.11 mmol) at the same temperature and left stirring for next 3 h. The reaction mixture was diluted with water (ca. 150 mL) and brine (150 mL). The aqueous layer was extracted with EA (ca. 300 mL x 2). The combined organic layers were washed with brine (ca. 100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified by silica gel column chromatography (20 -> 30% EA in hexane with 20% DCM as co-solvent) to give the pure product. tert-Butyl (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (10):

[0178] Boc anhydride (8.74 g, 40 mmol) and molecular I2 (0.69 g, 2.67 mmol) were added to a solution of racemic mixture of 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 9 (10.1 g, 31 mmol) in THF (5.0 mL, 5.0 M) and stirred for next 72 h at room temperature (30 °C). The reaction mass was concentrated and purified. The crude was purified by silica gel column chromatography (10 → 30% EA in hexane with 5-10% DCM) to give the pure product.

[0179] tert-Butyl (1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (11):

[0180] The mixture racemic tert-butyl (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 10 (10.3 g, 21.5 mmol) was taken in EtOH:water (10:1, 110.0 mL, 0.20 M) and charged with Fe powder (3.57 g, 63.9 mmol) followed by concentrated HCl (0.8 mL, cat.). It was refluxed at 90° C. for next 3 h. The reaction mass was filtered through Celite under warm conditions using hot EA (50-100 mL). The filtrate was concentrated, taken in EA (ca. 1000-1200 mL) and washed with water (ca. 300-500 mL) and brine (ca. 300 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (10→30% EA in hx) to give the pure product. tert-Butyl ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (12) and tert-butyl ((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (13): tert-Butyl (1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (11) (7000 mg) was purified by chiral chromatography using (AD column, HPLC = 20 mL / min, heptane / EtOH = 70 / 30, 724 psi) to give 3100 mg of tert-butyl ((4bR, 9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (12) (peak 2, tR 15.59 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.48 (br t,J=7.7Hz,1H),7.37(br s,1H),7.11(br s,1H),7.02(br d,J=7.1Hz,1H),6.95(s,1H),6.72(br s,1H),1.42(br s,5H),1.13(br s,4H)LCMS:447.2 / 449.2[M+H] + and 3060 mg of tert-butyl ((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (13) (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] + Obtained as. [ka] Intermediates (14 and 18) were prepared according to J. Am. Chem. Soc. 2013, 135, 82-85. ((1S,2S)-2-Methylcyclopropyl)boronic acid (15):

[0181] A solution of (4S,5S)-N4,N4,N5,N5-tetramethyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane-4,5-dicarboxamide 14 (4.21 g, 14.4 mmol) in water (145 mL) was stirred at room temperature for 12 h. The aqueous layer was extracted with ether (100 mL x 3) and the combined ethereal layers were washed with water, dried over Na2SO4, and the solvent was evaporated at low temperature to give the product. The crude was carried on to the next step without purification. 6-Methyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione (17):

[0182] Toluene:To a solution of ((1S,2S)-2-methylcyclopropyl)boronic acid 15 (800 mg, 8.0 mmol) in DMSO (80 mL), 2,2'-(methylazanediyl)diacetic acid 16 (1.766 mg, 12 mmol) was added. The resulting reaction mass was refluxed under Dean-Stack conditions for 3 h. Toluene was evaporated under vacuum, the organic layer was diluted with water, the aqueous layer was extracted with ethyl acetate (100 mL × 3), the combined organic layers were washed with water, dried over Na2SO4, and the solvent was evaporated to give the crude. The crude was triturated with ether, the solid was filtered and washed with ether to give the product. ((1R,2R)-2-Methylcyclopropyl)boronic acid (19):

[0183] A solution of (4R,5R)-N4,N4,N5,N5-tetramethyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,2-dioxaborolane-4,5-dicarboxamide 18 (11.3 g, 31.7 mmol, based on starting material from previous step) in distilled water (317 mL, 0.1 M) was stirred at room temperature for 12 h. The reaction mixture was extracted with diethyl ether (500 mL×3) and the combined organic layers were washed with water (×1), dried over anhydrous Na2SO4, and concentrated at low temperature to give the crude product. This crude product was used in the next step without purification. 6-Methyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione (20):

[0184] To a solution of ((1R,2R)-2-methylcyclopropyl)boronic acid 19 (6.03 g, 60.3 mmol) in toluene / DMSO (10 / 1, 300 mL / 30 mL), 2,2 '-(Methylazanediyl)diacetic acid 16 (13.3 g, 90.5 mmol) was added and then refluxed under Dean-Stark conditions for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The organic layer was washed with water (200 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated. Diethyl ether was added to the residue, then the desired product was generated. 1 H NMR(300MHz,CDCl3)δ 3.92(d,J=16.6Hz,2H),3.72(dd,J=16.6,4.8Hz,2H),3.04(s,3H),1.10(d,J=5.8Hz,3H),0.7 0(dt,J=11.3,5.7Hz,1H),0.47-0.35(m,1H),0.34-0.22(m,1H),-0.61(dt,J=9.2,6.1Hz,1H). [ka] Methyl tosylglycinate (23):

[0185] Methyl glycinate hydrochloride 21 (50.0 g, 398.2 mmol) was dissolved in DCM (800 mL). p-Tosyl chloride 22 (75.9 g, 398.2 mmol) was then added slowly. The reaction mixture was cooled to 0° C. DIPEA (208 mL, 1194.7 mmol) was then added slowly and the reaction was stirred at 0° C. for 10 min. The reaction was warmed to 30° C. and stirred for 18 h. The reaction was quenched with 1N HCl, the aqueous layer was extracted with DCM (500 mL×3), and the combined organic layers were washed with water (500 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated to give the crude. The crude was purified by trituration with DCM:Hex to give the product. Methyl 3-hydroxy-3-methyl-1-tosylpyrrolidine-2-carboxylate (25):

[0186] Methyl tosyl glycinate 23 (58.50 g, 240.5 mmol) and methyl vinyl ketone 24 (26 mL, 529.0 mmol) were dissolved in THL (241 mL), then DBU (79 mL, 529.0 mmol) was added slowly and the reaction mass was stirred at room temperature (30° C.) for 12 h. The reaction mixture was diluted with ether (1000 mL). The organic phase was washed with a solution of 1N HCl. After the pH of the aqueous phase became acidic, the organic phase was washed with a solution of 5% Na2CO3 and with water until the pH was neutral. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum to give the product. The crude was used in the next step without purification. Methyl 3-methyl-1-tosyl-4,5-dihydro-1H-pyrrole-2-carboxylate (26):

[0187] Methyl 3-hydroxy-3-methyl-1-tosylpyrrolidine-2-carboxylate 2 5 (69 g, 220 mmol) was dissolved in anhydrous pyridine (550 mL), POCl3 (61 mL, 660 mmol) was added slowly and the reaction mass was stirred at room temperature (30 °C) for 12 h. The reaction mixture was poured into ice water, the aqueous layer was extracted with ether (5 times), the combined organic layers were washed with 5% HCl solution, and after the pH of the aqueous layer became acidic, the organic layer was washed with a solution of 5% Na2CO3, and then with water until the pH was neutral. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum. The crude was purified by silica gel column chromatography to give the product. Methyl 3-methyl-1H-pyrrole-2-carboxylate (27):

[0188] Methyl 3-methyl-1-tosyl-4,5-dihydro-1H-pyrrole-2-carboxylate 26 (30 g, 102 mmol) was dissolved in THF (204 mL), DBU (46 mL, 306 mmol) was added slowly and the resulting reaction mass was stirred at 50° C. for 20 h. The reaction mass was cooled to room temperature and diluted with ether. The organic layer was washed with 1N HCl, then 5% NaHCO3, then water. The organic layer was dried over Na2SO4 and evaporated to give the crude. The crude was filtered through a silica gel plug and the solvent was evaporated to give the product. Methyl 3-methyl-4-(methylthio)-1H-pyrrole-2-carboxylate (28):

[0189] Methyl 3-methyl-1H-pyrrole-2-carboxylate 27 (460 mg, 3.3 mmol) and CuI (314 mg, 0.5 mmol) were taken in DMSO (3.3 mL, 1.0 M). This was then charged with dimethyl disulfide (0.531 mL, 6.0 mmol) and heated at 110° C. for next 48 h. The reaction was quenched with water (50 mL) and EA (50 mL). The layers were filtered through Celite and then separated. The aqueous layer was extracted with EA (50 mL) and the combined organic layers were washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated to give the crude. The crude was purified by silica gel column chromatography (10→15% EA in hexanes) to give the product. Methyl 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylate (29):

[0190] Methyl 3-methyl-5-(methylthio)-1H-pyrrole-2-carboxylate 28 (185 mg, 1.0 mmol) was taken in MeOH (10 mL) to which a solution of OXONE (1.85 g, 2.0 mmol) in water (10 mL) was added dropwise at room temperature. The reaction mass was then stirred for next 3 h at room temperature (25° C.). The volatiles were then removed under reduced pressure and the suspension of the solid in water was extracted with EA (70 mL×2) using only a small amount of water to dissolve the inorganics. The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (30→40% EA in hexane) to give the pure product. 3-Methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid (30):

[0191] To a solution of ethyl 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylate 29 (390 mg, 1.68 mmol) in HO:THF (17 mL) was added LiOH.HO (353 mg, 8.4 mmol). The resulting reaction mass was then stirred at 80° C. for 12 h. The reaction mass was acidified with 1N HCl, the precipitated solid was extracted with ethyl acetate (100 mL×2) and the combined organic layer was washed with water and brine solution. The organic layer was dried over anhydrous NaSO and the solvent was evaporated to give the product which was used directly in the next step without purification. [ka] tert-Butyl ((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (31):

[0192] tert-Butyl ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (112 mg, 0.25 mmol) was taken in nitrogen purged toluene:water (5 mL). To this was added Pd(OAc)2 (6 mg 0.03 mmol), RuPhos (24 mg, 0.05 mmol), K3PO4 (213 mg, 1.0 mmol), and 6-methyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione 20 (79 mg, 0.38 mmol). The reaction mass was refluxed at 100° C. for 2 h and the reaction was filtered through a bed of Celite. The filtrate was evaporated to give the crude material, which was purified by silica gel column chromatography to give the product. (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-(1R,2R)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride (32):

[0193] tert-Butyl ((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 31 (70 mg, 0.21 mmol) was dissolved in DCM (2 mL). To this was added 4N HCl in 1,4-dioxane (0.6 mL, 2.1 mmol). The reaction mass was stirred at room temperature (30° C.) for 12 hours. The solvent was evaporated under vacuum to give the crude product. The crude was used without purification. N-(4bR,9bR)-1-amino-4b-hydroxy-7-(1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide (33):

[0194] 3-Methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid 30 (48 mg, 0.23 mmol) was taken up in DMF (4 mL, 0.05 M). U (111 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) were added and stirred for 20 min, then (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride 32 (70 mg, 0.2 mmol) was added and stirred at 30° C. for 36 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, 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 and again by ADH chiral column chromatography to give the product. 1 H-NMR(300MHz,MeOD)δ 0.66-0.72(m,1H),0.78-0.84(m,1H),0.95-1.03(m,1H),1.13(d,J=6.0Hz,3H),1.49-1.55(m,1H),2.48(s,3H),3.05(s,3H),6.45(s,1H) ,6.63-6.67(m,1H),6.76(d,J=8.1Hz,1H),7.02(d,J=7.2Hz,1H),2.27(d,J=8.1Hz,1H),7.38(s,1H),7.43-7.49(m,1H).LCMS:508.4[M+H] + . Example 2: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide [ka]

[0195] This compound was prepared similarly to the compound above. LCMS: 420.2 [M+H] + . Example 3: N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide [ka]

[0196] This compound was prepared similarly to Example 1 above. LCMS: 458.2 [M+H] + . Example 4: N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxamide (51): [ka] 4b,9b-Dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (35):

[0197] 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 maintained at reflux at 110° C. for next 4 hours. This was stirred at room temperature for next 12 hours. This was then charged with 500 g-600 g of Celite. This was stirred and filtered through a Celite pad. The residue was washed with ethyl acetate (300-500 mL). The filtrate obtained was concentrated to give crude product 5, which was used further as such. 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude, 1.31 mol) was taken in glacial AcOH (2 L) and charged with 3-isopropylphenol 34 (196 g, 1.44 mol) and maintained at reflux for next 10 h, which was then concentrated and purified by silica gel column chromatography (30% EA in hexane) to give the pure product. 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (36):

[0198] 4b,9b-Dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 35 (50 g, 0.147 moles) was taken in DCM (500 mL) and then this suspension was charged with oxalyl chloride (1.2 eq.) in a single lot. This was then slowly charged with DMF (50 mL). The reaction mass was then left stirring at room temperature for next 6 hours. This was quenched with water (500 mL) and the layers were separated. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic layers were washed with water (300 mL) and brine (300 mL). This was dried over sodium sulfate and concentrated to give a crude mass which was then purified on a short pad of silica (30% ethyl acetate in hexane) to give the pure product. 1H-NMR(300MHz, CDCl3):δ 1.18(dd,J=3.6Hz,J=6.9Hz,6H),2.84(sept,J=6.9Hz,1H),6.34(s,1H),6.70(s,1H),6.94(d d,J=1.0Hz,J=7.8Hz,1H),7.45(d,J=7.8Hz,1H),7.81-7.83(m,1H),8.21(m,1H),8.52(m,1H). 9b-Amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (37):

[0199] 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 36 (36.0 g, 0.1 mol) was taken in THF (350 mL) and cooled to -40°C. To this clear solution, 2.0 M solution of NH3 in IPA (100 mL, 0.20 mol) was added using a dropping funnel and the temperature was maintained below -20°C. The reaction mass was monitored at -20°C for 1 hour and then warmed to room temperature. It was stirred at room temperature until the reaction was complete and then concentrated completely. The crude was taken in ethyl acetate (500 mL) and washed with water (200 mL x 2) and brine (100 mL). It was dried over anhydrous Na2SO4 and then concentrated to get a crude mass which was purified on a short pad of silica to get the pure product. 1 H-NMR(300MHz,CDCl3)δ 1.18(d,J=6.9Hz,6H),2.84(sept,J=6.9Hz,1H),3.46(s,1H),6.25(s,1H),6.74(s,2H),6.90(dd,J=1.2Hz,J=7.8Hz, 1H),7.55(d,J=7.8Hz,1H),7.77(t,J=8.1Hz,1H),8.22(dd,J=1.2Hz,J=8.4Hz,1H),8.52(dd,J=1.2Hz,J=8.1Hz,1H). [ka] 3-Nitrobutan-2-yl acetate (39):

[0200] 3-Nitrobutan-2-ol 38 (7.5 g, 63 mmol) was taken in DCM (37.5 mL, 1.7 M) and charged with acetic anhydride (11.3 mL, 120 mmol) followed by DMAP (305 mg, 2.52 mmol). After stirring for next 24 h at room temperature (20 °C), the reaction mass was quenched with MeOH (8 mL) and stirred for next 1 h. It was then taken in DCM (250 mL) and washed with saturated NaHCO3 (100 mL x 2), water (100 mL), and brine (ca. 100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the pure product as an oil. Ethyl formyl glycinate (41):

[0201] To a solution of glycine ester hydrochloride 40 (20.0 g, 0.143 mol) in ethyl formate (90 mL, 1.6 M) was added pTSA (1.36 g, 7.2 mmol). It was refluxed and TEA (22.0 mL, 0.157 mol) was added dropwise at this temperature. The reaction mass was refluxed for next 24 h or while being monitored by TLC. It was then cooled to room temperature (20° C.) and then concentrated. The crude was then filtered through a short pad of silica with 50% EA in hexane (3000 mL). It was then concentrated to give the product which was used directly in the next step. NMR showed that the product was 99.9%. The product had TEA in it, which was taken as is for the next step since the TEA is used in excess in the next step. Ethyl 2-isocyanoacetate (42):

[0202] To a solution of ethyl formyl glycinate 41 (9.40 g, 80 mmol) and TEA (28 mL, 0.2 mol) in DCM (80 mL, 1.0 M) at 0° C., POCl3 (7.5 mL, 80 mmol) was added dropwise slowly. The solution turned red, which was then allowed to reach room temperature after the addition was complete and stirred for next 4 h. The reaction mass was then quenched slowly with Na2CO3 solution and solid Na2CO3 and stirred at room temperature for next 30 min. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL×2). The combined organic layers were then washed with water (100 mL) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the pure product as a liquid.

[0203] Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate (43): 3-Nitrobutan-2-yl acetate 39 (8.9 g, 55.0 mmol) and ethyl 2-isocyanoacetate 42 (8.1 g, 71.5 mmol) were taken in THE:water (1:1, 110 mL, 0.5 M) to which anhydrous K2CO3 (12.2 g, 88.0 mmol) was slowly added in portions under vigorous stirring and then the reaction mass was stirred at room temperature for next 3 days. The reaction mass was then concentrated to a thick slurry. It was then diluted with ice-cold water (100 mL) and then slowly neutralized with 5% HCl (2N, pH=5) at 0°C. It was then extracted with EA (150 mL x 3). The combined organic layer was washed with 5% brine (100 mL x 2). It was then dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude was purified by silica gel column chromatography (0→10% EA in hexanes) to give the pure product. Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (44):

[0204] Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate 43 (1.67 g, 10.0 mmol) was taken in CHCl3 (40 mL, 0.25 M) to which chlorosulfonic acid (10.0 mL, 150.0 mmol) was added at 0° C. The reaction mass was stirred for next 3 h at 0° C. The reaction mass was quenched with crushed ice (120 mL) and extracted with DCM (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was passed through a short pad of silica gel with DCM and the filtrate was concentrated to give the pure product. Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (46):

[0205] Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 44 (530 mg, 2.0 mmol) was taken in DCM (20 mL, 0.1 M) to which tert-butyl (2-aminoethyl)carbamate 45 (385 mg, 2.4 mmol) was added followed by DIPEA (0.52 mL, 3.0 mmol) at room temperature. The reaction mass was then stirred for next 2 h at room temperature (25° C.). The reaction mass was quenched with water (50 mL) and then extracted with DCM (70 mL×2). The combined organic layer was washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude was purified by silica gel column chromatography (30% EA in hexane) to give the pure product. 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (47):

[0206] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfonate amoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 46 (682 mg, 1.75 mmol) was taken in THF:MeOH:H2O (1:1:10, 18.0 mL, 0.1 M) and charged with LiOH.H2O (367 mg, 5.0 mmol) and the reaction was refluxed at 80 °C for 5 h. The reaction mass was concentrated to remove volatiles. It was then acidified with 1N HCl (pH < 2-3). The precipitated solid was then filtered, washed with cold water and dried to give the pure product. [ka] tert-Butyl (2-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole)-2-sulfonamido)ethyl)carbamate (48):

[0207] 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid 47 (452 ​​mg, 1.25 mmol) was taken up in DMF (5 mL, 0.25 M) and cooled to 0° C. To this was charged EDCI (360 mg, 1.88 mmol) followed by HOBt (254 mg, 1.88 mmol). After 10 min, it was charged with 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (425 mg, 1.25 mmol) followed by DIPEA (0.55 mL, 3.13 mmol) and allowed to reach room temperature (35° C.) over the next 18 h. The reaction mass was then quenched with water (60 mL) and extracted with EA (100 mL×2). The combined organic layers were washed with water (50 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude. The crude was purified by silica gel column chromatography (40% EA in hexane) to give the product. 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide (49):

[0208] tert-Butyl (2-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole)-2-sulfonamido)ethyl)carbamate 48 (275 mg, 0.4 mmol) was taken up in DCM (8 mL, 0.05 M) and this was mixed with 4 M HCl in dioxane (1.0 mL, 4.0 mmol). l) was added. It was stirred for 15 hours at room temperature (25° C.). The reaction was diluted with DCM (20 mL) and stirred with saturated NaHCO3 (20 mL) for 10 minutes. As the free amine was not fully liberated, 0.5 mL of TEA was added. It was then diluted with DCM (100 mL) and the layers were separated. The organic layer was washed with saturated NaHCO3 (20 mL), water (30 mL), and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give a solid. 5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide (50):

[0209] 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 49 (88 mg, 0.15 mmol) was taken in MeCN:glacial AcOH (2:1, 3 mL, 0.05 M) cooled to 0° C. To this was charged 35% aqueous HCHO (0.125 mL, 1.5 mmol) followed by the addition of NaBH3CN (33 mg, 0.53 mmol). This was stirred for next 0.5 h at 0° C. The reaction mass was quenched with water (40 mL) and extracted with EA (40 mL×2). The combined organic layer was washed with water (30 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0→10% MeOH in DCM, 0.05% TEA) to give the pure product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxamide (51):

[0210] 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 50 (46 mg, 0.075 mmol) was taken in EtOH:water (10:1, 5.0 mL, 0.015 M) and charged with iron powder (13 mg, 0.23 mmol) followed by 1 M HCl (3 drops). It was refluxed at 90° C. for next 1.5 h. The reaction mass was cooled to 50° C. and then neutralized with TEA (1 drop). The reaction mixture was then filtered through Celite under hot conditions with EA (20 mL). The filtrate was concentrated, taken up in EA (100 mL) and washed with water (20 mL) and brine (20 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by thin-layer preparative chromatography (10% MeOH in DCM) to give the pure product. 1 H-NMR(300MHz,CD3OD)δ 1.19(d,J=6.9Hz,6H),2.17(s,3H),2.20(s,3H),2.43(s,6H),2.65(t,J=6.6Hz,2H),2.82(sept,J=6.9Hz,1H),3.06(t,J=6.6Hz,2H),6.6 9(s,1H),6.77(d,J=7.8Hz,1H),6.85(d,J=7.8Hz,1H),7.03(d,J=7.2Hz,1H),7.36(d,J=7.8Hz,1H),7.45-7.50(m,1H).LCMS:582.3[M+H] + . Example 5: N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide (62) [ka] 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54):

[0211] Anhydrous lithium chloride (7.06 g, 166.5 mmol), CuCl (16.5 g, 166.5 mmol) and dry N,N-dimethylformamide (500 mL) were added to a reaction flask under nitrogen and the mixture was stirred at room temperature for 1 h, then potassium acetate (16.4 g, 166.5 mmol), B2Pin253 (42.3 g, 166.5 mmol) and cyclopropylacetylene 52 (10 g, 151.3 mmol) were added sequentially and stirring was continued at room temperature for 20 h. The reaction mass was quenched with a saturated solution of NH4Cl (100 mL), ethyl acetate (100 mL) was added and filtered through a bed of celite. The filtrate was extracted with hexane (200 mL x 3), and the combined organic layers were collected, washed with water (100 mL x 3) and brine (100 mL), dried over Na2SO4, and the solvent was evaporated under vacuum to give the crude product, which was purified by silica gel column chromatography (hexane) to give the product as an oil. [ka] tert-Butyl 2-(azetidin-1-yl)acetate (57):

[0212] Azetidine hydrochloride 56 (73 g, 78 mmol) was taken in THF:water (4:1, 170 mL, 0.3 M) and cooled to 0° C. To this was added 2N NaOH (78 mL, 157 mmol) in water and stirred for 10 min. To this was then charged tert-butyl 2-bromoacetate 55 (7.2 mL, 49 mmol) dropwise at 0° C. and stirred for next 1 h at 30° C. The reaction mixture was then extracted with EA (150 mL×2) and the combined organic layers were washed with saturated brine (ca. 50 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product as a liquid. 2-(Azetidin-1-yl)acetic acid hydrochloride (58):

[0213] tert-Butyl 2-(azetidin-1-yl)acetate 57 (6.7 g, 39 mmol) was cooled to 0° C. and slowly charged with 4 M HCl in dioxane (98 mL, 0.4 M). The reaction mixture was then stirred at room temperature (30° C.) for the next 24 h. The precipitated solid was then filtered, washed with cold 1,4-dioxane (ca. 20-30 mL) and dried to give the pure product. [ka] tert-Butyl ((4bR,9bR)-1-amino-7-(1-cyclopropylvinyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (59):

[0214] tert-Butyl (1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (3.36 g, 7.50 mmol), Pd(dppf)Cl2 (613 mg, 0.75 mmol), and K2CO3 (3.11 g, 22.5 mmol) were taken in a sealed tube and charged with toluene:water (5:1, 75 mL, 0.10 M) that had been previously purged with nitrogen. The reaction mixture was purged again with N2 (10 min), then charged with 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 54 (2.15 g, 11.3 mmol) and maintained at 90 °C for the next 3 h. The reaction mixture was passed through a bed of Celite and concentrated. It was taken up in EA and water and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (20→30% EA in hexane) to give the pure product. tert-Butyl ((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (60):

[0215] tert-Butyl (1-amino-7-(1-cyclopropylvinyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 59 (5.43 g, 12.5 mmol) was taken in DCM (125 mL, 0.10 M) and charged with [((4S,5S)-Cy2-UBaphox)Ir(COD)]BARF (433 mg, 0.25 mmol) under nitrogen. It was then flushed with H2 gas and then kept under H2 atmosphere (60 psi) at room temperature (20 °C) for next 4 h. The reaction mass was then concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0 → 10 → 30% EA in hexane with 10% DCM as co-solvent) to give the pure product. (4bR,9bR)-1,9b-diamino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (61):

[0216] tert-Butyl((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-yne Deno[1,2-b]benzofuran-9b-yl)carbamate 60 (2.18 g, 5.00 mmol) was taken in DCM (50 mL, 0.1 M) and immediately charged with 4.0 M HCl in dioxane (12.5 mL, 50.0 mmol). The reaction mixture was then stirred for the next 6 h at room temperature (20 °C). The reaction mixture was diluted with EA (ca. 150 mL) and stirred with saturated NaHCO3 (ca. 100 mL) for 5-10 min. The layers were separated and the aqueous layer was extracted with EA (~100 mL). The combined organic layers were washed with water (100 mL) and brine (~100 mL). It was dried over anhydrous Na2SO4 and concentrated to give the product which was used directly in the next step without further purification. N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide (62):

[0217] 2-(azetidin-1-yl)acetic acid hydrochloride 58 (1.02 g, 6.75 mmol) in 45 mL of anhydrous DMF (0.1 M) was charged with HATU (2.57 g, 6.75 mmol) and DIPEA (2.35 mL, 13.5 mmol) at 0° C. After 10 min, it was charged with (4bR,9bR)-1,9b-diamino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 61 (1.51 g, 4.50 mmol) and stirred at room temperature (20° C.) for 15 h. The reaction mass was quenched with water (ca. 100 mL) and saturated NaHCO3 (ca. 100 mL). It was extracted with EA (100 mL×3). The combined organic layers were washed with water (100 mL×2), brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (0→10% MeOH in DCM) to give the pure product. 1 H-NMR(500MHz,MeOD)δ 7.50-7.39(m,1H),7.29(d,J=8.0Hz,1H),6.99(d,J=7.3Hz,1H),6.85(dd,J=8.0,1.3Hz ,1H),6.72(d,J=8.5Hz,1H),6.69(d,J=1.3Hz,1H),3.37(t,J=7.3Hz,4H),3.18(s,2H),2 .09(p,J=7.1Hz,2H),1.91-1.83(m,1H),1.25(d,J=7.0Hz,3H),0.94-0.79(m,1H),0.55 -0.47(m,1H),0.40-0.26(m,1H),0.17-0.13(m,1H),0.07-0.03(m,1H).LCMS:432.3[MH] - .LCMS: 434.2[M+H] + .

[0218] Example 6: N-(1-amino-7-((1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide. [ka]

[0219] This compound was prepared similarly to Example 5 above. LCMS: 522.2 [M+H] + . Example 7: N-(1-amino-4b-hydroxy-7-(2-methylcyclobutyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylate Samid. [ka]

[0220] This compound was prepared similarly to Example 5 above. LCMS: 522.2 [M+H] + . Example 8: N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide [ka]

[0221] This compound was prepared similarly to Example 5 above. LCMS: 458.1 [M+H] + . Example 9: N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (83): [ka] [ka] 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (64):

[0222] To a solution of 3-hydroxybenzaldehyde (30 g, 0.25 mol) and imidazole (21.7 g, 0.32 mol) in dry dichloromethane (250 mL) was added tert-butylchlorodimethylsilane (44.4 g, 0.30 mol) slowly at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and washed with DCM. The organic layer was washed with water, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified on a silica gel column eluted with EA / Hexane (0 / 100→1 / 10) to give the desired product. 1 H NMR(300MHz,CDCl3)δ 9.95(s,1H),7.40(tdd,J=21.4,12.8,9.5Hz,3H),7.11(ddd,J=7.9,2.5,1.2Hz,1H),1.00(s,9H),0.23(d,J=3.0Hz,6H). (E)-tert-butyldimethyl(3-(prop-1-en-1-yl)phenoxy)silane (66):

[0223] To a solution of 3-((tert-butyldimethylsilyl)oxy)benzaldehyde 64 (30 g, 0.13 mol), propionaldehyde 65 (11.5 mL, 0.16 mol), and malononitrile (20.95 g, 0.17 mol) in acetonitrile (630 mL, 0.2 M) was added acetic acid (13.7 mL, 0.24 mol) dropwise at room temperature. The reaction mixture was stirred for 10 min, and then ammonium acetate (12.2 g, 0.16 mol) was added. The resulting solution was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered, concentrated, and purified on a silica gel column eluted with n-Hex to give the desired product. 1 H NMR(300MHz,CDl3)δ 7.14(td,J=7.8, 2.8Hz,1H),6.92(d,J=7.5Hz,1H),6.81(s,1H),6.68(d,J=8.0Hz,1H),6.35(d,J=15.9H) z,1H),6.22(m,1H),1.88(d,J=6.1Hz,3H),0.99(d,J=2.6Hz,9H),0.20(d,J=2.6Hz,6H). tert-Butyldimethyl(3-((trans)-2-methylcyclopropyl)phenoxy)silane (67):

[0224] Diethylzinc (50 mL, 1.0 M in hexanes, 0.05 mol) was added dropwise via cannula to dry dichloromethane (150 mL) with stirring at -40°C. After 10 min, a solution of diiodomethane (8 mL, 0.1 mol) in dry dichloromethane (25 mL) was added dropwise at -40°C to the reaction mixture. The reaction mixture was stirred at -40°C for 1 h. A solution of trichloroacetic acid (0.82 g, 0.005 mol), DME (2.59 mL, 0.025 mol) in dry dichloromethane (25 mL) was added dropwise at -40°C to the reaction mixture. The reaction mixture was stirred at -15°C for 1 h. To this reaction mixture was added dropwise a solution of (E)-tert-butyldimethyl(3-(prop-1-en-1-yl)phenoxy)silane 66 (6.21 g, 0.025 mol) in dry dichloromethane (25 mL) at -15°C. After 10 min, the reaction mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was carefully poured into ice water at 0°C. The solid formed was filtered and the filtrate was extracted with dichloromethane, dried over MgSO4, concentrated and purified on a silica gel column eluted with n-Hex / EA (100 / 0 -> 50 / 1) to give the desired racemic product in trans configuration as an oil. 1 H NMR(300MHz,CDCl3)δ 7.08(t,J=7.8Hz,1H),6.60(m,2H),6.48(t,J=2.0Hz,1H),1.87(dd,J=6.4,1.3Hz,0.20H),1.51(dt, J=8.9,3.3Hz,1H),1.19(dd,J=15.5,5.8Hz,3H),1.01(m,9H),0.81(m,2H),0.71(m,1H),0.18(m,6H). 3-((trans)-2-Methylcyclopropyl)phenol (68):

[0225] To a solution of racemic tert-butyldimethyl(3-((trans)-2-methylcyclopropyl)phenoxy)silane 67 (32.93 g, 0.12545 mol) in ethanol (300 mL) was added concentrated HCl (30 mL) dropwise with stirring. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified on a silica gel column, eluted with EA / Hex (1 / 20→1 / 15) to give 3-((1S,2S)-2-methylcyclopropyl)phenol (product). 1 H NMR(300MHz,CDCl3)δ 7.10(t,J=7.9Hz,1H),6.59(m,2H),6.49(m,1H),4.66(d,J=8.7Hz,1H),1.52(dt,J=8.9,4.6H z,1H),1.15(t,J=10.4Hz,3H),1.04(tdd,J=10.3,5.7,4.5Hz,1H),0.86(m,1H),0.72(m,1H). 4b,9b-Dihydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (69):

[0226] To a solution of 4-nitro-1H-indene-1,3(2H)-dione 4 (16.4 g, 0.086 mol) in dioxane:AcOH (10:1, v / v, 140 mL / 14 mL, 0.6 M) was added selenium dioxide (19 g, 0.17 mol). The reaction mixture was refluxed at 130° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a pad of Celite, and concentrated to give the crude product 5, which was used in the next step without purification. To a solution of 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude) in glacial acetic acid (140 mL) was added a racemic mixture of 3-((trans)-2-methylcyclopropyl)phenol (12.7 g, 0.085 mol). The reaction mixture was refluxed at 80° C. for 3 h, cooled to room temperature, diluted with EA, filtered, and concentrated. The residue was purified by silane chromatography (HCl). Purification on a gel column and elution with EA / Hexane (1 / 2→2 / 3) gave the desired product. 1H NMR(300MHz,CDCl3)δ 8.48(dd,J=8.0,0.9Hz,1H),8.16(dd,J=7.6,1.0Hz,1H),7.77(t,J=7.8Hz,1H),7.40(d,J=7.9Hz,1H),6.72(ddd,J= 7.9,3.9,1.4Hz,1H),6.45(m,1H),1.50(m,1H),1.12(m,3H),0.98(m,1H),0.81(dt,J=14.8,5.5Hz,1H),0.75(m,1H). 9b-Chloro-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (70):

[0227] To a solution of racemic 4b,9b-dihydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 69 (10.1 g, 0.03 mol) in dry dichloromethane (143 mL) was added oxalyl chloride (2.90 mL, 0.03 mol) dropwise at room temperature. Dry DMF (10 mL) was added dropwise to the reaction mixture with stirring at room temperature (about 2 h). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water, the organic layer was dried over MgSO4, filtered, concentrated and purified on a silica gel column eluted with EA / Hex (1 / 4→1 / 2) to give the desired product. 1 H NMR(300MHz,CDCl3)δ 8.49(dd,J=8.0,1.1Hz,1H),8.19(dd,J=7.7,1.1Hz,1H),7.80(t,J=7.9Hz,1H),7.38(d,J=8.0Hz,1H),6.75(dt,J=8.1,1.6Hz,1H),6 .44(t,J=1.4Hz,1H),6.29(s,1H),1.50(m,1H),1.13(dd,J=5.7,1.2Hz,3H),0.99(m,1H),0.82(dt,J=12.4,4.4Hz,1H),0.76(m,1H). 9b-Amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (71):

[0228] To a solution of racemic 9b-chloro-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (6.47 g, 0.017 mol) in dry THF (90 mL) was added ammonia solution (26.1 mL, 0.052 mol, 2.0 M in IPA) dropwise (about 10 min) at -40°C. The reaction mixture was stirred at -40°C for 1 h and at -20°C for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine and water. The organic layer was dried over MgSO4, filtered, concentrated and purified on a silica gel column eluted with EA / Hex (1 / 2 -> 2 / 3) to give the desired product. 1 H NMR(300MHz,CDCl3)δ 8.48(m,1H),8.10(d,J=7.6Hz,1H),7.73(dd,J=13.5,5.6Hz,1H),7.27(d,J=7.4Hz,1H),6.68(m,1H),6.45(d,J=2.7Hz,1H), 1.48(d,J=5.1Hz,1H),1.13(t,J=5.0Hz,3H),0.98(d,J=6.7Hz,1H),0.81(dd,J=5.0,1.9Hz,1H),0.73(dd,J=7.3,4.9Hz,1H). [ka] Methyl 3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (73):

[0229] To a solution of methyl 3-methyl-1H-pyrrole-2-carboxylate 27 (3.5 g, 25.2 mmol) in dry DMF (63 mL) was added NaH (1.51 g, 37.8 mmol) at 0 °C, followed by benzenesulfonyl chloride 72 (4.82 mL, 37.8 mmol). The reaction mixture was stirred at 0 °C to room temperature for 15 h. The reaction was quenched with ice water (300 mL), the aqueous layer was extracted with ethyl acetate (3 × 100 mL), and the combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) and the resulting product was recrystallized using DCM and HX. 5-(Methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-sulfinic acid (74):

[0230] Methyl 3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 73 (5.03 g, 18 mmol) was dissolved in THF (180 mL). The resulting solution was cooled to -78°C, lithium diisopropylamide (18 mL, 36 mmol) was added dropwise at -78°C and the reaction mass was stirred at -78°C for next 1 h. Sulfur dioxide (gas) was bubbled slowly into the cold solution at -78°C for 30 min. The resulting reaction mass was slowly warmed to room temperature and stirred at room temperature for 12 h. THF was removed under vacuum and the resulting residue was dissolved in water and washed with ethyl acetate (50 mL x 2). The aqueous layer was acidified to pH ~1 using 1N HCl, the aqueous layer was extracted with ethyl acetate (200 mL x 3), the combined organic layer was washed with water and brine solution, the organic layer was dried over Na2SO4 and the solvent was evaporated to give the product which was used directly in the next step without purification. Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (75):

[0231] 5-(Methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-sulfinic acid 74 (3.9 g, 11.4 mmol) was taken in THF (115 mL) and cooled to 0° C. To this was added NCS (1.83 g, 13.7 mmol). The reaction mass was stirred at room temperature for 15 hours. THF was removed under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate Route(77):

[0232] Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 75 (491.2 mg, 1.3 mmol) was dissolved in DCM (13 mL). To this was added tert-butyl piperazine-1-carboxylate 76 (290.6 mg, 1.56 mmol) followed by DIPEA (0.340 mL, 1.95 mmol). The reaction mass was stirred at room temperature for 12 h. The reaction mass was diluted with DCM (100 mL), washed with water (50 mL×3), dried over Na2SO4 and the solvent was evaporated to give the crude. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (78):

[0233] tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate 77 (660 mg, 1.25 mmol) was dissolved in MeOH:H2O (13 mL). To this solution was added K2CO3 (518.3 mg, 3.75 mmol). The reaction mass was stirred at 50 °C for 12 h. Methanol was evaporated and the resulting residue was dissolved in water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3) and the combined organic layer was washed with water and brine solution. 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. 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid (79):

[0234] tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate 78 (360 mg, 0.93 mmol) was taken in MeOH:H2O (1:10) (10 mL) to which LiOH.H2O (195 mg, 4.65 mmol) was added. The reaction mass was heated at 70 °C for 8 h. MeOH was removed under vacuum and the aqueous layer was diluted with water (10 mL) and acidified to pH ∼1 using 1N HCl. The product was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water and brine solution, dried over Na2SO4 and the solvent was evaporated to give the product (79), which was used directly in the next step without purification. [ka] tert-Butyl 4-((5-((4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (80).

[0235] To a solution of 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 79 (397 mg, 1.1 mmol) in DMF (11 mL) at 0° C., EDCI (306 mg, 1.6 mmol) was added followed by HOBt (216 mg, 1.6 mmol). The mixture was stirred for 30 min and then racemic mixture of 9b-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 71 (375 mg, 1.1 mmol) was added followed by DIPEA (0.6 mL, 3.2 mmol). The reaction mass was stirred at 30° C. for 20 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine solution. The organic layers were dried over Na2SO4 and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography to give a solid product. N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide (81):

[0236] To a solution of racemic tert-butyl 4-((5-((4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate 80 (250 mg, 0.35 mmol) in DCM (7 mL, 0.05 M) was added 4N HCl in 1,4-dioxane (0.9 mL, 3.5 mmol) and the reaction mass was stirred at room temperature (30° C.) for 12 hours. The solvent was evaporated under vacuum and water (10 mL) was added to give a residue, It was basified with 10% NaHCO3 solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to give a solid product which was used directly in the next step without further purification. N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (82):

[0237] To a solution of racemic N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 81 (100 mg, 0.16 mmol) in glacial AcOH:MeCN (1:1) (4 mL) at 0° C. was added an aqueous solution of formaldehyde (35%) (0.15 mL, 1.6 mmol) followed by NaBH3CN (36 mg, 0.6 mmol). The reaction mass was stirred at 0° C. for 2 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to give the crude product. The crude material was purified by silica gel column chromatography to give a solid product. N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (83):

[0238] To a solution of racemic N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide 82 (36 mg, 0.06 mmol) in EtOH:H2O (10:1) (6 mL) was added Fe powder (10 mg, 0.2 mmol) and concentrated HCl (1 drop) and the reaction was stirred at 90 °C for 3 h. The hot reaction was filtered through a bed of Celite. The filtrate was evaporated under vacuum. The residue was dissolved in water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated. The crude material was purified by silica gel column chromatography to give a solid product. 1 H-NMR(300MHz,MeOD)δ 0.70-0.76(m,1H),0.81-0.89(m,1H),0.98-1.02(m,1H),1.16(d,J=5.7H z,1H),1.53-1.59(m,1H),2.29(s,3H),2.30(s,3H),2.50-2.53(m,4H),2 .99-3.12(m,4H),6.48(s,1H),6.54(s,1H),6.69-6.78(m,2H),7.04(d,J =7.2Hz,1H),7.33(d,J=6.3Hz,1H),7.46-7.51(m,1H).LCMS:592.2(M+H] + . Example 10: (2S,3S)-N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide [ka]

[0239] This compound was prepared similarly to Example 9 above. LCMS: 466.4 [M+H] + . Example 11: N-(1-amino-4b-hydroxy-7-(1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(((S)-3-(dimethylamino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxamide (89) [ka] Methyl (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (84).

[0240] Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 75 (985 mg, 2.6 mmol) was dissolved in DCM (26 mL). To this was added tert-butyl (S)-pyrrolidin-3-ylcarbamate (583 mg, 3.1 mmol), followed by DIPEA (0.7 mL, 3.9 mmol). ) was added. The reaction was stirred at 30° C. for 15 h. The reaction mass was diluted with DCM, washed with water and brine, the organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography to give a solid product. (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid (85):

[0241] To a solution of methyl (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 84 (1.10 g, 2.1 mmol) in MeOH:THF:H2O (1:1:10) (42 mL) was added LiOH.H2O (855 mg, 20.8 mmol) and the reaction was stirred at 80 °C for 15 h. The organic solvents were evaporated. The reaction mixture was acidified with 1N HCl solution, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum to give a solid product. tert-Butyl ((3S)-1-((5-((4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)pyrrolidin-3-yl)carbamate (86).

[0242] To a solution of (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 85 (276 mg, 0.7 mmol) in DMF (7 mL) at 0° C., EDCI (212 mg, 1.1 mmol) was added followed by HOBt (149 mg, 1.1 mmol). The mixture was stirred for 30 min, then a racemic mixture of 9b-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 71 (260 mg, 0.7 mmol) was added followed by DIPEA (0.4 mL, 2.2 mmol). The reaction mixture was stirred at room temperature (30° C.) for 20 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and the organic layer was dried over Na2SO4. The solvent was evaporated under vacuum to give the crude. The crude was purified by silica gel column chromatography to give the product. 5-(((S)-3-aminopyrrolidin-1-yl)sulfonyl)-N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-1H-pyrrole-2-carboxamide (87):

[0243] To a stirred solution of the racemic mixture of tert-butyl ((3S)-1-((5-((4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)pyrrolidin-3-yl)carbamate 86 (170 mg, 0.24 mmol) in DCM (5 mL, 0.05 M) was added 4N HCl in 1,4-dioxane (0.6 mL, 24 mmol) and the reaction was stirred at room temperature (30° C.) for 12 h. The solvent was evaporated and the residue was dissolved in water (10 mL) and basified with 10% NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water and brine, and the organic layer was dried over Na2SO4. The solvent was evaporated in vacuum to give the product. 5-(((S)-3-(Dimethylamino)pyrrolidin-1-yl)sulfonyl)-N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran -9b-yl)-3-methyl-1H-pyrrole-2-carboxamide (88):

[0244] To a stirred solution of racemic mixture of 5-(((S)-3-aminopyrrolidin-1-yl)sulfonyl)-N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-1H-pyrrole-2-carboxamide 87 (120 mg, 0.2 mmol) in glacial AcOH:MeCN=1:1 (7 mL, 0.03 M) at 0° C., formaldehyde (35% aqueous solution) (0.34 mL, 3.9 mmol) was added followed by NaBH3CN (62 mg, 1.0 mmol). The reaction mass was stirred at 0° C. for 2 hours. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude material, which was purified by silica gel column chromatography to give the product. N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(((S)-3-(dimethylamino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxamide (89):

[0245] To a stirred solution of racemic mixture of 5-(((S)-3-(dimethylamino)pyrrolidin-1-yl)sulfonyl)-N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-1H-pyrrole-2-carboxamide 88 (32 mg, 0.05 mmol) in EtOH:H20 (10:1) (5 mL) was added Fe powder (8 mg, 0.2 mmol) and concentrated HCl (1 drop) and the reaction mass was stirred at 90° C. for 3 h. The hot reaction mass was filtered through a bed of Celite. The filtrate was evaporated under vacuum and the residue obtained was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude product. The crude material was purified by silica gel column chromatography to give a solid product. 1H-NMR(300MHz,MeOD)δ 0.70-0.76(m,1H),0.82-0.89(m,1H),0.97-1.07(m,1H),1.16(d,J=5.7Hz,3H),1.53-1.59( m,1H),1.62-1.72(m,1H),2.02-2.08(m,1H),2.22(s,6H),2.31(s,3H),2.64-2.75(m,1H),2 .98-3.05(m,1H),3.16-3.27(m,1H),3.41-3.53(m,2H),6.48(s,1H),6.58(s,1H),6.69-6.7 7(m,2H),7.04(d,J=7.2Hz,1H),7.33(d,J=7.2Hz,1H),7.47-7.52(m,1H).LCMS:606.3(M+H] + . Example 12: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka] [ka] tert-Butyl 4-((5-(ethoxycarbonyl)-3,4-dimethyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (123):

[0246] Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (530 mg, 2.0 mmol) was taken in DCM (20 mL, 0.1 M) to which was added tert-butyl piperazine-1-carboxylate (448 mg, 2.4 mmol) at room temperature followed by DIPEA (0.52 mL, 3.0 mmol). The reaction mass was then stirred for next 18 hours at room temperature (25° C.). The reaction mass was quenched with water (50 mL) and then extracted with DCM (70 mL×2). The combined organic layer was washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10→20% EA in hexane) to obtain the pure product. 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (124):

[0247] tert-Butyl 4-((5-(ethoxycarbonyl)-3,4-dimethyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (580 mg, 1.4 mmol) was taken in THF:MeOH:HO (1:1:10, 28.0 mL, 0.05 M) and charged with LiOH.HO (294 mg, 7.0 mmol) and the reaction was refluxed at 80° C. for 5 h. The reaction mass was concentrated to remove volatiles. It was then acidified with 1N HCl (pH<2-3). The precipitated solid was then filtered, washed with cold water and dried to give the product. tert-Butyl 4-(5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran 9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (125):

[0248] 5-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (264 mg, 0.75 mmol) was taken in DMF (4 mL, 0.2 M) and cooled to 0° C. To this was charged EDC.HCl (216 mg, 1.125 mmol) and HOBt (152 mg, 1.125 mmol). After 10 min, it was charged with 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (255 mg, 0.75 mmol) followed by the addition of DIPEA (0.33 mL, 1.875 mmol) and allowed to reach room temperature (35° C.) by itself. This was stirred for the next 18 h. The reaction mass was then quenched with water (30 mL) and extracted with EA (50 mL×2). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography (20→50% EA:MeOH (4:1) in hexanes) to give impure product, which was purified again with MeOH / DCM system to give pure product. N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(piperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (126):

[0249] tert-Butyl 4-(5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (135 mg, 0.2 mmol) was taken in DCM (2.0 mL, 0.1 M) to which was added 4M HCl in dioxane (0.50 mL, 2.0 mmol). This was stirred for 15 h at room temperature (25° C.). The reaction mass was concentrated and the residue was taken in EA (20-30 mL) and stirred with saturated NaHCO3 (approximately 20 mL) for 5-10 min. This was extracted with EA (50 mL×2). The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used in the next step without further purification. N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (127):

[0250] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(piperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (90 mg, 0.15 mmol) was taken in MeCN:glacial AcOH (2:1, 3 mL, 0.05 M) cooled to 0° C. To this was charged 35% aqueous HCHO (0.13 mL, 1.5 mmol) followed by the addition of NaBH3CN (33 mg, 0.525 mmol). This was stirred for next 2 h at 0° C. The reaction mass was quenched with water (20 mL), saturated NaHCO3 (20 mL) and extracted with EA (40 mL×2). The combined organic layer was washed with water (30 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by thin-layer silica gel column chromatography (0→5% MeOH in DCM) to give the pure product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-di Methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (128):

[0251] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (60 mg, 0.1 mmol) was taken up in EtOH:water (10:1, 5.0 mL, 0.02 M) and Fe powder (17 mg, 0.3 mmol) was added followed by 6.0 M HCl (1 drop) was charged. It was refluxed at 90° C. for next 2.0 h. The reaction mass was filtered through Celite under warm condition using EA (30 mL). The filtrate was concentrated, taken up in EA (100 mL) and washed with saturated NaHCO3 (20 mL×2), water (20 mL×2) and brine (20 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude. The crude was purified by silica gel column chromatography (0→10% MeOH in DCM) to give the pure product. 1H NMR(500MHz,METHANOL-d4)δ:7.48(br s,2H),7.05(br s,1H),6.89(br s,1H),6.70(br s,2H),3.10(br s,4H),2.87(dt,J=13.4,6.6Hz,1H),2.51(br t,J=4.4Hz,4H),2.29(s,3H),2.22(s,3H),2.21(s,3H),1.21(d,J=6.9Hz,6H);LCMS:594.2(M+H] + Example 13: N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b])benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0252] The above compound was prepared according to the following scheme. [ka] tert-Butyl 4-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (122): 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 79 (384 mg, 1.0 mmol) was taken up in DMF (10 mL, 0.1 M) and cooled to 0° C. To this was charged EDCI (288 mg, 1.5 mmol) followed by HOBt (203 mg, 1.5 mmol). After 10 min, it was charged with 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (340 mg, 1.0 mmol) followed by DIPEA (0.43 mL, 2.5 mmol) and allowed to reach room temperature (35° C.) for the next 12 h. The reaction mass was then quenched with water (30 mL) and extracted with EA (50 mL×2). The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography (25→30% EA in hexane) to give the product. N-(4-((11-azaneyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide (122-1)

[0253] To a stirred solution of tert-butyl 4-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (340 mg, 0.49 mmol) in DCM (10 mL) was added 4N HCl in dioxane (1.2 mL, 4.9 mmol) at room temperature. The resulting reaction mass was stirred at room temperature for 15 h. The reaction mass was evaporated to dryness and the resulting residue was dissolved in water (50 mL), basified with a saturated solution of NaHCO3, the product was extracted with EA (50 mL x 3) and the combined organic layer was washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product. The crude material was purified by silica gel column chromatography (MeOH:DCM=1:20) to give the desired product. I got something. N-(4-((11-azaneyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (122-2)

[0254] To a stirred solution of N-(4-((11-azaneyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 122-1 (100 mg, 0.17 mmol) in glacial AcOH:MeCN (4 mL) at 0° C. was added 35% formaldehyde solution (0.15 mL, 1.7 mmol) followed by NaBH3CN (36 mg, 0.6 mmol) and the resulting reaction mass was stirred at 0° C. for 2 h. The reaction mass was quenched with water and the desired product was extracted with EA (50 mL×3) and the combined organic layers were washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (MeOH:DCM=1:20) to give the desired product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (122-3)

[0255] Fe powder (14 mg, 0.25 mmol) was added to a stirred solution of N-(4-((11-azaneyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (51 mg, 0.08 mmol) in EtOH:HO (3 mL) followed by addition of concentrated HCl (1 drop). The resulting reaction mass was refluxed at 90° C. for 3 h. The hot reaction mass was filtered through a bed of Celite and washed with EA. The organic layer was evaporated to dryness and the resulting residue was dissolved in EA (100 mL) and washed with water (50 mL×2) and brine solution. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography to give the desired product. 1H NMR(300MHz,MeOD)δ 7.42-7.33(m,1H),7.03(d,J=7.4Hz,1H),6.87(d,J=7.9Hz,1H),6.81-6.72(m,1H),6.69(s,1H),6.52(s,1 H),3.11-2.98(m,4H),2.89-2.80(m,1H),2.59-2.46(m,4H),2.28(s,3H),1.19(d,J=6.9Hz,6H).Mass: [M+H] + :580.1 Example 14: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka] [ka]

[0256] This compound was prepared similarly to Example 12 using the 3,4-dimethylpyrrole derivative according to the scheme above. (300MHz,MeOD)δ 0.70-0.76(m,1H),0.81-0.89(m,1H),0.98-1.02(m,1H),1.16(d,J=5.7Hz,1 H),1.53-1.59(m,1H),2.29(s,3H),2.30(s,3H),2.50-2.53(m,4H),2.99-3.1 2(m,4H),6.48(s,1H),6.54(s,1H),6.69-6.78(m,2H),7.04(d,J=7.2Hz,1H) ,7.33(d,J=6.3Hz,1H),7.46-7.51(m,1H).LCMS:592.1(M+H]+,HPLC purity:95.4% Example 15: (2S,3S)—N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide [ka]

[0257] This compound was prepared similarly to Example 12 above. LCMS: 466.3 [M+H] + . Example 16: N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0258] This compound was prepared similarly to Example 12 above. LCMS: 508.3 [M+H] + . Example 17: N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b)]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide (92) [ka] tert-Butyl ((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (90):

[0259] tert-Butyl ((4bR,9bR)-1-amino-7-(1-cyclopropylvinyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 59 (174 mg, 0.40 mmol) was taken in DCM (8.0 mL, 0.05 M) and charged with [((4R,5R)-Cy2-UBaphox)Ir(COD)]BARF (13.9 mg, 0.008 mmol) under nitrogen. It was then flushed with H2 gas and then kept under H2 atmosphere (60 psi) at room temperature (20 °C) for next 4 h. The reaction mass was then concentrated and passed through a short plug of silica. It was concentrated to give the crude product. The crude product was purified by silica gel column chromatography, then by preparative HPLC (ADH column (Diacel 250×20 mm, EtOH:MeOH:Hexane=36:4:60). (4bR,9bR)-1,9b-diamino-7-((R)-1-cyclopropylethyl )-4b-Hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (91):

[0260] Enantiopure tert-butyl ((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 90 (70 mg, 0.16 mmol) was taken up in DCM (1.6 mL, 0.1 M) and immediately charged with 4.0 M HCl in dioxane (0.40 mL, 1.60 mmol). The reaction mixture was then stirred for the next 6 h at room temperature (20 °C). The reaction mixture was diluted with EA (~50 mL) and stirred with saturated NaHCO3 (~30 mL) for 5-10 min. The layers were separated and the aqueous layer was extracted with EA (~30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (~30 mL). It was dried over anhydrous Na2SO4 and concentrated to give the crude solid product, which was used directly in the next step without further purification. N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidin-1-yl)acetamide (92):

[0261] 2-(azetidin-1-yl)acetic acid hydrochloride 58 (34 mg, 0.23 mmol) in 1.5 mL of anhydrous DMF (0.1 M) was charged with HATU (87.5 mg, 0.23 mmol) and DIPEA (79 μL, 0.23 mmol) at 0° C. After 10 min, it was charged with (4bR,9bR)-1,9b-diamino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 91 (51 mg, 0.15 mmol) and stirred at room temperature (20° C.) for 15 h. The reaction mass was quenched with water (ca. 20 mL) and saturated NaHCO3 (ca. 30 mL). It was extracted with EA (50 mL×3). The combined organic layers were washed with water (30 mL×2), brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (0→10% MeOH in DCM) to give a solid product. 1 H-NMR (300MHz, MeOD) δ 7.51-7.39(m,1H),7.28(d,J=7.9Hz,1H),6.99(d,J=7.0Hz,1H),6.85(dd,J=7.9 ,1.3Hz,1H),6.78-6.65(m,2H),3.38(t,J=7.2Hz,4H),3.19(s,2H),2.14-2.03( m,2H),1.91-1.84(m,1H),1.25(d,J=7.0Hz,3H),0.96-0.80(m,1H),0.54-0.49( m,1H),0.37-0.32(m,1H),0.23-0.12(m,1H),0.10-0.02(m,1H).LCMS:432.2[MH] - .LCMS: 434.3 [M+H] + .

[0262] Example 18: N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide [ka]

[0263] This compound was prepared similarly to Example 15 above. LCMS: 475.1 [M+H] + . Examples 19 and 20: N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (101) and N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (102): [ka] [ka] 4b,9b-Dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (94):

[0264] 4-Nitro-1H-indene-1,3(2H)-dione 4 (10.0 g, 52.3 mmol) was dissolved in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added and the mixture was reduced at 105-110 °C for 5 h. The reaction mass was then filtered through Celite under hot conditions and then the volatiles were concentrated to remove to give crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5. The crude was dissolved in acetic acid (106 mL) to which was added 3-isopropoxyphenol 93 (8.1 g, 53 mmol). The resulting reaction mass was heated at 80° C. for 4 hours. The reaction mass was cooled to room temperature and diluted with ethyl acetate. The reaction mass was filtered through Celite bed and washed with ethyl acetate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give a solid product. 9b-Chloro-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (95):

[0265] 4b,9b-Dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 94 (5.4 g, 15 mmol) was dissolved in DCM (75 mL). To this, oxalyl chloride (2.6 mL, 30 mmol) was added followed by dropwise addition of DMF (5.4 mL). The reaction mass was stirred at room temperature for 18 hours. The reaction was diluted with DCM (300 mL) and the organic layer was washed with water (200 mL×2) and brine solution and then dried over Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to give a solid product. 9b-Amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (96):

[0266] This compound was prepared similarly to compound 37 above. tert-Butyl 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate (97):

[0267] 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 79 (240 mg 0.65 mmol) was dissolved in DMF (6.5 mL). The resulting solution was cooled to 0° C. and EDCI (187 mg, 0.975 mmol), HOBT (132 mg, 0.975 mmol), and DIPEA (0.283 mL, 1.625 mmol) were added at 0° C. The reaction mass was stirred for 30 min. Then 9b-amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 96 (232 mg, 0.65 mmol) was added and the reaction was stirred at 30° C. for 15 h. The reaction mass was quenched with water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water and brine solution and dried over Na2SO4. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (methanol:DCM) to give a solid product. N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide (98):

[0268] tert-Butyl 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylate 97 (145 mg, 0.2 mmol) was dissolved in DCM (4 mL). To this solution was added 4M HCl in dioxane (0.5 mL). The clear solution was stirred at room temperature for 15 h. DCM was evaporated under vacuum. The residue was diluted with water (1 The crude was dissolved in 100 mL of ethyl acetate (100 mL×2) and the aqueous solution was neutralized with a saturated solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (100 mL×2) and the combined organic layers were washed with water and brine solution. The organic layers were dried over Na2SO4 and the solvent was evaporated to give the crude solid product. The crude was used directly in the next step without purification. N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (99):

[0269] N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 98 (115 mg, 0.188 mmol) was dissolved in glacial acetic acid:MeCN (1:1) (5 mL). The solution was cooled to 0° C. and to this was added formaldehyde (0.161 mL, 1.88 mmol) followed by NaBH3CN (41 mg, 0.658 mmol). The resulting suspension was stirred at 0° C.-5° C. for 1.5 h. Acetonitrile was evaporated, the residue was quenched with water and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water and then with brine solution. The organic layer was dried over Na2SO4 and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (methanol:DCM) to give a solid product. N-(1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (100):

[0270] N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide 99 (66 mg, 0.105 mmol) was dissolved in EtOH-water mixture (1:1, 3.5 mL) and Fe powder (18 mg, 0.315 mmol) and concentrated HCl (1 drop) were added. The clear solution was refluxed at 90° C. for 3 h. The hot reaction mass was filtered through a celite pad and washed with ethyl acetate. The organic layer was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with water (75 mL×2) followed by brine solution. The combined organic layers were dried over Na2SO4 and evaporated under vacuum to obtain the crude product. The crude material was purified by silica gel column chromatography (methanol:DCM) to give a solid product. 1 H-NMR(300MHz,CD30D)δ 1.28(dd,J=6Hz,J=1.6Hz,6H),2.29(s,6H),2.51-2.54(m,4H),3.06(br,4H),4.51-4.59(m,1H)6.38(d,J=1.9 Hz,1H),6.54(br,2H),6.79(br,1H),7.04(d,J=7.2Hz,1H),7.34(br,1H),7.47-7.52(m,1H).LCMS:596.5[M+1] + . N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (101) and N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (102): Racemic N-(1-amino-4b-hydroxy-7-isopropoxy-10- Oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (100) (90 mg) was purified by chiral chromatography using (IA column, HPLC = 20 mL / min, heptane / EtOH = 30 / 70, 2562 psi). Upon purification, 37.5 mg of N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (101) was obtained (peak 2, tR 16.32 min), 1H NMR(METHANOL-d4)δ:7.43-7.53(m,1H),7.39(br d,J=12.3Hz,1H),7.02(br s,1H),6.72(br s,1H),6.55(s,2H),6.36(br s,1H),4.54(dt,J=12.0,5.9Hz,1H),3.11(br s,4H),2.75(br s,4H),2.45(br s,3H),2.29(s,3H),1.25-1.28(m,6H);LCMS:596.6[M+H] + and 36.4 mg of N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (102) (peak 1, tR 5.70 min); 1H NMR (METHANOL-d4) δ: 7.48 (br s,1H), 7.24-7.42 (m,1H), 7.03 (br d,J=5.9Hz,1H), 6.67-6.82 (m,1H), 6.53 (s,2H), 6.36 (br s,1H),4.54(dt,J=11.9,6.1Hz,1H),3.07(br s,4H),2.59(br s,4H),2.33(s,3H),2.28(s,3H),1.24-1.31(m,6H);LCMS:596.0[M+H] + Obtained as. Example 21: N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka] N-[9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19 B-1): In a 50 mL round-bottom flask was added 5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxylic acid (259 mg, 1.27 mmol, 1.50 equiv.), HOBt (172 mg, 1.27 mmol, 1.50 equiv.), EDCI (243 mg, 1.27 mmol, 1.50 equiv.), N,N-dimethylformamide (5 mL), 1-amino-9-hydroxy-5-[ (1S,2R)-2-Methylcyclopropyl]-l1-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (300 mg, 0.85 mmol, 1.00 equiv.), and triethylamine (257 mg, 2.54 mmol, 3.00 equiv.) were added. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This gave 250 mg (55%) of N-[9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19 B-1) as a yellow solid. N-[14-amino-9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19B-2): A 50 mL round bottom flask was charged with N-[9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19B-1) (250 mg, 0.47 mmol, 1.00 equiv), Fe (78 mg, 3.00 equiv), ethanol (10 mL), water (1 mL), and hydrogen chloride (0.1 mL). The resulting solution was stirred in an oil bath at 85 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This gave 108 mg (46%) of N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide (19B-2). 1 H NMR(300MHz,CD3OD)δ 7.54-7.43(m,1H),7.41-7.35(m,1H),7.08-7.00(m,1H),6.90-6.80(m,1H),6.80-6.75(m,1H),6.69-6.60(m,2H),3.13(s,3H),2 .29(s,3H),2.12-1.98(m,1H),1.23-1.05(m,1H),1.03-0.88(m,1H),0.81-0.72(m,3H),0.64-0.52(m,1H);LC-MS(ES,m / z)[M+H] + 508.0 (The stereochemistry of the cyclopropane is relative and the absolute stereochemistry is unknown) Examples 22, 29, and 30: N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (29), N-((4bR,9bR )-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (22), and N-((4bS,9bS)-1-amino-7-((R) -1-Cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (30) [ka] [ka] (1R)-1-[3-(benzyloxy)phenyl]ethan-1-ol (19C-1): A 100 mL 3-neck round bottom flask was charged with 1-[3-(benzyloxy)phenyl]ethan-1-one (10 g, 44.19 mmol, 1.00 equiv), MeCN (30 mL), triethylamine (6.7 g, 66.21 mmol, 1.50 equiv), [Ru(p-cymene)Cl2]2 (136 mg, 0.22 mmol, 0.01 equiv), (1R,2R)-TsDpen (330 mg, 0.89 mmol, 0.02 equiv), and HCOH (6.1 g, 3.00 equiv). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated under vacuum. The mixture was concentrated at rt. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (20 / 80). This gave 4 g (40%) of (1R)-1-[3-(benzyloxy)phenyl]ethan-1-ol as a colorless oil. (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate (19C-2): A 50 mL round bottom flask was charged with (1R)-1-[3-(benzyloxy)phenyl]ethan-1-ol (3.5 g, 15.33 mmol, 1.00 equiv), CH3CN (15 mL), N,N-bis(propan-2-yl)carbamoyl chloride (2.9 g, 17.72 mmol, 1.15 equiv), and TEA (1.9 g, 18.78 mmol, 1.20 equiv). The resulting solution was stirred at 80° C. for 12 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (15 / 85). This gave 5.3 g (97%) of (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate as a yellow oil. 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19C-3): A 500 mL 3-neck round bottom flask was charged with (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate (5.3 g, 14.91 mmol, 1.00 equiv), ether (100 mL), and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 29.75 mmol, 2.00 equiv). LDA (14.9 mL, 2 mol / L, 2.00 equiv) was then added dropwise at -20°C. The resulting solution was stirred at room temperature for 12 hours. The reaction was then quenched by the addition of methanol. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (15 / 85). This gave 4.1 g (73%) of 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil. 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene (19C-4): A 100 mL round bottom flask was charged with 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4 g, 10.57 mmol, 1.00 equiv.), n-pentane (50 mL), and TBAF-3H2O (5 g, 15.87 mmol, 1.50 equiv.). The resulting solution was stirred at 45° C. for 12 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (10 / 90). This gave 2.4 g (90%) of 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene as a yellow oil. 3-[(1R)-1-cyclopropylethyl]phenol (19C-5): A 100 mL round bottom flask was charged with 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene (2.1 g, 8.32 mmol, 1.00 equiv), methanol (20 mL), and palladium on carbon (200 mg). The resulting solution was stirred at room temperature under H2 atmosphere for 2 h. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (15 / 85). This gave 1.3 g (96%) of 3-[(1R)-1-cyclopropylethyl]phenol as a colorless oil. 5-[(1R)-1-Cyclopropylethyl]-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19C-6): In a 100 mL round-bottom flask, 3-[(1R)-1-cyclopropylethyl]phenol (1.3 g, 8.01 mmol, 1.00 equiv.), acetic acid (20 mL), and 2,2-dichlorophenyl Hydroxy-4-nitro-2,3-dihydro-1H-indene-1,3-dione (1.8 g, 8.07 mmol, 1.00 equiv.) was charged. The resulting solution was stirred at 120 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (30 / 70). This gave 2.2 g (75%) of 5-[(1R)-1-cyclopropylethyl]-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a yellow solid. 1-Chloro-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^][10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19C-7): A 100 mL round bottom flask was charged with 5-[(1R)-1-cyclopropylethyl]-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (4.1 g, 11.16 mmol, 1.00 equiv), dichloromethane (20 mL), N,N-dimethylformamide (2 mL), and oxalyl chloride (16.7 mL, 3.00 equiv). The resulting solution was stirred at 45 °C for 2 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted with dichloromethane. The organic layers were combined and concentrated under vacuum. This gave 4.5 g (crude) of 1-chloro-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a brown oil. 1-Amino-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19C-8): A 250 mL round bottom flask was charged with 1-chloro-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2.7].0^[10.15]]hexadeca-2(7).3.5.10.12.14-hexaen-16-one (4.5 g, 11.66 mmol, 1.00 equiv) in THF (30 mL) and NH3 in IPA (17.5 mL, 3.00 equiv) was added dropwise at -50 °C. The resulting solution was stirred at -50 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (35 / 65). This gave 3.5 g (82%) of 1-amino-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a yellow solid. N-[5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca]2(7),3,5,10,12,14-hexaen-1-yl]-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-9): In a 50 mL round bottom flask, add 1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (1.3 g, 8.33 mmol, 1.20 equiv.), EDCI (1.6 g, 8.35 mmol, 1.20 equiv.), HOBt (1.1 g, 8.14 mmol, 1.20 equiv.), N,N-dimethylformamide (5 mL), 1-amino-5 -[(1R)-1-Cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (2.5 g, 6.82 mmol, 1.00 equiv.) and triethylamine (2.3 mL, 3.00 equiv.) were added. The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This gave 1.4 g (41%) of N-[5-[((1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide as a yellow solid. N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-10): A 25 mL round bottom flask was charged with N-[5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca]2(7),3,5,10,12,14-hexaen-1-yl]-l,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (120 g, 237.86 mmol, 1.00 equiv), ethanol (10 mL), iron (40 mg, 0.72 mmol, 3.00 equiv), water (1 mL), and concentrated hydrogen chloride (0.01 mL). The resulting solution was stirred at 85 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with DCM / MeOH (25 / 1) to give 100 mg of N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-10, Example 29). 1H NMR(300MHz,CD3OD)7.55-7.39(m,2H),7.05-7.01(m,1H),6.93-6.70(m,3H),3.21(s,3H),2.35(s,3H),2.04-1.84(m,1H),1.30-1 .27(m,3H),0.94-0.89(m,1H),0.57-0.52(m,1H),0.38-0.34(m,1H),0.22-0.16(m,1H),0.09-0.02(m,1H);LCMS:(ES,m / z):[M+H] + 475.2 N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-11, Example 22) and N-((4bS,9bS)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-12, Example 30): Racemic N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-10), (103.9 mg) was purified using (IA column, HPLC = 20 mL / min, heptane / IPA = 60 / 40). and purified by chiral chromatography to give 42.8 mg of N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-11) (peak 1, tR 7.76 min), 1H NMR (400 MHz, METHANOL-d4) δ: 8.32-8.47 (m, 2H), 7.97 (br d, J = 7.2 Hz, 1H), 7.86 (br d, J = 7.8 Hz, 1H), 7.62 -7.71(m,2H),4.17(s,3H),3.31(s,3H),2.80-2.93(m,1H),2.24(d,J=7.0Hz,3H),1.81-1.90(m,1H),1.46- 1.55(m,1H),1.28-1.36(m,1H),1.15(dq,J=9.4,4.7Hz,1H),1.04(dq,J=9.5,4.8Hz,1H);LCMS:475.2[M+H]+ and 35.8 mg of N-((4bS,9bS)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (19C-12) (peak 2, tR 16.43 min); NMR(500MHz,METHANOL-d4)δ:7.38-7.51(m,2H),7.01(br d,J=6.9Hz,1H),6.85-6.94(m,1H),6.70(br s,2H),3.20(s,3H),2.34(s,3H),1.86-1.94(m,1H),1.27(d,J=7.1Hz,3H),0.85-0.93(m,1H),0.50-0.55(m ,1H),0.31-0.38(m,1H),0.18(dq,J=9.8,4.8Hz,1H),0.06(dq,J=9.4,4.8Hz,1H);LCMS:475.2[M+H]+. Example 23: N-(1-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka] 1-[3-(benzyloxy)phenyl]ethan-1-one (19D-1): In a 500 mL round bottom flask, add 1-(3-hydroxyphenyl)ethan-1-one (2 A solution of 1-[3-(benzyloxy)phenyl]ethan-1-one (1:10, 1:20 g, 146.90 mmol, 1.00 equiv.), CH3CN (180 mL), (bromomethyl)benzene (20 mL, 1.20 equiv.), and potassium carbonate (40.8 g, 2.00 equiv.) was charged to the reaction vessel. The resulting solution was stirred at 80° C. in an oil bath for 2 h. The solids were filtered off. The reaction was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This gave 30.5 g (92%) of 1-[3-(benzyloxy)phenyl]ethan-1-one as a yellow oil. 2-[3-(benzyloxy)phenyl]butan-2-ol (19D-2): A 250 mL round bottom flask was charged with a solution of 1-[3-(benzyloxy)phenyl]ethan-1-one (5 g, 22.10 mmol, 1.00 equiv) and THF (100 mL). Bromo(ethyl)magnesium (22 mL, 3.00 equiv) was then added at 0° C. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding 300 mL of water. The resulting solution was extracted with 3×200 mL of chloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1). This gave 3.1 g (55%) of 2-[3-(benzyloxy)phenyl]butan-2-ol as a colorless oil. 1-(benzyloxy)-3-(butan-2-yl)benzene (19D-3): A 250 mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 2-[3-(benzyloxy)phenyl]butan-2-ol (6.2 g, 24.19 mmol, 1.00 equiv.) in dichloromethane (120 mL). Triethylsilane (18.2 mL, 5.00 equiv.) and trifluoroacetic acid (18.05 mL, 1.00 equiv.) were then added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding 100 mL of water and extracted with 3×50 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied to a silica gel column with petroleum ether (100%). This gave 3.8 g (65%) of 1-(benzyloxy)-3-(butan-2-yl)benzene as a yellow oil. 3-(Butan-2-yl)phenol (19D-4): A 100 mL round bottom flask was charged with a solution of 1-(benzyloxy)-3-(butan-2-yl)benzene (3.8 g, 15.81 mmol, 1.00 equiv) in methanol (38 mL) and palladium on carbon (380 g). The resulting solution was stirred under H2 at room temperature for 2 h. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 20). This gave 2.0 g (84%) of 3-(butan-2-yl)phenol as a yellow solid. 5-(butan-2-yl)-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19D-5): A 100 mL round bottom flask was charged with a solution of 3-(butan-2-yl)phenol (1.5 g, 9.99 mmol, 1.00 equiv.) in acetic acid (35 mL) and 2,2-dihydroxy-4-nitro-2,3-dihydro-1H-indene-1,3-dione (1.85 g, 8.29 mmol, 1.00 equiv.). The resulting solution was stirred in an oil bath at 120° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 2). This gave 1.37 g (39%) of 5-(butan-2-yl)-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a yellow solid. 5-(butan-2-yl)-1-chloro-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19D-6): In a 50 mL round-bottom flask, add 5-(butan-2-yl) 1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexafluoropropanediol (III) in dichloromethane (20 mL). A solution of saen-16-one (1.37 g, 3.86 mmol, 1.00 equiv), oxalyl chloride (1.1 mL, 3.00 equiv), and N,N-dimethylformamide (2 mL) was added. The resulting solution was stirred in an oil bath at 40° C. for 2 h. The reaction was then quenched by adding 50 mL of water / ice. The resulting solution was extracted with 3×100 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 5). This gave 1.2 g (83%) of 5-(butan-2-yl)-1-chloro-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a brown oil. 1-Amino-5-(butan-2-yl)-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (19D-7): A 50 mL round bottom flask was charged with a solution of 5-(butan-2-yl)-1-chloro-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (1.2 g, 3.21 mmol, 1.00 equiv.) in tetrahydrofuran (18 mL). This was followed by the addition of NH3 in IPA (4.8 mL, 3.00 equiv.) at -50 °C. The resulting solution was stirred at -40 to 10 °C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 2). This gave 630 mg (55%) of 1-amino-5-(butan-2-yl)-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one as a yellow solid. N-[5-(butan-]-yl)-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca]2(7),3,5,10,12,14-hexaen-1-yl]-4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19D-8): A 25 mL round-bottom flask was charged with a solution of 4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxylic acid (122 mg, 0.60 mmol, 1.50 equiv) in N,N-dimethylformamide (2 mL), EDCI (115 mg, 0.60 mmol, 1.50 equiv), HOBt (81 mg, 0.60 mmol, 1.50 equiv), 1-amino-5-(butan-2-yl)-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-16-one (150 mg, 0.42 mmol, 1.00 equiv), and triethylamine (121 mg, 1.20 mmol, 2.50 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This gave 140 mg (61%) of N-[5-(butan-2-yl)-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7]0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide as a yellow solid. N-[14-amino-5-(butan-2-yl)-9-hydroxy-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-1-yl]-4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19D-9): In a 50 mL round-bottom flask, add N-[5-(butan-2-yl)-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca]2(7),3,5,10,12, A solution of 14-hexaen-1-yl]-4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (140 mg, 0.26 mmol, 1.00 equiv.), water (0.5 mL), Fe (40.32 mg, 3.00 equiv.), and hydrogen chloride (0.05 mL) was added. The resulting solution was stirred in an oil bath at 85° C. for 2 h. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This gave 22.1 mg (17%) of N-(1-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide (19D-9). 1 HNMR(300MHz,CD3OD)δ 7.61-7.35(m,3H),7.18-7.05(m,1H),6.90-6.63(m,3H),3.01(s,3H),2.62-2.40(m,4H ),1.65-1.50(m,2H),1.19(d,J=6.9Hz,3H),0.90-0.78(m,3H);LC-MS:(ES,m / z):[M+H] + :510.1 Example 24: N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0271] This compound was prepared similarly to Example 18 above. LCMS: 592.3 [M+H] + . Example 25: N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide (111): [ka] [ka] Dimethyl 2-(hydroxyamino)malonate (104):

[0272] To glacial acetic acid (55 mL) was added dimethyl malonate 103 (21.7 mL, 190 mmol) under stirring, followed by dropwise addition (about 2 h) of a solution of sodium nitrite (26.2 g, 380 mmol) in 70 mL of water. The resulting mixture was stirred at room temperature for 16 h. The reaction mass was extracted with ethyl acetate. The combined extracts were washed with water and with 5% sodium bicarbonate solution until the aqueous solution was slightly alkaline. The organic layer was dried over Na2SO4 and the solvent was evaporated to give a solid product. The crude was used in the next step without further purification. Methyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (106):

[0273] To a solution of acetylacetone 105 (10.3 mL, 100 mmol) in acetic acid (40 mL), a solution of dimethyl 2-(hydroxyimino)malonate 104 (17 g, 105 mmol) in 20 mL of acetic acid and 10 mL of water was added slowly at the same time as zinc dust (26 g, 400 mmol) at 95 °C. The reaction mixture was stirred at the same temperature for 2 h. The hot reaction mass was poured into 1000 mL of water. The solid precipitate was filtered, washed with water, dried in air at room temperature, dissolved in DCM, filtered from zinc dust residue, concentrated and dried in air at room temperature. The product was dissolved in DCM, filtered through a silica pad and washed with DCM. The solvent was evaporated to give the product. Methyl 4-(chlorosulfonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (107):

[0274] Methyl 3,5-dimethyl-1H-pyrrole-2-carboxylate 106 (383 mg, 2.5 mmol) was dissolved in chloroform (0.25 M) and the clear solution was cooled to 0° C. To the cold solution, chlorosulfonic acid (2.5 mL, 37.5 mmol) was added slowly. The reaction was stirred at 0° C. for 2.5 h. The reaction mass was slowly poured into ice cold water. The product was extracted with DCM (50 mL×2). The combined organic layers were washed with water (50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product. The crude product was dissolved in DCM and filtered through a silica gel plug and washed with DCM to give the product. Methyl 3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxylate (108):

[0275] Methyl 4-(chlorosulfonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate 107 (377.5 mg, 1.5 mmol) was taken in THF (15 mL) and cooled to -10 °C. To this was added a solution of NH3 (5 mL) in THF (prepared by purging ammonia gas into THF at -20 °C). The reaction mass was slowly warmed to room temperature and stirred for 2 h. THF was removed under vacuum to give a residue. The residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL x 3) and dried over Na2SO4. The solvent was evaporated to give the crude. The residue was purified by trituration with DCM and filtered to give the product. 3.5-Dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxylic acid (109):

[0276] To a solution of methyl 3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxylate 108 (255 mg, 1.1 mmol) in MeOH:H2O (1:10) (11 mL) was added LiOH.H2O (461.6 mg, 11 mmol). The reaction mass was stirred at room temperature for 12 h. MeOH was removed under vacuum and the aqueous layer was diluted with water (10 mL) and acidified to pH ∼1 using 1N HCl. The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water and brine solution, dried over Na2SO4 and the solvent was evaporated to give a solid product which was used directly in the next step without purification. N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3.5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide (110):

[0277] 3,5-Dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxylic acid 109 (200 mg 0.91 mmol) was dissolved in DMF (9 mL) and the resulting solution was cooled to 0° C. EDCI (216.7 mg, 1.365 mmol), HOBT (184.5 mg, 1.365 mmol), and DIPEA (0.396 mL, 2.275 mmol) were added at 0° C. and the reaction mass was stirred for 30 min. Then 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (312 mg, 0.91 mmol) was added and the reaction mixture was stirred at 30° C. for 15 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4 and evaporated in vacuum. The crude was purified by column chromatography (methanol:DCM) to give (110). N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide (111):

[0278] To a solution of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide 110 (110 mg, 0.2 mmol) in EtOH-water mixture (1:1, 7 mL) was added Fe powder (33.5 mg, 0.6 mmol) and concentrated HC (1 drop). The resulting solution was refluxed at 90° C. for 3 h. The hot reaction mass was filtered through a celite pad and washed with ethyl acetate. The organic layer was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL×2) followed by brine solution. The combined organic layers were dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (methanol:DCM) to give the product. (300MHz, CD30D) δ 1.2 (dd, J = 6.2Hz, J = 0.9Hz, 6H), 2.44 (s, 3H), 2.49 (s, 3H), 2.84-2.87 (m, 1H), 6.70 (m, 2H), 6.89(m 1H),7.04(m 1H),7.48(m,2H).LCMS:510.78[M+1] + .LCMS:511.5[M+H] + . Example 26: N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0279] This compound was prepared similarly to Example 26 above. LCMS: 508.0 [M+H] + . Example 27: N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0280] This compound was prepared similarly to Example 26 above. LCMS: 508.2 [M+H] + . Example 28: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka] [ka] tert-Butyl ((S)-1-(((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (113):

[0281] (tert-Butoxycarbonyl)-L-phenylalanine 112 (4.80 g, 16.4 mmol) was taken up in DMF (110 mL, 0.15 M) and cooled to 0° C. It was then charged with EDCI (4.73 g, 24.7 mmol) followed by HOBt (3.33 g, 24.7 mmol). It was stirred for the next 20 minutes and charged with 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 9 (6.20 g, 16.4 mmol) followed by the addition of DIPEA (8.6 mL, 49.3 mmol). It was stirred for the next 24 hours at 30° C. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography to give the product along with other isomers. (S)-2-amino-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenylpropanamide (114):

[0282] tert-Butyl ((S)-1-(((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2- b]Benzofuran-9b-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate 113 (1.475 g, 2.36 mmol) was dissolved in DCM (47 mL). To the resulting solution was added HCl in dioxane (5.9 mL 23.6 mmol) and the reaction mass was stirred at room temperature for 18 hours. The reaction mass was evaporated to dryness, the residue was dissolved in water and the aqueous layer was basified with aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (150 mL x 2) and the combined organic layers were washed with water (100 mL) and then with brine solution. The combined organic layers were dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude product which was used directly in the next step without purification. (S)-N-(4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenyl-2-(3-phenylthioureido)propanamide (116):

[0283] Isothiocyanatobenzene 115 (0.425 mL, 3.54 mmol) was added to a solution of (S)-2-amino-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenylpropanamide 114 (1.25 g, 2.36 mmol) in DCM (24 mL) at 0° C. Then the reaction mass was allowed to warm to room temperature and the resulting mixture was stirred at 28° C. for 24 h. The reaction mass was evaporated to dryness to give the crude product. The crude product was purified by short silica gel column chromatography (ethyl acetate:hexane) to give the product. (4bS,9bS)-9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (117):

[0284] (S)-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenyl-2-(3-phenylthioureido)propanamide 116 (1.70 g, 2.58 mmol) was dissolved in DCM (260 mL). To this solution was added TFA (8.8 mL, 77.4 mmol) at room temperature. The reaction mass was then warmed to 50° C. for 12 h. DCM was evaporated and the resulting residue was dissolved in water. The aqueous layer was basified by a saturated solution of NaHCO3 and then the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated to give the crude. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. tert-Butyl ((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (118):

[0285] (4bS,9bS)-9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 117 (472 mg, 1.25 mmol) was dissolved in THF (1.25 mL). To this was added Boc anhydride (546 mg, 2.5 mmol) followed by iodine (32 mg, 0.125 mmol). The reaction mass was stirred at room temperature for 36 hours. The reaction mass was evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. tert-Butyl ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (12):

[0286] tert-Butyl ((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro -10-Oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 118 (460 mg, 0.96 mmol) was dissolved in EtOH-water mixture (1:1, 10 mL). Fe powder (161 mg, 2.88 mmol) and concentrated HCl (2 drops) were added. The clear solution was refluxed at 90° C. for 3 h. The hot reaction mass was filtered through a Celite pad and washed with ethyl acetate. The organic layer was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (250 mL) and washed with water (100 mL×2) followed by brine solution. The combined organic layers were dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product. tert-Butyl ((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (119):

[0287] To a degassed solution of tert-butyl ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (326 mg, 0.73 mmol) in toluene (12.5 mL) was added water (2.5 mL), Pd(OAc)2 (16.4 mg, 0.073 mmol), RuPhos (68 mg, 0.146 mmol), and K3PO4 (620 mg, 2.92 mmol). Then, 6-methyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione 17 (231 mg, 1.095 mmol) was added. The resulting reaction mass was purged with N2 for 10 minutes and then the reaction mass was stirred at 100°C for 1 hour. The reaction mass was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL x 2), dried over Na2SO4 and the solvent was evaporated to get the crude. The crude was purified by silica gel column chromatography (ethyl acetate:hexane) to get the product. (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride (120):

[0288] tert-Butyl ((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 119 (250 mg 0.59 mmol) was dissolved in DCM (12 mL). To this solution, HCl in dioxane (1.5 mL, 5.9 mmol) was added and the reaction mass was stirred for 12 h. The reaction mass was evaporated to dryness to give the product (crude), which was used as such in the next step. N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide (121):

[0289] 3-Methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid 30 (97.6 mg 0.48 mmol) was dissolved in DMF (8 mL). The resulting solution was cooled to 0° C. HATU (28.2 mg, 0.60 mmol) and DIPEA (0.210 mL, 1.2 mmol) were added at 0° C. and the reaction mass was stirred for 30 min. Then (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride 120 (144 mg, 0.4 mmol) was added and the reaction was stirred at 30° C. for 15 h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine solution and added Na After drying over 2SO4, the solvent was evaporated under vacuum. The crude was purified by silica gel column chromatography (MeOH:DCM) and then by preparative HPLC (ethanol:hexane) to give the product. (300MHz,MeOD)δ 0.66-0.72(m,1H),0.78-0.84(m,1H),0.95-1.03(m,1H),1.13(d,J=6.0Hz,3H),1.49-1.55(m,1H),2.48(s,3H),3.05(s,3H),6.45(s,1H) ,6.63-6.67(m,1H),6.76(d,J=8.1Hz,1H),7.02(d,J=7.2Hz,1H),2.27(d,J=8.1Hz,1H),7.38(s,1H),7.43-7.49(m,1H).LCMS:508.1[M+H] + . The biological activity of the compounds of the present invention was determined using the following methods: Determination of drug efficacy against picornaviruses using a cytopathic effect (CPE) inhibition assay

[0290] In this assay, HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblasts), and RD cells (derived from human rhabdomyosarcoma) were used. For comparison, ribavirin (Riv), pleconaril (pleco), and BTA-798 (BTA) were used as controls. The reagents were dissolved in 100% dimethyl sulfoxide (DMSO) at concentrations of 10-40 mg / mL. Water-soluble reagents were dissolved in PBS(-) solution and stored at -20°C. On the day of the experiment, they were used at 3-5x concentrations so that the concentration of dimethyl sulfoxide in each well was 0.5%-1%.

[0291] A virus-induced cytopathic effect (CPE) inhibition assay was used to determine pharmaceutical efficacy. For this, cells suitable for the virus were grown in 96-well plates, after which dilutions of the virus in DME supplemented with 2% FBS (DME / 2% FBS) or MEM supplemented with 2% FBS (MEM / 2% FBS) were inoculated in a volume of 100 l into each well of the plate at a concentration corresponding to 100 CCID50 (50% cell culture infectious dose) and incubated at 33 °C or 37 °C for 30 min to 1 h to allow the virus to adsorb onto the cells. After removing the culture medium, aliquots of drug dilutions at various concentrations were added to each well in a volume of 100 μL. HRV (human rhinovirus) was grown at 33 °C, whereas the other viruses were incubated for 2 to 3 days in a CO2 incubator at 37 °C. Alternatively, 50 μL of each drug dilution with a 2-fold higher concentration was added, followed by the addition of 50 μL of the virus dilution, after which the cells were cultured for 2 to 3 days without removing the medium. Virus was incubated in host HeLa cells in DME / 2% or MEM / 2% FBS at 37° C. for 2-3 days.

[0292] In HeLa cells, the MTT assay was used to determine the EC 50 Drugs were measured for CPE (50% maximum effective concentration). For RD and MRC-5 cells, CPE was determined using FDA (fluorescein diacetate) or MTT. To determine the effect of drug toxicity on efficacy results, mock infection was also included at the time of inoculation of the virus. Virus-free medium was added to the cell cultures and then subjected to the same treatment as mock-infected cells inoculated with virus; that is, medium was removed after 1 hour of incubation and another dilution of drug in medium was added. After 2-3 days of incubation, cells were observed under a microscope and the CC that killed 50% of the cells was determined using an MTT assay, which compares the number of viable cells in the mock-infected wells containing the drug with the number of viable cells in the control wells not containing the drug. 50(50% cytotoxicity concentration). For the FDA hydrolysis assay, FDA was added to each well after removal of the medium and incubated for 20–30 min, after which the fluorescence intensity was measured using a spectrofluorometer to determine CPE in the same way as for MTT.

[0293] That is, the viability (% viability) of mock-infected cells for cytotoxicity measurements was calculated using the following formula 1:

[0294] Cell-drug = Viability x [A(drug)-A(background solution) / A(cell control)-(background x 100% solution)]

[0295] 100% cell survival means 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%. This concentration of the drug is expressed as CC50. Higher values ​​mean less cytotoxicity.

[0296] 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)].

[0297] When the survival rate is 100%, the antiviral effect is 100%, but when the survival rate is 0%, the antiviral effect is not present. The concentration of the drug at which the cells in the virus-infected well can show 50% survival rate is called the EC 50 The lower this value, the better the antiviral effect.

[0298] Table 1 below shows the LCs that show cytotoxicity for some compounds. 50 and EC2 concentrations showing activity against many rhinoviruses belonging to the picornavirus family 50 Concentrations are listed. Determining drug efficacy against picornaviruses using a multicycle cytopathic effect (CPE) reduction assay

[0299] A multi-cycle CPE reduction assay was used to determine drug efficacy against picornaviruses. First, the antiviral activity of compounds was determined by a CPE reduction assay based on MIS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.

[0300] Specifically, cells grown to confluence in 96-well plates were incubated at 50% cell culture infectious dose (CCID 50 ) were infected with 100 virus. After a 2-h adsorption period at 37°C, the virus was removed and serial dilutions of compound were added. Cultures were further incubated at 37°C for 3 days until complete CPE was observed in infected and untreated virus controls (VC). After removing the medium, 90 μL of culture medium and 10 μL of MTS-phenazine methosulfate (Promega, Leiden, The Netherlands) were added to each well. After a 2-h incubation period at 37°C, the optical density (OD) of each well was read at 498 nm in a microplate reader.

[0301] The %CPE value for evaluating antiviral activity was calculated using the following formula 3: %CPE=100×[OD(CC)−OD(virus+compound) / OD(CC)−OD(VC)].

[0302] The %CPE value for measuring the cytotoxicity of the drug was calculated according to the following formula 4:

[0303] %CPE = 100 x [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)]

[0304] In the above formulas 3 and 4, OD(CC) represents the OD of the background cell culture that was neither induced by the virus nor treated by the chemical, and OD(VC) represents the OD of the control cell culture that was induced by the virus but not treated by the chemical. OD(virus+compound) represents the OD of virus-infected cell cultures treated with concentrated compound, OD(compound) represents the OD of cell cultures treated with concentrated compound only, and OD(blank) represents the OD of wells to which only cell culture was added.

[0305] Effective concentration (EC 50 ) represents the drug concentration at which 50% of cells remain viable due to induced viral CPE, and the cytotoxic concentration (CC 50 ) represent the concentration of drug that killed 50% of the cells and were calculated by logarithmic interpolation.

[0306] In Table 1 below, the toxic concentrations (CC) of some of the compounds in the examples against various viruses are shown. 50 ) and effective concentration (EC 50 ) are listed. [Table 2]

[0307] As shown in Table 1 above, most of the compounds according to the present invention have high CC 50 The results show that the compounds have low cytotoxicity, as shown by the concentration of the cytosine. Furthermore, the compounds according to the present invention have been found to have high antiviral activity against many rhinoviruses (HRV) in most cases.

[0308] Therefore, the compounds in the embodiments according to the present invention exhibit low cytotoxicity and high antiviral activity against various rhinoviruses, and therefore can be used as pharmacological compositions for preventing or treating diseases caused by picomaviruses to which rhinoviruses belong. It can be used usefully for things.

[0309] Therefore, the compounds in the examples according to the present invention have low cytotoxicity and exhibit antiviral activity against picomaviruses, which include coxsackieviruses, polioviruses and rhinoviruses, and are therefore useful in treating diseases caused by such viruses, such as polio, acute myeloid leukemia, and other myelopathy. The composition can be effectively used for the prevention or treatment of diseases of the respiratory system, cardiocirculatory system, and nervous system, including chronic 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, sinusitis, and otitis media.

[0310] 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 high antiviral activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and therefore can be effectively used as a pharmaceutical composition for preventing or treating viral diseases such as polio, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. In one embodiment, for example, the following items are provided: (Item 1) A compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, G 1 is selected from linear or branched C1-C4 alkyl, C3-C4 cycloalkyl, or linear or branched C1-C4 alkoxy; said C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy may be substituted with 1, 2, or 3 substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl; L is a bond or CH; E is a) -CH(CHOHCH3)(NMe2); or b) a monocyclic 4- to 6-membered heterocyclyl containing one or two nitrogen atoms or a 5- to 6-membered heteroaryl containing one nitrogen atom, The 5- to 6-membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, -SO2R; each R is independently selected from the group consisting of linear or branched C1-C3 alkyl, monocyclic 5- to 6-membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 wherein the monocyclic 5- to 6-membered heterocyclyl is optionally selected from C1-C3 alkyl or NR 3 R 4 Replaced with; Each R 1 and R 2 is independently selected from H and C1-C3 alkyl, said C1-C3 alkyl optionally being selected from NR 3 R 4 Replaced with; Each R 3 and R 4 are independently selected from H or methyl. (Item 2) The compound according to item 1, having the formula (II), or a pharma- ceutically acceptable salt thereof: [ka] (Item 3) The compound according to item 1, having the formula (III), or a pharma- ceutically acceptable salt thereof: [ka] (Item 4) 4. The compound according to any one of items 1 to 3, wherein L is a bond, or a pharma- ceutically acceptable salt thereof. (Item 5) 5. The compound according to any one of items 1 to 4, wherein E is -CH(CHOHCH3)(NMe2), or a pharma- ceutically acceptable salt thereof. (Item 6) The compound according to any one of items 1 to 4, wherein E is a monocyclic 5-6 membered heteroaryl containing one nitrogen atom, and the 5-6 membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of straight or branched C1-C3 alkyl, -OH, -SO2R, or a pharma- ceutically acceptable salt thereof. (Item 7) G 1 is a straight or branched chain C1-C4 alkyl optionally substituted with one, two or three substituents independently selected from cyclopropyl and straight or branched chain C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof. (Item 8) G 1 is optionally substituted with 1, 2, or 3 substituents independently selected from linear or branched C1-C3 alkyl, or a pharma- ceutically acceptable salt thereof. (Item 9) G 1 optionally, independently from cyclopropyl and linear or branched C1-C3 alkyl 7. The compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is a straight or branched chain C1-C4 alkoxy substituted with one, two, or three substituents selected from the group consisting of: (Item 10) A compound according to any one of items 1 and 7 to 9, having the formula (Ia), or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A 1 is selected from the group consisting of H, linear or branched C1-C3 alkyl, and SO2R; A 2 is selected from the group consisting of H and SO2R. (Item 11) A 1 is methyl or SO2CH3. (Item 12) A 2 is SO2R, and R is CH3; monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms and substituted with CH3 or N(CH3)2; and NR 1 R 2 12. The compound according to item 10 or 11, selected from the group consisting of: (Item 13) A compound according to any one of items 1, 4-6, and 10-12, having formula (Ib), or a pharma- ceutically acceptable salt thereof: [ka] (wherein Y is H or CH3). (Item 14) A compound according to any one of items 1, 4-6, and 10-12, having formula (Ic), or a pharma- ceutically acceptable salt thereof: [ka] wherein X is selected from the group consisting of methyl, ethyl, and cyclopropyl. (Item 15) A compound according to item 1, or a pharma- ceutically acceptable salt thereof, selected from the following: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] . (Item 16) A compound according to item 1, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: [Table 4] . (Item 17) The compound according to any one of items 1 to 15, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof for preventing or treating a viral disease. (Item 18) A pharmaceutical composition for preventing or treating a viral disease, comprising the compound according to any one of items 1 to 15, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient. (Item 19) A combination comprising the compound according to any one of items 1 to 15 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to item 9, and one or more therapeutically active agents. (Item 20) A method for treating a viral disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of items 1 to 15 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 18, or a combination according to item 19. (Item 21) Use of the compound according to item 15 or a pharma- ceutically acceptable salt or an optical isomer thereof, or the pharmaceutical composition according to item 18, or the combination according to item 19, for preventing or treating a viral disease. (Item 22) Item 16. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is caused by a Coxsackievirus. (Item 23) Item 16. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is caused by poliovirus. (Item 24) Item 16. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is caused by an echovirus. (Item 25) Item 16. The method according to item 15, wherein the viral disease is caused by an enterovirus. 20. A method according to claim 19, or a pharmaceutical composition according to claim 21, or a method according to claim 22, or a use according to claim 23. (Item 26) Item 16. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is caused by a rhinovirus. (Item 27) Item 16. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is caused by a picornavirus. (Item 28) 22. The compound according to item 15, or the pharmaceutical composition according to item 18, or the method according to item 20, or the use according to item 21, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. (Item 29) Item 17. The compound according to item 16, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof for preventing or treating a viral disease. (Item 30) Item 17. A pharmaceutical composition for preventing or treating a viral disease, comprising the compound according to item 16, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and a pharma- ceutically acceptable diluent or excipient. (Item 31) A combination comprising the compound according to item 16 or a pharma- ceutically acceptable salt thereof and one or more therapeutically active agents. (Item 32) A method for treating a viral disease, comprising administering to a subject a therapeutically effective amount of a compound according to item 16 or a pharma- ceutically acceptable salt thereof. (Item 33) 17. Use of the compound according to item 16, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, for preventing or treating a viral disease. (Item 34) Item 17. The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is caused by a Coxsackievirus. (Item 35) The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is caused by a poliovirus. (Item 36) Item 17. The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is caused by an echovirus. (Item 37) Item 17. The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is caused by an enterovirus. (Item 38) Item 17. The compound according to item 16, wherein the viral disease is caused by a rhinovirus. 30. The method according to item 32, or the use according to item 33. (Item 39) Item 17. The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is caused by a picornavirus. (Item 40) 34. The compound according to item 16, or the pharmaceutical composition according to item 30, or the method according to item 32, or the use according to item 33, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

Claims

[Claim 1] The invention described in the specification.

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