Antiviral 1,3-di-oxo-indene compounds

Abstract

The present application provides compounds of Formula (I) as described herein, and pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions to treat viral infections.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel 1,3-dioxoindene compounds, which are inhibitors of picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, and thus are useful in treating viral infections, including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. The present invention provides novel tetracyclic pyridinone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions to treat and prevent viral diseases. BACKGROUND

[0002] Picornaviruses are non-enveloped positive single stranded RNA viruses with a RNA genome of 7.2 Kb - 8.5 Kb long. These viruses are very small and spherical in shape, with a size of about 22 nm - 30 nm, and were first identified very early. Viruses belonging to the picornavirus family are enteroviruses, including rhinovirus, poliovirus, coxsackievirus A, coxsackievirus B, and echovirus and hepatitis A virus.

[0003] Diseases caused by picornaviruses are diverse, from respiratory diseases to digestive diseases, to circulatory diseases, and to skin diseases, examples of which include poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, and foot-and-mouth disease. However, there are no therapeutic agents for curing these diseases. Most of the drugs being developed are uncoated inhibitors. Viruses belonging to the picornavirus family cause various diseases, including the aforementioned respiratory diseases, which cause health, social, and economic problems. Picornaviruses are the main causative agents of waterborne diseases. Since RNA viruses are very stable and difficult to disinfect, they continuously cause related diseases.

[0004] Human rhinovirus (hRV) has recently been associated with most asthma exacerbations and is known to even be present in the bronchial tissue of many stable asthmatic patients. Comparison of corresponding bronchial mucosa biopsy samples taken from asthmatic and non-asthmatic patients showed that human rhinovirus was detected significantly more frequently in the lower respiratory tract of asthmatic patients than in non-asthmatic patients. A correlation between the presence of human rhinovirus and the clinical severity of asthma was also reported. In addition, rhinovirus causes chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media, as well as asthma.

[0005] Nasoviruses are the main cause of the common cold, while enteroviruses induce diseases including meningitis, respiratory infections. Extensive efforts to provide vaccination against poliovirus have significantly reduced the incidence of poliomyelitis worldwide, but cases of the disease are still reported in Niger, Nigeria, Egypt, India, Pakistan and Afghanistan. Thanks to the vaccine against hepatitis A virus, hepatitis A is now potentially controllable to some extent. However, no vaccine has been developed so far against coxsackie, echovirus or rhinovirus.

[0006] In particular, coxsackie B is the main cause of myocarditis, which in severe cases can develop into idiopathic dilated cardiomyopathy requiring heart transplantation.

[0007] Enviroxime derivatives are considered the most promising candidates with broad anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with the synthesis of positive-strand RNA by binding to the viral protein 3A required for the formation of RNA intermediates in the viral replication process (Heinz B A and Vance L M: J Virol, 1995, 69(7), 4189-97). However, in clinical studies, the compound was observed to have no significant or little therapeutic effect, while adverse pharmacokinetics and undesirable side effects were detected (Miller F D et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

[0008] The protease inhibitor AG 7088 has been developed on the basis of knowledge about the fine structure and function of the viral protease 2C. In cell cultures in the nanomolar concentration range, AG 7088 has an effect against 48 types of rhinovirus and coxsackie viruses A21, B3, enterovirus 70 and echovirus 11 (Pattick A K et al.: Antimicrob Agents Chemother, 1999, 43(10), 2444-50).

[0009] Due to the clarification of the molecular structure of the viral capsid, the prerequisites for the purposeful design of capsid blockers "WIN substances" have been obtained (Diana G D: Curr Med Chem 2003, 2, 1-12). They inhibit the adsorption and / or uncoating of rhinoviruses and enteroviruses. Some WIN substances have a highly specific action only against individual genera or virus types of picornaviruses. Other derivatives inhibit the replication of rhinoviruses and enteroviruses. For example, Arildone, disoxaril and pirodavir belong to the WIN substances. These compounds show very good antiviral effects in cell culture. However, poor solubility (Arildone), low bioavailability (Arildone and disoxaril), rapid metabolism and excretion (disoxaril and WIN 54954) and side effects, such as skin rash (WIN 54954) make clinical application impossible.

[0010] Pleconaril, a WIN substance, has very good oral bioavailability and, after its incorporation into the hydrophobic pocket in the viral capsid, it inhibits the penetration of rhinoviruses, echoviruses and coxsackie viruses (Pevear D C et al.: Antimicrob Agents Chemother 1999, 43(9), 2109-15; McKinlay M A et al.: Annu Rev Microbiol 1992, 46, 635-54). Therefore, pleconaril can be effective against a broad spectrum of viral diseases, ranging from the common cold to viral meningitis or myocarditis. Resistance against rhinovirus, enterovirus 71 and coxsackievirus B3 has been observed (Ledford R M et al.: J Virol 2004, 78(7), 3663-74; Groarke J M et al.: J Infect Dis 1999, 179(6), 1538-41). However, the proven therapeutic effect was not sufficient for the registration of pleconaril (Picovir, Viropharma, USA) as a medicament for the treatment of rhinovirus infections in the USA. In March 2002, the Food and Drug Administration (FDA) rejected the corresponding application because the rate of therapeutic success was too low and side effects were observed.

[0011] BTA-798 was found to have a higher antiviral activity than pleconaril, as assessed in vitro and in vivo with rhinoviruses, and is now being tested 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 drug approved for the treatment of enterovirus or rhinovirus has been developed to date. There is still a need for new treatments and therapies against enterovirus or rhinovirus.

[0013] In the present invention, effective antiviral drugs against picornavirus including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus were intensively and thoroughly researched, and finally it was found that novel 1,3-dioxoindene derivatives exhibit high inhibitory activity against picornavirus including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus. SUMMARY

[0014] The present invention provides novel compounds having 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 to treat disease conditions associated with or caused by viruses. Other 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):

[0016]

[0017] wherein,

[0018] G 1 selected from linear or branched C1-C4alkyl, C3-C4cycloalkyl, or linear or branched C1-C4alkoxy; wherein the C1-C4alkyl, C3-C4cycloalkyl, and C1-C4alkoxy can be substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3alkyl;

[0019] L is a bond or CH2;

[0020] E is

[0021] a) -CH(CHOHCH3)(NMe2); or

[0022] b) a monocyclic 4-6 membered heterocyclyl containing one or two nitrogen atoms or a 5-6 membered heteroaryl containing one nitrogen atom, wherein the 4-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of linear or branched C1-C3alkyl, -OH, =O, SO2R; wherein each R is independently selected from linear or branched C1-C3alkyl, monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2; wherein the monocyclic 5-6 membered heterocyclyl is optionally substituted with C1-C3 alkyl or NR 3 R 4 substituted;

[0023] each R 1 and R 2 are independently selected from H and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with NR 3 R 4 substituted; and

[0024] each R 3 and R 4 are independently selected from H or methyl. In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application and one or more pharmaceutically acceptable carriers. In another aspect, the present application provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the present application and one or more therapeutically active agents. DETAILED DESCRIPTION

[0025] For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural.

[0026] As used in the specification, unless expressly defined otherwise in context, the terms have the following meanings:

[0027] As used herein, the term "subject" refers to an animal. In certain aspects, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a human. As used herein, "patient" refers to a human subject. As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0028] As used herein, the term "inhibition" or "inhibiting" refers to a reduction or suppression of a given pathology, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0029] As used herein, the terms "treating" or "treatment" of any disease or disorder means, in one embodiment, improving the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, "treating" or "treatment" means alleviating or ameliorating at least one physical parameter including those which can not be discernible by the patient. In another embodiment, "treating" or "treatment" means 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 another embodiment, "treating" or "treatment" means preventing or delaying the onset or development or progression of the disease or disorder.

[0030] As used herein, the terms "a," "an," "the," and like terms used in the context of the present application (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated by the context.

[0031] Unless otherwise indicated herein, or otherwise apparent from context, all methods described herein can be performed in any suitable order. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application unless otherwise claimed.

[0032] "Optionally substituted" means that the group in question can be substituted at one or more positions with any one or any combination of the groups listed thereafter. The number, location, and selection of substituents will be understood to cover only those that result in reasonably stable compounds; thus, 'oxo' is not a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom does not have three hydroxyl or amino substituents. Unless otherwise indicated, optional substituents are typically up to four groups selected from halo, oxo, CN, amino, hydroxyl, -C 1-3 groups of -alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, wherein each R* is independently H or C 1-3 alkyl.

[0033] Unless otherwise indicated, "aryl" as used herein means a phenyl or naphthyl group. Unless otherwise indicated, aryl groups can be optionally substituted with up to four groups selected from halo, CN, amino, hydroxyl, C 1-3groups of alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, where each R* is independently H or C 1-3 alkyl.

[0034] As used herein, "halo" or "halogen" can be fluoro, chloro, bromo, or iodo.

[0035] As used herein, "C 1-6 alkyl" or "C1-C6alkyl" means a straight or branched chain alkyl group having from 1 to 6 carbon atoms. If a different number of carbon atoms is specified, such as C4or C3, the definition will be modified accordingly, such as "C 1-4 alkyl" will mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl.

[0036] As used herein, "C 1-6 alkoxy" means a straight or branched chain alkoxy group (-O-alkyl) having from 1 to 6 carbon atoms. If a different number of carbon atoms is specified, such as C4or C3, the definition will be modified accordingly, such as "C 1-4 alkoxy" will mean methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and t-butoxy.

[0037] As used herein, "C 1-4 haloalkyl" or "C1-C4haloalkyl" means a straight or branched chain alkyl group having from 1 to 4 carbon atoms wherein at least one hydrogen has been replaced with a halogen. The number of halogen substitutions can be one to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C6or C3, the definition will be modified accordingly. Thus, "C 1-4 haloalkyl" will mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl, at least one of which has been replaced with a halogen, such as where the halogen is fluoro: CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-.

[0038] As used herein, "C 3-8 cycloalkyl" means a saturated monocyclic hydrocarbon ring of from 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. If a different number of carbon atoms is specified, such as C3-C6, the definition will be modified accordingly.

[0039] “4- to 8-membered heterocyclyl,” “5- to 6-membered heterocyclyl,” “3- to 10-membered heterocyclyl,” “3- to 14-membered heterocyclyl,” “4- to 14-membered heterocyclyl,” and “5- to 14-membered heterocyclyl” refer to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered, and 5- to 14-membered heterocyclic rings, respectively; unless otherwise indicated, such rings contain from 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the ring can be saturated or partially saturated, but not aromatic. Heterocyclyl groups can be attached to another group at a nitrogen or carbon atom. The term “heterocyclyl” includes monocyclic, fused ring, and bridged ring groups. Examples of such heterocyclyl groups 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, ethylenedioxy, oxetane, or thiazole. In certain embodiments, if not otherwise specified, a heterocyclyl group has 1-2 heteroatoms selected from N, O, and S as ring members and 4-7 ring atoms, and is optionally substituted with up to four groups selected from halo, oxo, CN, amino, hydroxyl, C 1-3 alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, where each R* is independently H or C 1-3 alkyl. Specifically, a heterocyclyl group containing a sulfur atom is optionally substituted with one or two oxo groups on the sulfur.

[0040] "Heteroaryl" is a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, the heteroaryl group 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 typically the heteroaryl ring contains no more than one divalent O or S in the ring. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, 2-pyrrolyl or 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-pyridyl, 3-pyridyl or 4-pyridyl, 3-pyridazinyl or 4-pyridazinyl, 3-pyrazinyl, 4-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl and 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl. The heteroaryl group is optionally substituted with up to four groups selected from halo, CN, amino, hydroxyl, C1-C4 alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR* and -CONR*2, wherein each R* is independently H or C1-C4 alkyl. 1-3 alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR* and -CONR*2, wherein each R* is independently H or C 1-3 alkyl.

[0041] The term "hydroxy" or "hydroxyl" refers to the group -OH.

[0042] Various embodiments of the application are described herein. It will be recognized that features specified in each embodiment can be combined with other specified features to provide additional embodiments. The following enumerated embodiments are representative of the application:

[0043] Embodiment 1. A compound of Formula (I):

[0044]

[0045] wherein,

[0046] G 1 selected from linear or branched C1-C4 alkyl, C3-C4 cycloalkyl, or linear or branched C1-C4 alkoxy; wherein the C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy groups can be substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl;

[0047] L is a chemical bond or a C1-C4 straight chain or branched alkylene linker;

[0048] E is

[0049] a) -CH(CHOHCH3)(NMe2); or

[0050] b) a monocyclic 4-6 membered heterocyclyl containing one or two nitrogen atoms or a 5-6 membered heteroaryl containing one nitrogen atom, wherein said 4-6 membered heterocyclyl and said 5-6 membered heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of straight chain or branched C1-C3 alkyl, -OH, =0, -SO2R; wherein each R is independently selected from straight chain or branched C1-C3 alkyl, monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 ; wherein said monocyclic 5-6 membered heterocyclyl is optionally substituted with C1-C3 alkyl or NR 3 R 4 ;

[0051] each R 1 and R 2 is independently selected from H and C1-C3 alkyl, wherein said C1-C3 alkyl is optionally substituted with NR 3 R 4 ; and

[0052] each R 3 and R 4 is independently selected from H or methyl.

[0053] Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula (II):

[0054]

[0055] Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula (III):

[0056]

[0057] Embodiment 4. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1 is straight chain or branched C1-C4 alkyl.

[0058] Embodiment 5. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1 is C3-C4 cycloalkyl.

[0059] Embodiment 6. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1 is linear or branched C1-C4alkoxy.

[0060] Embodiment 7. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the C1-C4alkyl, C3-C4cycloalkyl, and C1-C4alkoxy can be substituted with one, two, or three substituents.

[0061] Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the substituents are independently selected from cyclopropyl and linear or branched C1-C3alkyl.

[0062] Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is a C1-C4linear or branched alkylene linker. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is CH2.

[0063] Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein E is -C(CHOHCH3)(NMe2).

[0064] Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein E is monocyclic 4-6 membered heterocyclyl.

[0065] Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein E is monocyclic 4-6 membered heteroaryl.

[0066] Embodiment 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 4-6 membered heterocyclyl contains one or two nitrogen atoms.

[0067] Embodiment 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered heteroaryl contains one nitrogen atom.

[0068] Embodiment 15. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the 4-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one, two, or three substituents.

[0069] Embodiment 16. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein the substituent is independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =0, -SO2R.

[0070] Embodiment 17. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from linear or branched C1-C3 alkyl, monocyclic 5-6 membered heterocyclyl, and NR 1 R 2 .

[0071] Embodiment 18. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 5-6 membered heterocyclyl is optionally substituted with C1-C3 alkyl or NR 3 R 4 .

[0072] Embodiment 19. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from H and C1-C3 alkyl. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein C1-C3 alkyl is optionally substituted with NR 3 R 4 .

[0073] Embodiment 20. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 4 is independently selected from H or methyl.

[0074] Embodiment 21. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1 is linear or branched C1-C4 alkyl optionally substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl.

[0075] Embodiment 22. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1 is C3-C4 cycloalkyl optionally substituted with one, two, or three substituents independently selected from

[0076] Embodiment 23. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, wherein G 1straight or branched C1-C4alkyl substituted with one, two, or three substituents independently selected from the group consisting of cyclopropyl and straight or branched C1-C3alkyl.

[0077] Embodiment 24. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula (la):

[0078]

[0079] wherein A 1 is selected from the group consisting of H, straight or branched C1-C3alkyl, and SO2R; and

[0080] A 2 is selected from the group consisting of H and SO2R.

[0081] Embodiment 25. The compound according to the preceding embodiment, wherein A 1 is methyl or SO2CH3.

[0082] Embodiment 26. The compound according to the preceding embodiment, wherein A 2 is SO2R, and R is selected from the group consisting of CH3; monocyclic 5-6 membered heterocyclyl containing one or two nitrogen atoms and substituted with CH3or N(CH3)2; and NR 1 R 2 .

[0083] Embodiment 27. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula (lb):

[0084]

[0085] wherein Y is H or CH3.

[0086] Embodiment 28. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula (Ic):

[0087]

[0088] wherein X is selected from the group consisting of methyl, ethyl, and cyclopropyl.

[0089] Embodiment 29. The compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, of the compound 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-hydroxypyridinamide; 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; 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-hydroxypyridinamide; 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;(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)pyrrolidin-1-yl)sulfonyl)-3- methyl-1H-pyrrole-2-carboxamide; 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-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3- hydroxybutanamide; 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-9bH- indeno[1,2-b]benzofran-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]benzofran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H- pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH- indeno[1,2-b]benzofran-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]benzofran-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]benzofran- 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]benzofran-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]benzofran- 9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH- indeno[1,2-b]benzofran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-(l-amino-4b-hydroxy-7-((lS,2R)-2-methylcyclopropyl)-lO-oxo-4b,10- dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-lH- pyrrole-2-carboxamide and N-((4bR,9bR)-l-amino-4b-hydroxy-7-((lS,2S)-2- methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3- methyl-4-(methylsulfonyl)-lH-pyrrole-2-carboxamide. This embodiment includes each of the examples represented in the table of biologically active data herein.

[0090] Embodiment 30. A compound comprising each or any of the examples represented in the table of biologically active data herein.

[0091] Embodiment 31. A compound of Formula I to III or according to any one of the embodiments herein, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for use in the prevention or treatment of a viral disease.

[0092] Embodiment 32. A pharmaceutical composition for use in the prevention or treatment of a viral disease comprising a compound of Formula I to III or according to any one of the embodiments herein, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

[0093] Embodiment 33. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by Coxsackie virus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by poliovirus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by echovirus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by enterovirus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by rhinovirus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is caused by picornavirus. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof according to the embodiments herein or the pharmaceutical composition according to the embodiments herein, wherein the viral disease is poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, strep throat, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0094] Embodiment 34. Use of a compound of Formula I to III or a compound according to any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for the prevention or treatment of a viral disease.

[0095] Embodiment 35. The use according to the embodiments herein, wherein the viral disease is caused by Coxsackie virus.

[0096] Embodiment 36. The use according to the embodiments herein, wherein the viral disease is caused by poliovirus.

[0097] Embodiment 37. The use according to the embodiments herein, wherein the viral disease is caused by echovirus.

[0098] Embodiment 38. The use according to the embodiments herein, wherein the viral disease is caused by enterovirus.

[0099] Embodiment 39. The use according to the embodiments herein, wherein the viral disease is caused by rhinovirus.

[0100] Embodiment 40. Use according to the embodiments described herein, wherein the viral disease is caused by a Picornavirus.

[0101] Embodiment 41. Use according to the embodiments described herein, wherein the viral disease is poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

[0102] These compounds are novel and are useful as intermediates in the preparation of the compounds of formula (I) - (III) described herein.

[0103] Another embodiment of the present application provides a compound as described hereinabove, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0104] The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral disease and / or infection in a human is also within the scope of the present application.

[0105] Included within the scope of the present application is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0106] According to another aspect of this embodiment, the pharmaceutical composition according to the present application further comprises a therapeutically effective amount of at least one other antiviral agent.

[0107] The present application also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a viral infection or other viral infection in a human suffering from or at risk of suffering from an infection.

[0108] The present application also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a viral disease or other viral infection in a human suffering from or at risk of suffering from a disease.

[0109] Another aspect of the present application relates to a method of treating or preventing a viral disease and / or infection in a human by administering to the human an antivirally effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.

[0110] Another aspect of the present application refers to an article of manufacture comprising a composition effective for the treatment of a herpes viral disease and / or infection; and packaging material comprising a label which indicates that the composition can be used for the treatment of a disease and / or infection caused by a virus; wherein the composition comprises a compound of formula (I) according to the present application, or a pharmaceutically acceptable salt thereof.

[0111] Yet another aspect of the application relates to a method of inhibiting viral replication, comprising exposing a virus to an effective amount of a compound of Formula (I) or a salt thereof under conditions that inhibit viral replication. The method can be performed in vitro or in vivo.

[0112] Also included within the scope of the application is the use of a compound of Formula (I) or a salt thereof to inhibit replication of a virus.

[0113] In one embodiment, the application provides a pharmaceutical composition comprising a compound of the application and another therapeutic agent. Optionally, the pharmaceutical composition can comprise a pharmaceutically acceptable carrier as described above. In some embodiments, the compound of Formula (I) is co-administered with at least one additional agent selected from the group consisting of another viral inhibitor.

[0114] These additional agents can be combined with the compounds of the application to produce a single pharmaceutical dosage form. Alternatively, these additional agents can be administered to the patient separately from the compounds of the application, e.g., as part of a multiple dosage form regimen using, for example, a kit. Such additional agents can be administered to the patient prior to, simultaneously with, or following the administration of the compounds of the application or pharmaceutically acceptable salts thereof.

[0115] The dosage range of the compounds of the application that is suitable for use on a daily basis is typically 0.01 mg / kg to 100 mg / kg of body weight, such as 0.1 mg / kg to 50 mg / kg of body weight. Each dosage unit can conveniently contain 5% to 95% active compound (w / w). Sometimes such formulations contain 20% to 80% active compound.

[0116] The actual pharmaceutically effective amount or therapeutically dose will, of course, depend on factors such as the age and weight of the patient, the route of administration, and the disease severity. In any case, the combination will be administered in a dosage and manner that allows for a pharmaceutically effective amount to be delivered based on the unique characteristics of the patient.

[0117] When the compositions of the application comprise a combination of a compound of the application and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent(s) should be present in amounts that are each about 10% to 100%, and sometimes about 10% to 80%, of the dosage normally administered in a monotherapy regimen.

[0118] Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) effective to inhibit the formation and / or replication of a virus in a human, including but not limited to agents that interfere with host or viral mechanisms necessary for the formation and / or replication of a virus in a human.

[0119] Many of the compounds of the application contain one or more chiral centers. These compounds can be prepared and used as single isomers or as mixtures of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the application are used as single substantially pure isomers, meaning that at least 90% of the sample of the compound is the designated isomer, and less than 10% of the sample is any other isomer or mixture of isomers. In some embodiments, at least 95% of the sample is the single isomer. Selection of the appropriate isomer is within the ordinary skill of the art, as one isomer will generally be more active in the herpes virus DNA polymerase in vitro assays described herein and will be the single isomer. In cases where the in vitro activity difference between isomers is relatively small, e.g., less than about 4-fold, the single isomer can be selected based on the level of activity against viral replication in cell culture using methods such as those described herein: e.g., the isomer with the lower IC-50 or EC-50.

[0120] The compounds of the application can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0121] The present application also provides processes for preparing compounds of formula I as described herein and intermediates useful for preparing compounds of formula (I). Accordingly, the present application also includes processes for preparing compounds of formula (I). The present application also includes any variant of the present processes wherein an intermediate product available at any stage thereof is used as starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under the conditions of the reaction, or wherein the reaction components are used in the form of their salts or optically pure materials.

[0122] The present application also relates to those forms of the processes wherein a compound available as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or wherein the starting material is formed in situ under the conditions of the reaction or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by a process according to the application is prepared under process conditions and further treated in situ.

[0123] The term "optical isomer" or "stereoisomer" refers to any one of the various stereoisomeric forms in which a given compound of the application can exist and includes geometric isomers. It is understood that substituents can be attached at a chiral center of a carbon atom. The term "chiral" refers to molecules which have a nonsuperimposable mirror image, and the term "achiral" refers to molecules which are superimposable with their mirror image. Thus, the present application includes enantiomers, diastereomers, or racemates of the compounds. An "enantiomer" is a stereoisomer which is a non-superimposable mirror image of the other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to denote a racemic mixture when appropriate. A "diastereomer" is a stereoisomer that has at least two asymmetric atoms which are not mirror images of each other. Absolute stereochemistry is specified where possible, using the R- or S-configuration. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by the Cahn-Ingold-Prelog R-S system. Resolved compounds of unknown absolute configuration can be designated (+) or (-) by their ability to rotate plane-polarized light (+) or (-) at the sodium D line wavelength (589 nm). Certain of the compounds described herein contain one or more stereogenic centers or axes, and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0124] Depending on the choice of starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as a mixture of them, for example as a pure optical isomer, or as a mixture of isomers, such as a racemate and a diastereomeric mixture. The present application is intended to include all such possible isomers, including racematic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)-isomers and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compounds contain double bonds, the substituents can be in the E or Z configuration. If the compounds contain disubstituted cycloalkyls, the cycloalkyl substituent can have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0125] Any resulting isomeric mixtures can be separated into the pure or essentially pure geometric or optical isomers or diastereomers on the basis of their physico-chemical differences, for example, by chromatography and / or fractional crystallization.

[0126] Any resulting racemic forms of the end products or intermediates can be resolved by known methods, for example, by separation of their diastereomeric salts with optically active acids or bases and liberation of the optically active acid or base compound. In particular, basic moieties can thus be used to resolve the compounds of the application into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic products can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using chiral adsorbents.

[0127] In addition, the compounds of the application, including their salts, are also meant to cover the compounds in the form of their hydrates or include other solvents used for their crystallization. The compounds of the application can inherently or by design form solvates with pharmaceutically acceptable solvents; therefore, it is intended that the application embrace both solvated and unsolvated forms. The term "solvate" means a molecular complex of a compound of the application (including a pharmaceutically acceptable salt thereof) with one or more solvent molecules. Such solvent molecules are those normally used in the pharmaceutical arts, for example, water, ethanol, and the like. The term "hydrate" means a complex that contains water as the solvent molecule.

[0128] The compounds of the application, including their salts, hydrates, and solvates, can inherently or by design form polymorphs.

[0129] As used herein, the term "salt" or "salts" refers to an acid addition or base addition salt of a compound of the application. "Salts" specifically include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" means a salt that retains the biological effectiveness and properties of the compounds of the application and is not biologically or otherwise undesirable. In many cases, the compounds of the application are capable of forming acid and / or base salts by means of amino and / or carboxyl groups or groups similar thereto.

[0130] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, 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.

[0131] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0132] 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, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0133] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the Periodic Table of the Elements. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0134] 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, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0135] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of the appropriate base (such as sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or the like), or by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. Such reactions typically are carried out in water or in an organic solvent, or in a mixture of both. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0136] Any formula given herein is intended to represent both labeled and unlabeled forms of the compounds of the application. Isotopically labeled 13 C or 15 N. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be suitably 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. The present application includes various isotopically labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C, or those into which non-radioactive isotopes such as 2 H and 13 C are present in substantially higher amounts than the normal isotopic distribution. Such isotopically labeled compounds are useful in metabolic studies (e.g. with 14C), reaction kinetics studies (e.g., with 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or radiotherapy useful for patients. In particular, 18 F-labeled compounds of the application can be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent used in the

[0137] In addition, wider substitution with heavier isotopes, especially deuterium (i.e., 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium is considered a substituent of the compounds of the application herein and that samples of compounds having deuterium as a substituent typically have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. As used herein, the term “isotopic enrichment factor” means the ratio between the isotopic abundance of a particular isotope and the natural abundance. If a substituent in a compound of the application is represented as deuterium, such compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0138] Pharmaceutically acceptable solvates according to the application include those wherein the solvent of crystallization can be isotopically substituted, for example, D2O, d 6 acetone, d 6 DMSO.

[0139] Compounds of the application containing a group capable of acting as a hydrogen bond donor and / or acceptor can be capable of forming co-crystals with a suitable co-crystal former. These co-crystals can be prepared from a compound of the application by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting in solution a compound of the application with a co-crystal former under crystallization conditions, and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. The application thus further provides co-crystals comprising a compound of the application.

[0140] Unless otherwise indicated herein, or otherwise clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed.

[0141] The compounds of the application can be administered by known methods, including orally, parenterally, by inhalation, and the like. In certain embodiments, the compounds of the application are administered orally in the form of pills, tablets, capsules, solutions, or suspensions. In other embodiments, the compounds of the application are administered by injection or infusion. Infusion is typically performed intravenously, usually over a period of between about 15 minutes and 4 hours. In other embodiments, the compounds of the application are administered intranasally or by inhalation; inhalation methods are particularly suitable for the treatment of respiratory tract infections. The compounds of the application exhibit oral bioavailability, and thus in some embodiments, the compounds can be administered orally.

[0142] The compounds of the application can also be used in combination with other agents (combination partners) useful for treating viral infections in a subject (e.g., additional antiviral agents that are or are not of Formula I).

[0143] The term "combination" means either a fixed combination in one dosage unit form, as separate dosage forms for simultaneous or sequential use, or as a kit-of-parts for combined administration wherein the compound of the application and the combination partner can be administered independently at the same time or separately within time intervals, especially allowing that the combination partners show a cooperative, e.g. synergistic, effect or any combination thereof.

[0144] In certain embodiments of the application, the compounds of the application are used in combination with a second antiviral agent, such as those antiviral agents named herein.

[0145] A second antiviral agent can be administered in combination with a compound of the present application, wherein the second antiviral agent is administered prior to, simultaneously with, or following the administration of one or more compounds of the present application. When it is desirable to administer a compound of the present application and a second agent at the same time and by the same route of administration, the compound of the present application and the second agent can be formulated together in the same dosage form. An example of a dosage form containing a compound of the present application and a second agent is a tablet or capsule.

[0146] In some embodiments, the combination of a compound of the present application and a second antiviral agent can provide synergistic activity. The compound of the present application and the second antiviral agent can be administered together, separately but simultaneously, or sequentially.

[0147] An "effective amount" of a compound is an amount necessary or sufficient to treat or prevent a viral infection and / or disease or condition described herein. In one example, an effective amount of a viral inhibitor of Formula I is an amount sufficient to treat a viral infection in a subject. In another example, an effective amount of an inhibitor is an amount that is sufficient to treat a viral infection in a subject in need of such treatment. The effective amount can vary according to factors such as the subject's size and weight, the type of disease, or the particular compound of the present application. For example, the selection of a compound of the present application can affect what constitutes an "effective amount." One of ordinary skill in the art would be able to determine an effective amount for a compound of the present application without undue experimentation.

[0148] The administration regimen can affect what constitutes an effective amount. A compound of the present application can be administered to a subject prior to or following the onset of a viral infection. Furthermore, several divided doses or intermittent doses can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Furthermore, the dose of a compound of the present application can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0149] A compound of the present application can be used to treat a state, disorder, or disease as described herein, or to manufacture a pharmaceutical composition for the treatment of these diseases. The present application provides methods of using a compound of the present application to treat these diseases or to prepare a pharmaceutical composition containing a compound of the present application for the treatment of these diseases.

[0150] The term "pharmaceutical composition" includes a formulation suitable for administration to a mammal, e.g., a human. When a compound of the present application is administered as a pharmaceutical to a mammal (e.g., a human), it can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (e.g., 0.5% to 90%) of at least one compound of Formula (I), or any subgenus thereof, as an active ingredient in admixture with a pharmaceutically acceptable carrier, or an

[0151] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes a pharmaceutically-acceptable material, composition or vehicle, suitable for administering the compounds of the present application to mammals. Carriers include liquid or solid filler substances, diluents, excipients, solvents or encapsulating materials involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laureate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethylene glycol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Typically, the pharmaceutically-acceptable carrier is sterile and / or substantially isotonic with the recipient.

[0152] Wetting agents, emulsifiers and lubricants, 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 compositions.

[0153] Examples of pharmaceutically-acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0154] The formulations of the present application include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and / or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99%, sometimes from about 5% to about 70%, and sometimes from about 10% to about 30%, of the active ingredient, in 100% of the dosage form.

[0155] The process of making these formulations or compositions includes the step of bringing into association the compounds of the present application with the carrier(s) and, optionally, one or more accessory ingredients. In general, the process involves bringing the compounds of the present application into a homogeneous and intimate admixture with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0156] Formulations of the present application suitable for oral administration can be in the form of capsules, cachets, tablets, troches, lozenges (using a flavored basis, such as sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouth wash, etc., each containing a predetermined amount of the compounds of the present application as an active ingredient. The compounds of the present application can also be administered as a bolus, electuary or paste.

[0157] In solid dosage forms of the present application for oral administration (capsules, tablets, pills, dragees, granules, etc.), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acids; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc.

[0158] Tablets can be prepared by either compression or molding. The compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, disintegrating agent, surface-active agent or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with a liquid diluent.

[0159] The tablets and other solid dosage forms of the pharmaceutical compositions of the present application, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can also be formulated so as to provide a slow or controlled release of the active ingredient therein. By way of example, they can be formulated so as to provide slow or controlled release of the active ingredient in the gastrointestinal tract utilizing, for example, different proportions of hydroxypropylmethyl cellulose and other polymer matrices, liposomes and / or microspheres. They can be sterilized by, for example, filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium, immediately before use. These compositions also can optionally contain opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in, a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient(s) can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0160] Liquid dosage forms for oral administration of the compounds of the application include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0161] In addition to inert diluents, the oral compositions can include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and coloring agents.

[0162] Suspensions, in addition to the active ingredient, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0163] Formulations of the pharmaceutical compositions of the application for rectal or vaginal administration can be presented as a suppository, which can be prepared from a mixture of one or more compounds of the application with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity to release the active component.

[0164] Formulations of the present application suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0165] Dosage forms for the topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as can be required.

[0166] Ointments, pastes, creams and gels can contain, in addition to an active compound of this application, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0167] Powders and sprays can contain, in addition to a compound of this application, excipients such as lactose, talc, 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.

[0168] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper 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.

[0169] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this application.

[0170] Pharmaceutical compositions of the present application suitable for parenteral administration can include one or more compounds of the present application in combination with one or more pharmaceutically acceptable carriers, such as a sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, or sterile powders for reconstitution into such solutions or dispersions just prior to use, which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0171] Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the application include water, ethanol, glycol ethers, polyhydric alcohol (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0172] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0173] In some cases, in order to prolong the effect of a drug, it is desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0174] Injectable long-acting formulations are prepared by forming microencapsule matrices of the subject compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the particular polymer employed, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long-acting injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0175] The formulations of the present application can be administered orally, parenterally, topically, or rectally. They are, of course, given in forms suitable to the mode of administration chosen. For example, they will typically be given in the form of tablets or capsules, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion or inhalation; topically in the form of a lotion or ointment; and rectally in the form of a suppository.

[0176] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than oral and topical administration, and include, but are not limited to, injection, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Intravenous infusion is sometimes a method of delivery of the compounds of the present application. Infusion can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present application are administered by infusion over a period of between 15 minutes and 4 hours, typically between 0.5 hours and 3 hours. Such infusions can be used once a day, twice a day, or up to three times a day.

[0177] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" mean that the compound, drug or other material is not administered directly into the central nervous system, so that it enters the patient's system and is therefore subject to metabolism and other like processes, for example, subcutaneous administration.

[0178] These compounds can be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally (such as, for example, by spray), rectally, intravaginally, parenterally, intracisternally, and topically, such as by powders, ointments, or drops, including buccal and sublingual.

[0179] Regardless of the route of administration selected, the compounds of the application, which can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the application, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0180] Actual dosage levels of active ingredients in the pharmaceutical compositions of the present application can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0181] The selected dosage level will depend on a variety of factors including the activity of the particular compound of the present application employed, or of its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound being employed; the duration of the treatment; other drugs, compounds and / or materials used in combination with the particular compound employed; the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0182] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the application employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0183] In general, the compound of the present application is most desirably administered as a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present application. Therapeutically effective amounts of the compounds of the present application are readily determined by those of ordinary skill in the art as they depend on the particular compound employed, its potency, the age and condition of the patient, and the mode of administration.

[0184] If desired, the effective daily dose of the active compound can be administered as a single dose, or as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Compounds delivered orally or by inhalation are typically administered in one to four doses per day. Compounds delivered by injection are typically administered once per day, or once every other day.

[0185] Compounds delivered by infusion are typically administered in one to three doses per day. When multiple doses are administered within a day, the doses can be administered at intervals of about 4 hours, about 6 hours, about 8 hours, or about 12 hours.

[0186] While it is possible for a compound of the present application to be administered alone, it is sometimes desirable to administer the compound as a pharmaceutical composition, such as those described herein. Accordingly, methods using a compound of the present application include administering the compound as a pharmaceutical composition, wherein at least one compound of the present application is mixed with a pharmaceutically acceptable carrier prior to administration.

[0187] General synthetic procedures

[0188] Compounds as described herein can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0189] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalyst utilized in synthesizing the compounds of the present application either are commercially available or can be prepared by routine methods known to those skilled in the art of organic synthesis (Houben-Weyl 4th ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

[0190] List of abbreviations

[0191] Ac acetyl

[0192] ACN or MeCN acetonitrile

[0193] AcOEt / EtOAc ethyl acetate

[0194] AcOH acetic acid

[0195] aq aqueous

[0196] Bn benzyl

[0197] Bu butyl (nBu = normal butyl, tBu = tert-butyl)

[0198] CDI carbonyldiimidazole

[0199] CH3CN acetonitrile

[0200] DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

[0201] Boc2O di-tert-butyldicarbonate

[0202] DCE 1,2-dichloroethane

[0203] DCM dichloromethane

[0204] DIAD diisopropyl azodicarboxylate

[0205] DiBAl-H diisobutylaluminum hydride

[0206] DIPEA or DIEA N-ethyldiisopropylamine

[0207] DMA N,N-dimethylacetamide

[0208] DMAP dimethylaminopyridine

[0209] DMF N,N-dimethylformamide

[0210] DMSO dimethyl sulfoxide

[0211] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0212] EI electrospray ionization

[0213] Et2O diethyl ether

[0214] Et3N triethylamine

[0215] Ether diethyl ether

[0216] EtOAc ethyl acetate

[0217] EtOH ethanol

[0218] FC flash chromatography

[0219] h hour(s)

[0220] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0221] HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0222] HCl hydrochloric acid

[0223] HMPA hexamethylphosphoramide

[0224] HOBt 1-hydroxybenzotriazole

[0225] HPLC high performance liquid chromatography

[0226] H2O water

[0227] IPA isopropyl alcohol

[0228] L liter

[0229] LC-MS liquid chromatography mass spectrometry

[0230] LiHMDS lithium bis(trimethylsilyl)amide

[0231] MgSO4 magnesium sulfate

[0232] Me methyl

[0233] MeI methyl iodide

[0234] MeOH methanol

[0235] mg milligram

[0236] min minute

[0237] mL milliliter

[0238] MS mass spectrometry

[0239] MsCl methanesulfonyl chloride

[0240] NaHCO3 sodium bicarbonate

[0241] Na2SO4 sodium sulfate

[0242] NH2OH hydroxylamine

[0243] Pd / C palladium on carbon

[0244] Pd(OH)2 palladium hydroxide

[0245] PG protecting group

[0246] Ph phenyl

[0247] Ph3P triphenylphosphine

[0248] Prep preparative

[0249] Rf relative mobility

[0250] RP reversed phase

[0251] Rt retention time

[0252] RT room temperature

[0253] SFC supercritical fluid chromatography

[0254] SiO2 silica gel

[0255] SOCl2 thionyl chloride

[0256] propylphosphonic anhydride

[0257] TBAF tetrabutylammonium fluoride

[0258] TBDMS tert-butyldimethylsilyl

[0259] TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[0260] TEA triethylamine

[0261] TFA trifluoroacetic acid

[0262] THF tetrahydrofuran

[0263] TLC thin layer chromatography

[0264] TsCl tosyl chloride

[0265] TsOH toluenesulfonic acid

[0266] In view of the examples and schemes provided herein, the compounds of the application are prepared from commonly available compounds using procedures known to those skilled in the art.

[0267] Within the scope of this text, only readily removable groups that are not components of the specific desired end product of a compound of the invention are designated as "protecting groups" unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protection groups themselves and their cleavage reactions are described in standard reference works, for example, Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. Page 41627 (URL: http: / / www.science-of-synthesis.com (electronic version, Volume 48)); J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der Organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Thieme, Stuttgart 1982, and "Chemie der Peptide, Proteine" (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. Protecting groups are characterized in that they are readily removed, i.e. without undesired side reactions, for example by solvolysis, reduction, photolysis or, alternatively, under physiological conditions, for example by enzymatic cleavage.

[0268] Salts of compounds of the present application having at least one salt-forming group can be prepared in a manner known per se. For example, salts of compounds of the present application having acid groups can be formed, for example by treating the compound with a metal compound, such as an alkali metal salt of an appropriate organic carboxylic acid, for example the sodium salt of 2- ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound, such as the corresponding hydroxide, carbonate or bicarbonate, such as sodium or potassium hydroxide, carbonate or bicarbonate, with a corresponding calcium compound or with ammonia or an appropriate organic amine, sometimes using a stoichiometric or only a slight excess of the salt- forming agent. Acid addition salts of compounds of the present application are obtained in customary manner, for example by treating the compound with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present application containing both an acid and a basic salt-forming group, for example a free carboxyl group and a free amino group, can be formed, for example by neutralizing a salt, such as an acid addition salt, to the isoelectric point with a weak base, or by treatment with an ion exchanger.

[0269] Salts can be converted into the free compounds in a customary manner; metal and ammonium salts can be converted, for example, by treatment with a suitable acid, and acid addition salts by treatment with a suitable basic reagent.

[0270] Mixtures of isomers which can be obtained according to the present application can be separated into the individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning between a mixture of polymorphic solvents, by recrystallization and / or chromatography, for example on silica gel, or by medium pressure liquid chromatography, for example on a reversed phase column, and racemates can be separated, for example, by forming salts with optically pure salt-forming reagents and separating the diastereomeric mixtures thus obtained, for example by fractional crystallization, or by chromatography on an optically active column material.

[0271] Intermediates and final products can be worked up and / or purified according to standard methods, e.g. using chromatographic methods, partitioning methods, (re-) crystallization, etc.

[0272] LC-MS High resolution mass spectrometry

[0273] ESI-MS data were recorded using a LTQ-XL Orbitrap mass spectrometer with an electrospray ionization source (Thermo Fisher Scientific). The resolution of the MS system was approximately 30000. The drug candidates were infused from sample probes into the mass spectrometer by UPLC (Acquity, Waters). Separation was performed on an Acquity UPLC BEH C18 1 x 50 mm column with a flow rate of 0.15 mL / min and a gradient of 5% to 95% in 3 min. Solvent A was water containing 0.1% trifluoroacetic acid and solvent B was 75% methanol and 25% isopropanol containing 0.1% trifluoroacetic acid. The mass accuracy of the system has been found to be < 5 ppm.

[0274] Examples

[0275] The application is further illustrated by the following examples, which are not to be construed as limiting. The assays used throughout the examples are well established in the art: efficacy demonstration in these assays is generally considered to be predictive of efficacy in subjects.

[0276] The compounds of the present application can be prepared by organic synthesis methods known to one of ordinary skill in the art, with reference to the following reaction schemes and examples. General methods for synthesizing compounds of Formula (I) are provided in the following schemes.

[0277] Example 1 : N-((4bR,9bR)-1 -amino-4b-hydroxy-7-((1 R,2R)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1 H- pyrrole-2-carboxamide (33):

[0278]

[0279] Scheme-1

[0280]

[0281] 4-nitroisobenzofuran-1,3-dione (2):

[0282] An initial suspension of 3-nitrophthalic acid 1 (1.0 kg, 4.7 moles) in Ac2O (1 L tr) was refluxed at 140 °C for 2.5 hours. It was then cooled to 80 °C and slowly added to diethyl ether (4 L tr) with vigorous stirring. The precipitate was collected by filtration through a Buchner funnel and washed with Et2O to give the product.

[0283] 4-nitro-1,3-dioxo-2,3-dihydro-1 H-indene-2-carboxylic acid ethyl ester (3):

[0284] To a suspension of anhydride 2 (50 g, 0.26 moles) in dry DCM (260 mL) was added ethyl acetoacetate (42 mL, 0.31 moles) and Ac2O (48.5 mL, 0.52 moles) at ambient temperature. To this suspension was added dropwise Et3N (108 mL, 0.78 moles) over a 30 minute duration at room temperature (exothermic). A few millilitres of TEA were added. This was stirred at the same temperature for a further 15 minutes before evaporating off the DCM. The crude product obtained was then dissolved in 2 litres of water and cooled to 0 °C. This was secured with an overhead stirrer and 300 mL of 2N HCI was added dropwise to it under vigorous stirring conditions, keeping the temperature below 0 °C. The precipitate started to form slowly. This was stirred at 0 °C for a further 15 minutes before being filtered through a Buchner funnel and washed with ice cold water (500 mL). It was then air dried for three days to give the solid product.

[0285] 4-nitro-1 H-indene-1,3(2H)-dione (4):

[0286] Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1 H-indene-2-carboxylate 3 (272.5 g, 1.04 moles) was dissolved in 1 litre of MeCN:water (20:1, 1.0M). To this suspension was added TFA (60 mL, 1.14 moles) slowly at room temperature and then heated at 50 °C. After 4 hours the reaction mass was concentrated on a rotary evaporator until approximately 100 mL of solvent remained. The precipitated solid was then filtered off through a Buchner funnel and washed with (1 :1 ) CHCI3:hexane. This gave the product and the filtrate was concentrated again to give more product in a second batch.

[0287] 2,2-dihydroxy-4-nitro-1 H-indene-1,3(2H)-dione (5):

[0288] Dissolve 4-nitro-1H-indene-1,3(2H)-dione 4 (10.0 g, 52.3 mmol) in AcOH:dioxane (1:10, 105 mL, 0.5 M). To this, add SeO2(12.77 g, 115.1 mmol) and reflux at 105-110 °C for 5 h. Then, filter the reaction mass under hot condition over celite, then concentrate the volatiles to get crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione.

[0289] 7-bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10- one (7):

[0290] Then, dissolve the crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 in ice AcOH (210 mL, 0.25 mmol) and to this, add 3-bromophenol 6 (9.96 g, 57.5 mmol) and keep under reflux for another 12 h. Concentrate the reaction mass and dissolve in EA (500-600 mL). Filter it over celite and wash the residue with EA. Wash the filtrate with water (200 mL x 2) and brine (100 mL). Dry it over anhydrous Na2SO4and concentrate to get crude product. Purify the crude product by silica gel column chromatography (35-40% EA in hexane) twice to get pure product.

[0291] 7-bromo-9b-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10- one (8):

[0292] Dissolve 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) in DCM (520 mL, 0.2 M) and at room temperature, add oxalyl chloride (11 mL, 0.13 mol). To this, slowly add DMF (40 mL, 0.53 mol) (0.05 mL / min for 30 min and 0.1 mL / min for 30 min, then fast) and allow it to stir at ambient temperature (30 °C). Then, stir the reaction mixture at room temperature (20 °C) for another 12 h. Dilute the reaction mixture with water (~300 mL). Extract the aqueous layer with DCM (~500 mL x 2). Wash the combined organic layer with water (~300 mL) and brine (~300 mL). Dry it over anhydrous Na2SO4and concentrate to get crude product. Purify the crude product by silica gel column chromatography (10-30% EA in hexane) to get pure product.

[0293] 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one (9):

[0294] 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one (9):

[0295] (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b- yl)carbamic acid tert-butyl ester (10):

[0296] 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[l,2-b]benzofuran-10-one 9 (10.1 g, 31 mmol) in THF (5.0 mL, 5.0 M) and stirred for an additional 72 h at 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 get pure product.

[0297] (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b- yl)carbamic acid tert-butyl ester (10):

[0298] Racemic mixture of tert-butyl (7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 10 (10.3 g, 21.5 mmol) was dissolved in EtOH:water (10:1, 110.0 mL, 0.20 M) and to it was added Fe powder (3.57 g, 63.9 mmol) followed by concentrated HCl (0.8 mL, cat.). It was refluxed at 90 °C for another 3 h. The reaction mass was filtered through celite using hot EA (50 mL-100 mL) at warm conditions. The filtrate was concentrated and dissolved in EA (~1000 mL-1200 mL) and washed with water (~300 mL-500 mL) and brine (~300 mL). It was dried over anhydrous Na2SO4and concentrated to get the crude. The crude was purified by silica gel column chromatography (10%-30% EA / hx) to get the pure product.

[0299] 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):

[0300] 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): +and 3060 mg of ((4bS,9bS)-l-amino-7-bromo-4b-hydroxy-10-oxo-9b,10- dihydro-4bH-indeno[l,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (13) (peak 1, tR8.97 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] + .

[0301] Scheme-2

[0302]

[0303] Intermediates (14 and 18) were prepared according to literature reported in J. Am. Chem. Soc. 2013, 135, 82-85.

[0304] ((1S,2S)-2-methylcyclopropyl)boronic acid (15):

[0305] 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 diethyl ether (100 mL x 3), the combined ether layer was washed with water and dried over Na2S04and the solvent was evaporated at low temperature to get the product. The crude was used for the next step without purification.

[0306] 6-methyl-2-((1S,2S)-2-methylcyclopropyl)-l,3,6,2-dioxazaborocane-4,8-dione (17):

[0307] To a solution of ((1S,2S)-2-methylcyclopropyl)boronic acid 15 (800 mg, 8.0 mmol) in toluene:DMSO (80 mL) was added 2,2'-(methylazanediyl)diacetic acid 16 (1.766 mg, 12 mmol) and the resulting reaction mass was refluxed under Dean-Stark conditions for 3 h. Toluene was evaporated under vacuum, the organic layer was diluted with water and the aqueous layer was extracted with ethyl acetate (100 mL x 3), the combined organic layer was washed with water and dried over Na2S04and the solvent was evaporated to get the crude. The crude was triturated with diethyl ether, the solid was filtered off and washed with diethyl ether to get the product.

[0308] ((1R,2R)-2-methylcyclopropyl)boronic acid (19):

[0309] 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 x 3), the combined organic layers were washed with water (x 1), dried over anhydrous Na2SO4and concentrated at low temperature to give the crude product. The crude product was used in the next step without purification.

[0310] 6-methyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione (20):

[0311] 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) was added 2,2'-(methylazanediyl)diacetic acid 16 (13.3 g, 90.5 mmol) followed by refluxing under Dean-Stark conditions for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL). The organic layer was washed with water (200 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated. To the residue was added diethyl ether, which resulted in the desired product. 1 H NMR (300 MHz, CDC13) δ 3.92 (d, J = 16.6 Hz, 2H), 3.72 (dd, J = 16.6, 4.8 Hz, 2H), 3.04 (s, 3H), 1.10 (d, J = 5.8 Hz, 3H), 0.70 (dt, J = 11.3, 5.7 Hz, 1H), 0.47 - 0.35 (m, 1H), 0.34 - 0.22 (m, 1H), -0.61 (dt, J = 9.2, 6.1 Hz, 1H).

[0312] Scheme-3

[0313]

[0314] methyl tosylate (23):

[0315] Glycine methyl ester hydrochloride 21 (50.0 g, 398.2 mmol) was dissolved in DCM (800 mL). Then p-toluenesulfonyl chloride 22 (75.9 g, 398.2 mmol) was added slowly. The reaction mixture was cooled to 0 °C. Then DIPEA (208 mL, 1194.7 mmol) was 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 1 N HC1, the aqueous layer was extracted with DCM (500 mL x 3) and the combined organic layers were washed with water (500 mL) and brine (200 mL). The organic layer was dried over Na2S04, the solvent was evaporated to give the crude product. The crude product was purified by trituration with DCM:Hex to give the product.

[0316] 3-hydroxy-3-methyl-1 -toluene sulfonyl pyrrolidine-2-carboxylic acid methyl ester (25):

[0317] Tosyl glycine methyl ester 23 (58.50 g, 240.5 mmol) and methyl vinyl ketone 24 (26 mL, 529.0 mmol) were dissolved in THF (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 diethyl ether (1000 mL). The organic phase was washed with 1 N HC1 solution. Once the pH of the aqueous phase was acidic, the organic phase was washed with 5% Na2C03 solution and water until the pH was neutral. The organic phase was dried over anhydrous Na2S04 and evaporated under vacuum to give the product. The crude product was used for the next step without purification.

[0318] 3-methyl-1 -toluene sulfonyl-4,5-dihydro-1 H-pyrrole-2-carboxylic acid methyl ester (26):

[0319] 3-hydroxy-3-methyl-1 -toluene sulfonyl pyrrolidine-2-carboxylic acid methyl ester 25 (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 diethyl ether (5 times) and the combined organic layers were washed with 5% HC1 solution, once the pH of the aqueous layer was acidic, the organic layer was washed with 5% Na2C03 solution, then with water until the pH was neutral. The organic layer was dried over anhydrous Na2S04 and evaporated under vacuum. The crude product was purified by silica gel column chromatography to give the product.

[0320] 3-methyl-1 H-pyrrole-2-carboxylic acid methyl ester (27):

[0321] Methyl 3-methyl-l-tosyl-4,5-dihydro-lH-pyrrole-2-carboxylate 26 (30 g, 102 mmol) was dissolved in THF (204 mL) and 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 diethyl ether. The organic layer was washed with IN HC1, then 5% NaHC03, then water. The organic layer was dried over Na2S04and evaporated to get crude product. The crude product was filtered through a plug of silica gel and the solvent was evaporated to get the product.

[0322] Methyl 3-methyl-4-(methylthio)-lH-pyrrole-2-carboxylate (28):

[0323] Methyl 3-methyl-lH-pyrrole-2-carboxylate 27 (460 mg, 3.3 mmol) and CuI (314 mg, 0.5 mmol) were dissolved in DMSO (3.3 mL, 1.0 M). Then to this dimethyl disulfide (0.531 mL, 6.0 mmol) was added and heated at 110 °C for another 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 Na2S04and concentrated to get crude product. The crude product was purified by silica gel column chromatography (10-15% EA in hexane) to get the product.

[0324] Methyl 3-methyl-4-(methylsulfonyl)-lH-pyrrole-2-carboxylate (29):

[0325] Methyl 3-methyl-5-(methylthio)-lH-pyrrole-2-carboxylate 28 (185 mg, 1.0 mmol) was dissolved in MeOH (10 mL) and to this 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 another 3 h at room temperature (25 °C). The volatiles were then removed under reduced pressure and the solid in water suspension was extracted with EA (70 mL x 2) using an amount of water to dissolve only the inorganics. The combined organic layers were washed with water (30 ml) and brine (30 ml). This was dried over anhydrous Na2S04and concentrated to get crude product. The crude product was purified by silica gel column chromatography (30-40% EA in hexane) to get the pure product.

[0326] 3-methyl-4-(methylsulfonyl)-lH-pyrrole-2-carboxylic acid (30):

[0327] To a solution of ethyl 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylate 29 (390 mg, 1.68 mmol) in H2O:THF (17 mL) was added LiOH.H2O (353 mg, 8.4 mmol). The resulting reaction mass was then stirred at 80 °C for 12 h. The reaction mass was acidified with 1 N HC1, the precipitated solid was extracted with ethyl acetate (100 mL x 2), the combined organic layer was washed with water and washed with brine solution. The organic layer was dried over anhydrous Na2SO4, the solvent was evaporated to get the product which was used as such for the next step without purification.

[0328] Scheme-4

[0329]

[0330] ((4bR,9bR)-1 -amino-4b-hydroxy-7-((1 R,2R)-2-methylcyclopropyl)-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (31):

[0331] ((4bR,9bR)-1 -amino-4b-hydroxy-7-((1 R,2R)-2-methylcyclopropyl)-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (31):

[0332] (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-(1 R,2R)-2-methylcyclopropyl)-4b,9b-dihydro-10H- indeno[1,2-b]benzofuran-10-one hydrochloride (32):

[0333] ((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester 31 (70 mg, 0.21 mmol) was dissolved in DCM (2 mL). To this was added a solution of 4N HC1 in 1,4-dioxane (0.6 mL, 2.1 mmol). The reaction mass was stirred at room temperature (30 °C) for 12 h. The solvent was evaporated under vacuum to get the crude product. The crude was used without purification.

[0334] 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):

[0335] 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid 30 (48 mg, 0.23 mmol) was dissolved in DMF (4 mL, 0.05 M). To this was added HATU (111 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) 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 and the organic layer was dried over Na2S04and the solvent was evaporated to get the crude product. The crude was purified by silica gel column chromatography and again by ADH chiral column chromatography to get the product. 1 H-NMR (300 MHz, MeOD) δ 0.66-0.72 (m, 1H), 0.78-0.84 (m, 1H), 0.95-1.03 (m, 1H), 1.13 (d, J = 6.0 Hz, 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 = 8.1 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 2.27 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 7.43-7.49 (m, 1H). LCMS: 508.4 [M+H] + .

[0336] 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

[0337]

[0338] This compound was prepared similarly to the above compound. LCMS: 420.2 [M+H] + .

[0339] 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-hydroxypyridine amide

[0340]

[0341] This compound was prepared similarly to Example 1 above. LCMS: 458.2 [M+H] + .

[0342] 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):

[0343]

[0344] Scheme-5

[0345]

[0346] 4b,9b-Dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10- one (35):

[0347] To a solution of 4-nitro-1H-indene-1,3(2H)-dione (4) (250 g, 1.31 mole) in 1,4-dioxane (2 L) and AcOH (200 mL), SeO2(291 g, 2.62 mole) was added at room temperature and maintained at 110 °C for 4 h more under reflux. It was stirred at room temperature for another 12 h. Then 500 g - 600 g of celite was added to it. It was stirred and filtered through celite pad. The residue was washed with ethyl acetate (300 mL - 500 mL). The obtained filtrate was concentrated to get crude product 5, which was used as such for further use. 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude, 1.31 mole) was dissolved in ice AcOH (2 L) and 3-isopropylphenol 34 (196 g, 1.44 mole) was added and maintained at reflux for 10 h more. Then it was concentrated and purified by silica gel column chromatography (30% EA in hexane) to get pure product.

[0348] 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10- one (37):

[0349] 4b,9b-dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 35 (50 g, 0.147 mole) was dissolved in DCM (500 mL) and then oxalyl chloride (1.2 eq) was added to this suspension in a single batch. Then DMF (50 mL) was slowly added to it. The reaction mass was stirred at room temperature for another 6 h. It was quenched with water (500 mL) and the layers were separated. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic layer was washed with water (300 mL) and brine (300 mL). It was dried over sodium sulfate and concentrated to get crude material which was purified by short silica pad (30% ethyl acetate in hexane) to get pure product. 1 H-NMR (300 MHz, CDC13): δ 1.18 (dd, J = 3.6 Hz, J = 6.9 Hz, 6H), 2.84 (heptet, J = 6.9 Hz, 1H), 6.34 (s, 1H), 6.70 (s, 1H), 6.94 (dd, J = 1.0 Hz, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.81-7.83 (m, 1H), 8.21 (m, 1H), 8.52 (m, 1H).

[0350] 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10- one (37):

[0351] Dissolve 9b-chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H- indeno[l,2-b]benzofuran-10-one 36 (36.0 g, 0.1 mole) in THF (350 mL) and cool to -40 °C. Add to this clear solution a 2.0 M solution of NH3 in IPA (100 mL, 0.20 mole) using a dropping funnel and keep the temperature below -20 °C. Monitor the reaction mass at -20 °C for one hour and then allow it to warm to room temperature. Stir it at room temperature until the reaction is complete and then concentrate completely. Dissolve the crude in ethyl acetate (500 mL) and wash with water (200 mL x 2) and brine (100 mL). Dry it over anhydrous Na2S04and concentrate to get the crude material which is purified over a short silica pad to get the pure product. 1 H-NMR (300 MHz, CDC13) δ 1.18 (d, J = 6.9 Hz, 6H), 2.84 (septet, J = 6.9 Hz, 1H), 3.46 (s, 1H), 6.25 (s, 1H), 6.74 (s, 2H), 6.90 (dd, J = 1.2 Hz, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 8.22 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 8.52 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H).

[0352] Scheme-6

[0353]

[0354] Acetic acid 3-nitrobutan-2-yl ester (39):

[0355] Dissolve 3-nitrobutan-2-ol 38 (7.5 g, 63 mmol) in DCM (37.5 mL, 1.7 M) and add acetic anhydride (11.3 mL, 120 mmol) followed by DMAP (305 mg, 2.52 mmol). After stirring for another 24 hours at room temperature (20 °C), quench the reaction mass with MeOH (8 mL) and stir for another 1 hour. Then dissolve it in DCM (250 mL) and wash with saturated NaHC03(100 mL x 2), water (100 mL) and brine (~ 100 mL). Dry it over anhydrous Na2S04and concentrate to get the pure product as an oil.

[0356] Formylglycine ethyl ester (41):

[0357] To a solution of glycinate 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 another 24 h or 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 get the product which was used as such in the next step. NMR indicated that the product contained TEA. As the next step used excess TEA, it was used as such in the next step.

[0358] 2-isocyanoacetic acid ethyl ester (42):

[0359] To a solution of formyl glycine ethyl ester 41 (9.40 g, 80 mmol) and TEA (28 mL, 0.2 mol) in DCM (80 mL, 1.0 M) was added POCl3(7.5 mL, 80 mmol) slowly dropwise at 0 °C. The solution turned red and then it was allowed to reach room temperature after the addition was complete and stirred for another 4 h. The reaction mass was then quenched slowly over Na2CO3solution and solid Na2CO3and stirred for another 30 min at room temperature. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL x 2). The combined organic layers were then washed with water (100 mL) and brine (100 mL). It was dried over anhydrous Na2SO4and concentrated to get the pure product as a liquid.

[0360] 3,4-dimethyl-lH-pyrrole-2-carboxylic acid ethyl ester (43):

[0361] Acetic acid 3-nitrobutan-2-yl ester 39 (8.9 g, 55.0 mmol) and 2-isocyanoacetic acid ethyl ester 42 (8.1 g, 71.5 mmol) were dissolved in THE: water (1:1, 110 mL, 0.5 M) and anhydrous K2CO3(12.2 g, 88.0 mmol) was added portionwise slowly to it with vigorous stirring and then the reaction mass was stirred for another 3 days at room temperature. The reaction mass was then concentrated to a thick slurry. It was then diluted with ice cold water (100 mL) and then neutralized slowly with 5% HC1 (2N, pH = 5) at 0 °C. It was then extracted with EA (150 mL x 3). The combined organic layers were washed with 5% brine (100 mL x 2). It was then dried over anhydrous Na2SO4and concentrated to get the crude. The crude was purified by silica gel column chromatography (0%-10% EA in hexane) to get the pure product.

[0362] 5-(chlorosulfonyl)-3,4-dimethyl-lH-pyrrole-2-carboxylic acid ethyl ester (44):

[0363] Ethyl 3,4-dimethyl-lH-pyrrole-2-carboxylate 43 (1.67 g, 10.0 mmol) was dissolved in CHCl3(40 mL, 0.25 M) and to this was added chlorosulfonic acid (10.0 mL, 150.0 mmol) at 0 °C. The reaction mass was stirred for another 3 h at 0 °C. The reaction mass was quenched with crushed ice (120 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL). It was dried over anhydrous Na2S04and concentrated to get the crude product. The crude was passed through a short pad of silica gel in DCM and the filtrate was concentrated to get the pure product.

[0364] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-lH- pyrrole-2-carboxylate (46):

[0365] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-lH- pyrrole-2-carboxylate (46):

[0366] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-lH- pyrrole-2-carboxylate (46):

[0367] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-lH- pyrrole-2-carboxylate (46):

[0368] Scheme-7

[0369]

[0370] (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-pyrrol-2-yl)sulfonamido)ethyl)amino- carbamic acid tert-butyl ester (48):

[0371] (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-pyrrol-2-yl)sulfonamido)ethyl)amino- carbamic acid tert-butyl ester (48):

[0372] (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-pyrrol-2-yl)sulfonamido)ethyl)amino- carbamic acid tert-butyl ester (48):

[0373] 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-pyrrol-2- sulfonyl)amino)ethyl)carbamate 48 (275 mg, 0.4 mmol) was dissolved in DCM (8 mL, 0.05 M) and to it was added 4 M HC1 in dioxane (1.0 mL, 4.0 mmol). It was stirred at room temperature (25 °C) for 15 h. The reaction was diluted with DCM (20 mL) and stirred with saturated NaHC03(20 mL) for 10 min. The free amine did not release well and so 0.5 mL TEA was added. It was then diluted with DCM (100 mL) and the layers were separated. The organic layer was washed with saturated NaHC03(20 mL), water (30 mL), and brine (30 mL). It was dried over anhydrous Na2S04and concentrated to a solid.

[0374] 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):

[0375] 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):

[0376] 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):

[0377] To a solution of 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) in EtOH:water (10:1, 5.0 mL, 0.015 M) was added iron powder (13 mg, 0.23 mmol) followed by 1 M HC1 (3 drops). It was refluxed at 90 °C for another 1.5 h. The reaction was cooled to 50 °C, then it was neutralized with TEA (1 drop). The reaction mixture was then filtered through celite under hot condition using EA (20 mL). The filtrate was concentrated and dissolved in EA (100 mL) and washed with water (20 mL) and brine (20 mL). It was dried over anhydrous Na2S04and 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 (300 MHz, CD3OD) δ 1.19 (d, J = 6.9 Hz, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 2.43 (s, 6H), 2.65 (t, J = 6.6 Hz, 2H), 2.82 (hept, J = 6.9 Hz, 1H), 3.06 (t, J = 6.6 Hz, 2H), 6.69 (s, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.45-7.50 (m, 1H). LCMS: 582.3 [M+H] + .

[0378] 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)

[0379]

[0380] Scheme 8

[0381]

[0382] 2-(1-cyclopropylethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54):

[0383] To a reaction flask was added anhydrous lithium chloride (7.06 g, 166.5 mmol), CuCl (16.5 g, 166.5 mmol) and anhydrous N,N-dimethylformamide (500 mL) under nitrogen and the mixture was stirred at room temperature for 1 h before adding potassium acetate (16.4 g, 166.5 mmol), B2Pin2 53 (42.3 g, 166.5 mmol) and cyclopropylethynyl 52 (10 g, 151.3 mmol) sequentially and continued stirring at room temperature for 20 h. The reaction mass was quenched with saturated NH4Cl solution (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 layer was collected, washed with water (100 mL x 3) and brine (100 mL), dried over Na2SO4, the solvent was evaporated under vacuum to get the crude product. The crude product was purified by silica gel column chromatography (hexane) to get the product as an oil.

[0384] Scheme-9

[0385]

[0386] tert-Butyl 2-(azetidin-l-yl)acetate (57):

[0387] Azetidine hydrochloride 56 (73 g, 78 mmol) was dissolved in THF: water (4: 1, 170 mL, 0.3 M) and cooled to 0 °C. To this was added 2N NaOH aqueous solution (78 mL, 157 mmol) and stirred for 10 min. Then to this was added tert-butyl 2-bromoacetate 55 (7.2 mL, 49 mmol) dropwise at 0 °C and allowed to stir for another 1 h at 30 °C. Then the reaction mixture was extracted with EA (150 mL x 2) and the combined organic layer was washed with saturated brine (~ 50 mL). This was dried over anhydrous Na2SO4and concentrated to get the crude product as a liquid.

[0388] 2-(azetidin-l-yl)acetic acid hydrochloride (58):

[0389] tert-Butyl 2-(azetidin-l-yl)acetate 57 (6.7 g, 39 mmol) was cooled to 0 °C and 4M HC1 in dioxane (98 mL, 0.4 M) was added slowly. Then the reaction mixture was stirred at room temperature (30 °C) for another 24 h. The precipitated solid was then filtered off, washed with cold 1,4-dioxane (~ 20 mL - 30 mL) and dried to get the pure product.

[0390] Scheme-10

[0391]

[0392] ((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (60):

[0393] 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 placed in a sealed tube and toluene:water (5:1, 75 mL, 0.10 M) that had been purged with nitrogen was added. The reaction mixture was purged again with N2(10 min) and then 2-(1- cyclopropylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 54 (2.15 g, 11.3 mmol) was added and held at 90 °C for an additional 3 h. The reaction mixture was passed through a bed of celite and concentrated. It was dissolved in EA and water and the layers were separated. The organic layer was dried over anhydrous Na2SO4and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (20-30% EA in hexanes) to give the pure product.

[0394] ((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (60):

[0395] 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 placed in a sealed tube and toluene:water (5:1, 75 mL, 0.10 M) that had been purged with nitrogen was added. The reaction mixture was purged again with N2(10 min) and then 2-(1- cyclopropylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 54 (2.15 g, 11.3 mmol) was added and held at 90 °C for an additional 3 h. The reaction mixture was passed through a bed of celite and concentrated. It was dissolved in EA and water and the layers were separated. The organic layer was dried over anhydrous Na2SO4and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (20-30% EA in hexanes) to give the pure product.

[0396] (4bR,9bR)-1,9b-diamino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro-10H- indeno[1,2-b]benzofuran-10-one (61):

[0397] ((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester 60 (2.18 g, 5.00 mmol) was dissolved in DCM (50 mL, 0.1 M) and immediately added 4.0 M HC1 in dioxane (12.5 mL, 50.0 mmol). The reaction mixture was then stirred at room temperature (20 °C) for an additional 6 h. The reaction mixture was diluted with EA (~ 150 mL) and stirred with saturated NaHC03(~ 100 mL) for 5-10 min.

[0398] 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 Na2S04and concentrated to give the product which was used as is in the next step without further purification.

[0399] 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):

[0400] To a solution of 2-(azetidin-1-yl)acetic acid hydrochloride 58 (1.02 g, 6.75 mmol) in 45 mL of anhydrous DMF (0.1 M) was added HATU (2.57 g, 6.75 mmol) and DIPEA (2.35 mL, 13.5 mmol) at 0 °C. After 10 min, (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) was added and stirred at room temperature (20 °C) for 15 h. The reaction was quenched with water (~ 100 mL) and saturated NaHC03(~ 100 mL). It was extracted with EA (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), brine (100 mL), and dried over anhydrous Na2S04and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% - 10% MeOH in DCM) to give the pure product. 1H-NMR (500 MHz, MeOD) δ 7.50-7.39 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.85 (dd, J = 8.0, 1.3 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 1.3 Hz, 1H), 3.37 (t, J = 7.3 Hz, 4H), 3.18 (s, 2H), 2.09 (p, J = 7.1 Hz, 2H), 1.91-1.83 (m, 1H), 1.25 (d, J = 7.0 Hz, 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 [M-H] - . LCMS: 434.2 [M+H] + .

[0401] 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.

[0402]

[0403] This compound was prepared in analogy to Example 5 described above. LCMS: 522.2 [M+H] + .

[0404] 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-carboxamide.

[0405]

[0406] This compound was prepared in analogy to Example 5 described above. LCMS: 522.2 [M+H] + .

[0407] 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-hydroxypyridinecarboxamide

[0408]

[0409] This compound was prepared in analogy to example 5 above. LCMS: 458.1 [M+H] + .

[0410] Example 9: N-(l-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin- 1-yl)sulfonyl)-lH-pyrrole-2-carboxamide (83):

[0411]

[0412] Scheme-11

[0413]

[0414] 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (64):

[0415] To a solution of 3-hydroxybenzaldehyde (30 g, 0.25 mol) and imidazole (21.7 g, 0.32 mol) in anhydrous dichloromethane (250 mL) was added slowly tert-butyldichlorodimethylsilane (44.4 g, 0.30 mol) 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 MgS04, filtered and concentrated. The residue was purified on a silica gel column eluting with EA / hexane (0 / 100 -> 1 / 10) to give the desired product. 1 HNMR (300 MHz, CDC13) δ 9.95 (s, 1H), 7.40 (tdd, J = 21.4, 12.8, 9.5 Hz, 3H), 7.11 (ddd, J = 7.9, 2.5, 1.2 Hz, 1H), 1.00 (s, 9H), 0.23 (d, J = 3.0 Hz, 6H).

[0416] (E)-tert-butyldimethyl(3-(prop-l-en-l-yl)phenoxy)silane (66):

[0417] 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, 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 (300 MHz, CDCl3) δ 7.14 (td, J = 7.8, 2.8 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 6.22 (m, 1H), 1.88 (d, J = 6.1 Hz, 3H), 0.99 (d, J = 2.6 Hz, 9H), 0.20 (d, J = 2.6 Hz, 6H).

[0418] tert-Butyldimethyl(3-((trans)-2-methylcyclopropyl)phenoxy)silane (67):

[0419] To anhydrous dichloromethane (150 mL) was added diethylzinc (50 mL, 1.0 M in hexanes, 0.05 mol) dropwise at -40 °C with stirring via cannula. After 10 min, to this reaction mixture was added a solution of diiodomethane (8 mL, 0.1 mol) in anhydrous dichloromethane (25 mL) dropwise at -40 °C. The reaction mixture was stirred at -40 °C for 1 h. To this reaction mixture was added a solution of trichloroacetic acid (0.82 g, 0.005 mol), DME (2.59 mL, 0.025 mol) in anhydrous dichloromethane (25 mL) dropwise at -40 °C. The reaction mixture was stirred at -15 °C for 1 h. To this reaction mixture was added a solution of (E)-tert-butyldimethyl(3-(prop-1-en-1-yl)phenoxy)silane 66 (6.21 g, 0.025 mol) in anhydrous dichloromethane (25 mL) dropwise 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 resulting solid was filtered off, and the filtrate was extracted with dichloromethane, dried over MgS04, 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 geometry as an oil. 1H NMR (300 MHz, CDC13) δ 7.08 (t, J = 7.8 Hz, 1H), 6.60 (m, 2H), 6.48 (t, J = 2.0 Hz, 1H), 1.87 (dd, J = 6.4, 1.3 Hz, 0.20H), 1.51 (dt, J = 8.9, 3.3 Hz, 1H), 1.19 (dd, J = 15.5, 5.8 Hz, 3H), 1.01 (m, 9H), 0.81 (m, 2H), 0.71 (m, 1H), 0.18 (m, 6H).

[0420] 3-((trans)-2-methylcyclopropyl)phenol (68):

[0421] 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 dropwise concentrated HC1 (30 mL) with stirring. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified on a silica gel column and eluted with EA / Hex (1 / 20 -> 1 / 15) to give 3-((1S,2S)-2-methylcyclopropyl)phenol (product). 1 H NMR (300 MHz, CDC13) δ 7.08 (t, J = 7.8 Hz, 1H), 6.60 (m, 2H), 6.48 (t, J = 2.0 Hz, 1H), 1.87 (dd, J = 6.4, 1.3 Hz, 0.20H), 1.51 (dt, J = 8.9, 3.3 Hz, 1H), 1.19 (dd, J = 15.5, 5.8 Hz, 3H), 1.01 (m, 9H), 0.81 (m, 2H), 0.71 (m, 1H), 0.18 (m, 6H).

[0422] 4b,9b-dihydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H- indeno[1,2-b]benzofuran-10-one (69):

[0423] 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 and diluted with ethyl acetate, filtered through a pad of celite, concentrated to give 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 on a silica gel column eluted with EA / hexanes (1 / 2 -> 2 / 3) to give the desired product. 1 H NMR (300 MHz, CDC13) δ 8.48 (dd, J = 8.0, 0.9 Hz, 1H), 8.16 (dd, J = 7.6, 1.0 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.72 (ddd, J = 7.9, 3.9, 1.4 Hz, 1H), 6.45 (m, 1H), 1.50 (m, 1H), 1.12 (m, 3H), 0.98 (m, 1H), 0.81 (dt, J = 14.8, 5.5 Hz, 1H), 0.75 (m, 1H).

[0424] 9b-chloro-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H- indeno[1,2-b]benzofuran-10-one (70):

[0425] 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 anhydrous dichloromethane (143 mL) at room temperature was added dropwise oxalyl chloride (2.90 mL, 0.03 mol). To the reaction mixture was added dropwise anhydrous DMF (10 mL) at room temperature with stirring (~2 h). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane, washed with water, the organic layer was dried over MgS04, filtered, concentrated and purified on a silica gel column eluted with EA / Hex (1 / 4 -> 1 / 2) to give the desired product. 1H NMR (300 MHz, CDC13) δ 8.49 (dd, J = 8.0, 1.1 Hz, 1H), 8.19 (dd, J = 7.7, 1.1 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.75 (dt, J = 8.1, 1.6 Hz, 1H), 6.44 (t, J = 1.4 Hz, 1H), 6.29 (s, 1H), 1.50 (m, 1H), 1.13 (dd, J = 5.7, 1.2 Hz, 3H), 0.99 (m, 1H), 0.82 (dt, J = 12.4, 4.4 Hz, 1H), 0.76 (m, 1H).

[0426] 9b-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro- 10H-indeno[l,2-b]benzofuran-10-one (71):

[0427] To a solution of racemic 9b-chloro-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4- nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran-10-one (6.47 g, 0.017 mol) in dry THF (90 mL) was added dropwise an ammonia solution (26.1 mL, 0.052 mol, 2.0 M in IPA) at -40 °C (~10 min). The reaction mixture was stirred at -40 °C for 1 h, 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 MgS04, filtered, concentrated and purified on a silica gel column eluting with EA / Hex (1 / 2 -> 2 / 3) to give the desired product. 1 H NMR (300 MHz, CDC13) δ 8.49 (dd, J = 8.0, 1.1 Hz, 1H), 8.19 (dd, J = 7.7, 1.1 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.75 (dt, J = 8.1, 1.6 Hz, 1H), 6.44 (t, J = 1.4 Hz, 1H), 6.29 (s, 1H), 1.50 (m, 1H), 1.13 (dd, J = 5.7, 1.2 Hz, 3H), 0.99 (m, 1H), 0.82 (dt, J = 12.4, 4.4 Hz, 1H), 0.76 (m, 1H).

[0428] Scheme-12

[0429]

[0430] 3-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (73):

[0431] To a solution of methyl 3-methyl-lH-pyrrole-2-carboxylate 27 (3.5 g, 25.2 mmol) in anhydrous DMF (63 mL) at 0 °C was added NaH (1.51 g, 37.8 mmol) 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 x 100 mL), the combined organic layers were dried over Na2S04and evaporated under vacuum. The crude was purified by silica gel column chromatography (ethyl acetate: hexane) and the obtained product was recrystallized using DCM and HX.

[0432] 5-(Methoxycarbonyl)-4-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-sulfmic acid (74):

[0433] Methyl 3-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-carboxylate 73 (5.03 g, 18 mmol) was dissolved in THF (180 mL). The resulting solution was cooled to -78 °C and lithium diisopropylamide (18 mL, 36 mmol) was added dropwise at -78 °C and the reaction mass was stirred at -78 °C for another 1 h. To the cold solution at -78 °C, sulfur dioxide (gas) was bubbled slowly for 30 min. The resulting reaction mass was slowly warmed to room temperature and stirred at room temperature for 12 h. The THF was removed under vacuum, the obtained residue was dissolved in water and washed with ethyl acetate (50 mL x 2). The aqueous layer was acidified to pH ~ 1 using 1 N HC1, the aqueous layer was extracted with ethyl acetate (200 mL x 3), the combined organic layers were washed with water and brine solution, the organic layer was dried over Na2S04and the solvent was evaporated to get the product which was used as such for the next step without purification.

[0434] Methyl 5-(chlorosulfonyl)-3-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-carboxylate (75):

[0435] Methyl 5-(chlorosulfonyl)-3-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-carboxylate (75):

[0436] Methyl 5-(chlorosulfonyl)-3-methyl-l-(phenylsulfonyl)-lH-pyrrole-2-carboxylate (75):

[0437] Methyl 5-(chlorosulfonyl)-3-methyl-l-(phenylsulfonyl)-lH-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) and washed with water (50 mL x 3) and dried over Na2S04, solvent was evaporated to get crude. The crude was purified by silica gel column chromatography (ethyl acetate: hexane) to get the product.

[0438] tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-lH-pyrrol-2-yl)sulfonyl)piperazine- 1 -carboxylate (78):

[0439] tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-lH-pyrrol-2-yl)sulfonyl)piperazine- 1 -carboxylate (78):

[0440] 5-((4-(tert-Butoxycarbonyl)piperazin-l-yl)sulfonyl)-3-methyl-lH-pyrrole-2- carboxylic acid (79):

[0441] tert-Butyl 4-((5-(methoxycarbonyl)-4-methyl-lH-pyrrol-2-yl)sulfonyl)piperazine- 1 -carboxylate (78):

[0442] Scheme-13

[0443]

[0444] 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-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (80):

[0445] At 0 °C, EDCI (306 mg, 1.6 mmol) was added 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), followed by HOBt (216 mg, 1.6 mmol). The mixture was stirred for 30 min, and 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 (375 mg, 1.1 mmol) was added, followed by DIPEA (0.6 mL, 3.2 mmol). The reaction mixture 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 then with a brine solution. The organic layer was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the solid product.

[0446] 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):

[0447] 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 4 N HC1 in 1,4- dioxane (0.9 mL, 3.5 mmol) and the reaction was stirred at room temperature (30 °C) for 12 h. The solvent was evaporated under vacuum, water (10 mL) was added and the residue was obtained and basified with 10% NaHC03solution. 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 Na2S04and the solvent was evaporated to obtain the solid product which was used as such in the next step without further purification.

[0448] 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)- 1 H-pyrrole-2-carboxamide (83):

[0449] 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)-1 H-pyrrole-2-carboxamide 81 (100 mg, 0.16 mmol) in ice AcOH:MeCN (1 :1) (4 mL) at 0 °C was added aqueous formaldehyde (35%) (0.15 mL, 1.6 mmol) followed by NaBH3CN (36 mg, 0.6 mmol). The reaction 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 Na2S04and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the solid product.

[0450] 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)- 1 H-pyrrole-2-carboxamide (83):

[0451] 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 Na2SO4and the solvent was evaporated. The crude was purified by silica gel column chromatography to get the product as a solid. 1 H-NMR (300 MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.81-0.89 (m, 1H), 0.98-1.02 (m, 1H), 1.16 (d, J = 5.7 Hz, 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 = 7.2 Hz, 1H), 7.33 (d, J = 6.3 Hz, 1H), 7.46-7.51 (m, 1H). LCMS: 592.2 (M+H] + .

[0452] 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

[0453]

[0454] This compound was prepared in analogy to Example 9 described above. LCMS: 466.4 [M+H] + .

[0455] 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)

[0456]

[0457] Scheme-14

[0458]

[0459] (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1- (phenylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (84):

[0460] 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). The reaction was stirred at 30 °C for 15 h. The reaction mass was diluted with DCM and washed with water and brine, the organic layer was dried over anhydrous Na2SO4and the solvent was evaporated to get the crude. The crude was purified by silica gel column chromatography to get the product as a solid.

[0461] (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2- carboxylic acid (85):

[0462] To a solution of (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1- (phenylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 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 solvent was evaporated. The reaction mixture was acidified with 1 N HC1 solution, the aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine. The organic layer was dried over Na2SO4and the solvent was evaporated under vacuum to get the product as a solid.

[0463] ((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)tert-butyl carbamate (86):

[0464] To a stirred solution of 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 HC1 in 1,4-dioxane (0.6 mL, 2.4 mmol) and the reaction was stirred at room temperature (30 °C) for 12 h. The solvent was evaporated, the residue was dissolved in water (10 mL) and basified with 10% NaHC03solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine and the organic layer was dried over Na2S04. The solvent was evaporated under vacuum to give the product.

[0465] 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):

[0466] To a stirred solution of 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 HC1 in 1,4-dioxane (0.6 mL, 2.4 mmol) and the reaction was stirred at room temperature (30 °C) for 12 h. The solvent was evaporated, the residue was dissolved in water (10 mL) and basified with 10% NaHC03solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine and the organic layer was dried over Na2S04. The solvent was evaporated under vacuum to give the product.

[0467] 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):

[0468] To a stirred solution of racemic mixture of 5-(((S)-3-amino 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 87 (120 mg, 0.2 mmol) in ice AcOH:MeCN = 1:1 (7 mL, 0.03 M) at 0 °C was added formaldehyde (35% aqueous solution) (0.34 mL, 3.9 mmol) followed by NaBH3CN (62 mg, 1.0 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 Na2SO4and the solvent was evaporated under vacuum to get the crude product. The crude product was purified by silica gel column chromatography to get the product.

[0469] 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):

[0470] 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:H2O (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, the obtained residue was dissolved in ethyl acetate, washed with water and brine. The organic layer was dried over Na2SO4and the solvent was evaporated under vacuum to get the crude product. The crude product was purified by silica gel column chromatography to get the product as a solid. 1H-NMR (300 MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.82-0.89 (m, 1H), 0.97-1.07 (m, 1H), 1.16 (d, J = 5.7 Hz, 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), 6.69-6.77 (m, 2H), 7.04 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.47-7.52 (m, 1H). LCMS: 606.3 (M+H] + .

[0471] 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

[0472]

[0473] Scheme-15

[0474]

[0475] 4-((5-(Ethoxycarbonyl)-3,4-dimethyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (123):

[0476] To a solution of ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (530 mg, 2.0 mmol) in DCM (20 mL, 0.1 M) was added tert-butyl piperazine-1-carboxylate (448 mg, 2.4 mmol) followed by DIPEA (0.52 mL, 3.0 mmol) at room temperature. The reaction was stirred at room temperature (25 °C) for another 18 h. The reaction was quenched with water (50 mL) and extracted with DCM (70 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (10-20% EA in hexane) to give the pure product.

[0477] 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3,4-dimethyl-1H-pyrrole-2- carboxylic acid (124):

[0478] tert-Butyl 4-((5-(ethoxycarbonyl)-3,4-dimethyl-1H-pyrrol-2-yl)sulfonyl)piperazine-1- carboxylate (580 mg, 1.4 mmol) was dissolved in THF:MeOH:H2O (1:1:10, 28.0 mL, 0.05 M) and LiOH.H2O (294 mg, 7.0 mmol) was added and the reaction was refluxed at 80 °C for 5 h. The reaction mass was concentrated to remove the volatiles. It was then acidified with 1 N HCI (pH <2-3). The precipitated solid was then filtered, washed with cold water and dried to get the product.

[0479] 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):

[0480] 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):

[0481] 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):

[0482] 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-carboxylate (135 mg, 0.2 mmol) was dissolved in DCM (2.0 mL, 0.1 M) and to it was added 4M HC1 in dioxane (0.50 mL, 2.0 mmol). It was stirred at room temperature (25 °C) for 15 hours. The reaction mass was concentrated and the residue was dissolved in EA (20 mL-30 mL) and stirred with saturated NaHC03(about 20 mL) for 5-10 minutes. It was extracted with EA (50 mL x 2).

[0483] The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2S04and concentrated to get the crude. The crude was used for the next step without further purification.

[0484] 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-carboxylate)-1H-pyrrole-2-carboxamide (127):

[0485] 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-carboxylate)-1H-pyrrole-2-carboxamide (127):

[0486] N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran- 9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-1-carboxylate)-1H-pyrrole-2-carboxamide (128):

[0487] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-l-carbonyl)-lH-pyrrole-2- carboxamide (60 mg, 0.1 mmol) was dissolved in EtOH:water (10: 1, 5.0 mL, 0.02 M) and to it was added Fe powder (17 mg, 0.3 mmol) followed by 6.0 M HC1 (1 drop). It was refluxed at 90 °C for another 2.0 h. The reaction mass was filtered through celite using EA (30 mL) at warm condition. The filtrate was concentrated and dissolved in EA (100 mL) and washed with saturated NaHC03(20 mL x 2), water (20 mL x 2) and brine (20 mL). It was dried over anhydrous Na2S04and concentrated to get the crude. The crude was purified by silica gel column chromatography (0% - 10% MeOH in DCM) to get the pure product.

[0488] 1H NMR (500 MHz, Methanol-d4) d: 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, 6.6 Hz, 1H), 2.51 (br t, J = 4.4 Hz, 4H), 2.29 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H); LCMS: 594.2 (M+H] +

[0489] Example 13: N-(l-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH- indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l-yl)sulfonyl)-lH- pyrrole-2-carboxamide

[0490]

[0491] The above compound was prepared by the following scheme.

[0492] Scheme-16

[0493]

[0494] 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)piperazin-1-yl 4- methylbenzenesulfonate (123)

[0495] To a stirred solution of 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3- methyl-1H-pyrrole-2-carboxylic acid 79 (384 mg, 1.0 mmol) in DMF (10 mL, 0.1 M) was cooled to 0 °C. To this was added EDCI (288 mg, 1.5 mmol) followed by HOBt (203 mg, 1.5 mmol). After 10 min, 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) was added followed by DIPEA (0.43 mL, 2.5 mmol) and allowed to reach room temperature (35 °C) for another 12 h. The reaction mass was then quenched with water (30 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4and concentrated. The crude was purified by silica gel column chromatography (25-30% EA in hexane) to get the product.

[0496] N-(4-((11-azene)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)

[0497] 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 HC1 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, the obtained residue was dissolved in water (50 mL) and basified with saturated solution of NaHC03, the product was extracted with EA (50 mL x 3), the combined organic layers were washed with water and brine solution. The organic layer was dried over anhydrous Na2S04, the solvent was evaporated to get the crude product. The crude was purified by silica gel column chromatography (MeOH:DCM = 1:20) to get the desired product.

[0498] N-(4-((l 1 -azene)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH- indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l-yl)sulfonyl)-lH- pyrrole-2-carboxamide (122-2)

[0499] To a stirred solution of N-(4-((l 1 -azene)peroxy)-4b-hydroxy-7-isopropyl-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-l- ylsulfonyl)-lH-pyrrole-2-carboxamide 122-1 (100 mg, 0.17 mmol) in ice 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), 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 x 3), the combined organic layer was washed with water and brine solution. The organic layer was dried over anhydrous Na2S04, the solvent was evaporated to get the crude product. The crude was purified by silica gel column chromatography (MeOH:DCM = 1:20) to get the desired product.

[0500] N-(l-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran- 9b-yl)-3-methyl-5-((4-methylpiperazin-l-yl)sulfonyl)-lH-pyrrole-2-carboxamide (122-3)

[0501] To a stirred solution of N-(4-((l 1 -azene)peroxy)-4b-hydroxy-7-isopropyl-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l- ylsulfonyl)-lH-pyrrole-2-carboxamide (51 mg, 0.08 mmol) in EtOH:H2O (3 mL) was added Fe powder (14 mg, 0.25 mmol) followed by concentrated HC1 (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, the obtained residue was dissolved in EA (100 mL) and washed with water (50 mL x 2) and brine solution. The organic layer was dried over anhydrous Na2S04, the solvent was evaporated to get the crude product. The crude was purified by silica gel column chromatography to get the desired product. 1H NMR (300 MHz, MeOD) δ 7.42-7.33 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.81-6.72 (m, 1H), 6.69 (s, 1H), 6.52 (s, 1H), 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 = 6.9 Hz, 6H). Mass: [M+H] + : 580.1

[0502] Example 14: N-((4bR,9bR)-l-amino-4b-hydroxy-7-((lS,2S)-2-methylcyclopropyl)-10- oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4- methylpiperazin-l-yl)sulfonyl)-lH-pyrrole-2-carboxamide

[0503]

[0504] Scheme-17

[0505]

[0506] This compound was prepared in analogy to Example 12, according to the above scheme, using 3,4-dimethylpyrrole derivative. (300 MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.81-0.89 (m, 1H), 0.98-1.02 (m, 1H), 1.16 (d, J = 5.7 Hz, 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 = 7.2 Hz, 1H), 7.33 (d, J = 6.3 Hz, 1H), 7.46-7.51 (m, 1H). LCMS: 592.1 (M+H]+, HPLC purity: 95.4%

[0507] Example 15: (2S,3S)-N-((4bR,9bR)-l-amino-7-((S)-l-cyclopropylethyl)-4b-hydroxy-10- oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3- hydroxybutanamide

[0508] This compound was prepared in analogy to Example 12, according to the above scheme, using 3,4-dimethylpyrrole derivative. (300 MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.81-0.89 (m, 1H), 0.98-1.02 (m, 1H), 1.16 (d, J = 5.7 Hz, 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 = 7.2 Hz, 1H), 7.33 (d, J = 6.3 Hz, 1H), 7.46-7.51 (m, 1H). LCMS: 592.1 (M+H]+, HPLC purity: 95.4%

[0509] The compound was prepared similarly to that in Example 12 above. LCMS: 466.3 [M+H] + .

[0510] 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

[0511]

[0512] The compound was prepared similarly to that in Example 12 above. LCMS: 508.3 [M+H] + .

[0513] 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-(azacyclobutane-1-yl)acetamide (92)

[0514]

[0515] Plan-18

[0516]

[0517] ((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)tert-butyl carbamate (90):

[0518] Under nitrogen atmosphere, tert-butyl carbamate 59 (174 mg, 0.40 mmol) was dissolved in DCM (8.0 mL, 0.05 M) and [((4R,5R)-Cy2-UBaphox)Ir(COD)]BARF (13.9 mg, 0.008 mmol) was added. The mixture was then purged with H2 gas and maintained at room temperature (20 °C) under H2 atmosphere (60 psi) for 4 hours. The reactants were then concentrated and passed through a short silica plug. The concentrate yielded a crude product. The crude product was purified by silica gel column chromatography, and then purified by preparative HPLC (ADH column (Diacel 250×20mm), EtOH:MeOH:hexane = 36:4:60).

[0519] (4bR,9bR)-1,9b-diamino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro- 10H-indeno[1,2-b]benzofuran-10-one (91):

[0520] 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 dissolved in DCM (1.6 mL, 0.1 M) and immediately added 4.0 M HC1 in dioxane (0.40 mL, 1.60 mmol). The reaction mixture was then stirred at room temperature (20 °C) for another 6 hours. The reaction mixture was diluted with EA (~ 50 mL) and stirred with saturated NaHC03(~ 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 Na2S04and concentrated to give the crude solid product which was used as is in the next step without further purification.

[0521] 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):

[0522] To a solution of 2-(azetidin-1-yl)acetic acid hydrochloride 58 (34 mg, 0.23 mmol) in 1.5 mL of anhydrous DMF (0.1 M) was added HATU (87.5 mg, 0.23 mmol) and DIPEA (79 μL, 0.23 mmol) at 0 °C. After 10 min, (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) was added and stirred at room temperature (20 °C) for 15 h. The reaction was quenched with water (~ 20 mL) and saturated NaHC03(~ 30 mL). It was extracted with EA (50 mL x 3). The combined organic layers were washed with water (30 mL x 2), brine (30 mL), dried over anhydrous Na2S04and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% - 10% MeOH in DCM) to give the solid product. 1H-NMR (300 MHz, MeOD) δ 7.51-7.39 (m, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.85 (dd, J = 7.9, 1.3 Hz, 1H), 6.78-6.65 (m, 2H), 3.38 (t, J = 7.2 Hz, 4H), 3.19 (s, 2H), 2.14-2.03 (m, 2H), 1.91-1.84 (m, 1H), 1.25 (d, J = 7.0 Hz, 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 [M-H] - . LCMS: 434.3 [M+H] + .

[0523] 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

[0524]

[0525] This compound was prepared in analogy to Example 15 described above. LCMS: 475.1 [M+H] + .

[0526] Example 19 and Example 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):

[0527]

[0528] Scheme-19

[0529]

[0530] 4b,9b-dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one (94):

[0531] Dissolve 4-nitro-lH-indene-l,3(2H)-dione 4 (10.0 g, 52.3 mmol) in AcOH:dioxane (1:10, 105 mL, 0.5 M). To this, add SeO2(12.77 g, 115.1 mmol) and reflux at 105-110 °C for 5 h. Then, filter the reaction mass under hot condition over celite and then concentrate the volatiles to get crude 2,2-dihydroxy-4-nitro-lH-indene-l,3(2H)-dione 5. Dissolve this crude in acetic acid (106 mL) and add to this 3-isopropoxyphenol 93 (8.1 g, 53 mmol). Heat the resulting reaction mass at 80 °C for 4 h. Cool the reaction mass to room temperature and dilute with ethyl acetate. Filter the reaction mass over a bed of celite and wash with ethyl acetate. Evaporate the solvent to dryness and purify the residue by silica gel column chromatography (ethyl acetate:hexane) to get the solid product.

[0532] 9b-chloro-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one (95):

[0533] Dissolve 4b,9b-dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one 94 (5.4 g, 15 mmol) in DCM (75 mL). To this, add oxalyl chloride (2.6 mL, 30 mmol) followed by dropwise addition of DMF (5.4 mL). Stir the reaction mass at room temperature for 18 h. Dilute the reaction with DCM (300 mL) and wash the organic layer with water (200 mL x 2) and brine solution and then dry over Na2SO4. Evaporate the solvent to get the crude product. Purify the crude product by silica gel column chromatography (ethyl acetate:hexane) to get the solid product.

[0534] 9b-amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran- 10-one (96):

[0535] This compound was prepared analogously to compound 37 described above.

[0536] 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)carbamoyl)-4-methyl-lH-pyrrol-2-yl)sulfonyl)piperazin-l-yl)acetic acid ( 99):

[0537] Dissolve 5-((4-(tert-butoxycarbonyl)piperazin-l-yl)sulfonyl)-3-methyl-lH-pyrrole-2- carboxylic acid 79 (240 mg 0.65 mmol) in DMF (6.5 mL). Cool the resulting solution to 0 °C and add EDCI (187 mg, 0.975 mmol), HOBT (132 mg, 0.975 mmol) and DIPEA (0.283 mL, 1.625 mmol) at 0 °C. Stir the reaction mass for 30 min. Then add 9b-amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H- indeno[l,2-b]benzofuran-10-one 96 (232 mg, 0.65 mmol) and stir the reaction at 30 °C for 15 h. Quench the reaction mass with water (100 mL) and extract the aqueous layer with ethyl acetate (3 x 100 mL). Wash the combined organic layers with water and wash with brine solution and dry over Na2S04. Evaporate the solvent under vacuum. Purify the residue by silica gel column chromatography (methanol:DCM) to get the solid product.

[0538] N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran- 9b-yl)-3-methyl-5-(piperazin-l-ylsulfonyl)-lH-pyrrole-2-carboxamide (98):

[0539] Dissolve 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)carbamoyl)-4-methyl-lH-pyrrol-2-yl)sulfonyl)piperazin-l-yl)acetic acid tert-butyl ester 97 (145 mg, 0.2 mmol) in DCM (4 mL). To this solution add 4M HC1 in dioxane (0.5 mL). Stir the clear solution at room temperature for 15 h. Evaporate the DCM under vacuum. Dissolve the residue in water (100 mL) and neutralize the aqueous solution with saturated NaHC03solution. Extract the aqueous layer with ethyl acetate (100 mL x 2) and wash the combined organic layers with water and wash with brine solution. Dry the organic layer over Na2S04and evaporate the solvent to get the crude solid product. The crude was used as such in the next step without purification.

[0540] 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):

[0541] 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 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 it 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 to 5 °C for 1.5 h. The acetonitrile was evaporated and the residue was quenched with water and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water then with brine solution. The organic layer was dried over Na2SO4and the solvent was evaporated to get the crude product. The crude product was purified by silica gel column chromatography (methanol: DCM) to get the solid product.

[0542] 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):

[0543] 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 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 it 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 to 5 °C for 1.5 h. The acetonitrile was evaporated and the residue was quenched with water and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water then with brine solution. The organic layer was dried over Na2SO4and the solvent was evaporated to get the crude product. The crude product was purified by silica gel column chromatography (methanol: DCM) to get the solid product. 1H-NMR (300 MHz, CD30D) δ 1.28 (dd, J = 6 Hz, J = 1.6 Hz, 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 = 7.2 Hz, 1H), 7.34 (br, 1H), 7.47-7.52 (m, 1H). LCMS: 596.5 [M+1] + .

[0544] N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2- b]benzofran-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]benzofran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2- carboxamide (102):

[0545] N-(l-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l-yl)sulfonyl)-lH-pyrrole-2- carboxamide (100) as a racemate was purified by chiral chromatography using (IA column, HPLC = 20 ml / min, heptane / EtOH = 30 / 70, 2562 psi) to give 37.5 mg of N-((4bR,9bR)-l-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH- indeno[l,2-b] -benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l-yl)sulfonyl)-lH- pyrrole-2-carboxamide (101) (peak 2, tR 16.32 min.),1H NMR (methanol-d4) δ: 7.43-7.53 (m, 1H), 7.39 (br d, J = 12.3 Hz, 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, 5.9 Hz, 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)-l-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10- dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-l- yl)sulfonyl)-lH-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 = 5.9 Hz, 1H), 6.67-6.82 (m, 1H), 6.53 (s, 2H), 6.36 (br s, 1H), 4.54 (dt, J = 11.9, 6.1 Hz, 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] + .

[0546] Example 21: N-(l-amino-4b-hydroxy-7-((lS,2R)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)- lH-pyrrole-2-carboxamide

[0547]

[0548] Scheme-19B

[0549]

[0550] N-[9-hydroxy-5-[(lS,2R)-2-methylcyclopropyl]-l l-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-methylsulfonyl-3-methyl-lH-pyrrole-2-carboxamide (19B-1):

[0551] Into a 50 mL round bottom flask, was placed 5-methylsulfonyl-3-methyl-lH- 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), l-amino-9-hydroxy-5-[(lS,2R)-2- methylcyclopropyl]-l l-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). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This resulted in 250 mg (55%) of N-[9-hydroxy-5-[(lS,2R)-2-methylcyclopropyl]-l l-nitro-16-oxo-8- oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadeca-2(7),3,5,10,12,14-hexaen-l-yl]- 5-methylsulfonyl-3-methyl-lH-pyrrole-2-carboxamide (19B-1) as a yellow solid.

[0552] 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):

[0553] Into a 50-mL round-bottom flask, was placed N-[9-hydroxy-5-[(1S,2R)-2- methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexa- 2(7),3,5,10,12,14-hexen-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), hydrogen chloride (0.1 mL). The resulting solution was stirred at 85 °C in an oil bath for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This resulted in 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).

[0554] 1 H NMR (300 MHz, 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 (stereochemistry on cyclopropane is relative to absolute unknown)

[0555] Example 22, Example 29, and Example 30: N-(l-amino-7-((R)-l- cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)- 1,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazole-4-carboxamide (29), N-((4bR,9bR)-l- amino-7-((R)-l-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)-l,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazole-4-carboxamide (22), and N-((4bS,9bS)-l-amino-7-((R)-l-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10- dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-l,5-dimethyl-2-oxo-2,3-dihydro-lH- imidazole-4-carboxamide (30)

[0556]

[0557] Scheme-19C

[0558]

[0559] (lR)-l-[3-(benzyloxy)phenyl]ethan-l-ol (19C-1):

[0560] Into a 100 mL 3-necked round-bottom flask, was placed l-[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), (lR,2R)-TsDpen (330 mg, 0.89 mmol, 0.02 equiv), HC02H (6.1 g, 3.00 equiv). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (20 / 80). This resulted in 4 g (40%) of (lR)-l-[3-(benzyloxy)phenyl]ethan-l-ol as a colorless oil.

[0561] (lR)-l-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate (19C-2):

[0562] Into a 50 mL round-bottom flask, was placed (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 in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (15 / 85). This resulted in 5.3 g (97%) of (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate as a yellow oil.

[0563] 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (19C-3):

[0564] Into a 500 mL 3-necked round-bottom flask, was placed (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propan-2-yl)carbamate (5.3 g, 14.91 mmol, 1.00 equiv), diethyl ether (100 mL), and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 29.75 mmol, 2.00 equiv). Then LDA (14.9 mL, 2 mol / L, 2.00 equiv) was added dropwise at -20 °C. The resulting solution was stirred at room temperature for 12 h. Then the reaction was quenched by the addition of methanol. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (15 / 85). This resulted in 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.

[0565] 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene (19C-4):

[0566] Into a 100 mL round-bottom flask, was placed 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 in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (10 / 90). This resulted in 2.4 g (90%) of 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene as a yellow oil.

[0567] 3-[(1R)-1-cyclopropylethyl]phenol (19C-5):

[0568] Into a 100 mL round-bottom flask, was placed 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 H2atmosphere for 2 h. The solids were filtered off. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (15 / 85). This resulted in 1.3 g (96%) of 3-[(1R)-1-cyclopropylethyl]phenol as a colorless oil.

[0569] 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):

[0570] Into a 100 mL round-bottom flask, was placed 3-[(1R)-1-cyclopropylethyl]phenol (1.3 g, 8.01 mmol, 1.00 equiv), acetic acid (20 mL), and 2,2-dihydroxy-4-nitro-2,3-dihydro-1H-indene-1,3-dione (1.8 g, 8.07 mmol, 1.00 equiv). The resulting solution was stirred at 120 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (30 / 70). This resulted in 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.

[0571] 1 -chloro-5-[(1 R)-1 -cyclopropylethyl]-9-hydroxy-11 -nitro-8- oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]pentadeca-2(7),3,5,10,12,14- hexene-16-one (19C-7):

[0572] Into a 100 mL round bottom flask, was placed 5-[(1 R)-1 - cyclopropylethyl]-1,9-dihydroxy-11 -nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]pentadeca-2(7),3,5,10,12,14-hexene-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 in vacuo. This resulted in 4.5 g (crude) of 1 -chloro-5-[(1 R)-1 -cyclopropylethyl]-9-hydroxy-11 -nitro-8- oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]pentadeca-2(7),3,5,10,12,14-hexene-16- one as a brown oil.

[0573] 1 -chloro-5-[(1 R)-1 -cyclopropylethyl]-9-hydroxy-11 -nitro-8- oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]pentadeca-2(7),3,5,10,12,14- hexene-16-one (19C-7):

[0574] Into a 250 mL round bottom flask, was placed 1 -chloro-5-[(1 R)-1 - cyclopropylethyl]-9-hydroxy-11 -nitro-8-oxatetracyclo[7.7.0.0^[2.7].0^[10.15]]pentadeca-2(7),3,5,10,12,14-hexene-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 in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (35 / 65). This resulted in 3.5 g (82%) of 1 -amino-5-[(1 R)-1 -cyclopropylethyl]-9-hydroxy-11 -nitro-8- oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]pentadeca-2(7),3,5,10,12,14-hexene-16- one as a yellow solid.

[0575] 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):

[0576] Into a 50 mL round bottom flask, was placed 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-hexen-16-one (2.5 g, 6.82 mmol, 1.00 equiv), and triethylamine (2.3 mL, 3.00 equiv). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This resulted in 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-hexen-1-yl]-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide as a yellow solid.

[0577] 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):

[0578] Into a 25 mL round bottom flask, was placed N-[5-[(1R)-1- cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetra- cyclo[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 (120 g, 237.86 mmol, 1.00 equiv), ethanol (10 mL), iron (40 mg, 0.72 mmol, 3.00 equiv), water (1 mL), concentrated hydrogen chloride (0.01 mL). The resulting solution was stirred at 85 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography with DCM / MeOH (25 / 1). This gave 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).

[0579] 1 H NMR (300 MHz, 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

[0580] 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):

[0581] N-(l-amino-7-((R)-l-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH- indeno[l,2-b]benzofuran-9b-yl)-l,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazole-4- carboxamide (19C-10) as a racemate was purified by chiral chromatography using (IA column, HPLC = 20 ml / min, heptane / IPA = 60 / 40) to give 42.8 mg of N-((4bR,9bR)-l-amino-7-((R)-l-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10- dihydro-4bH-indeno[l,2-b]benzofuran-9b-yl)-l,5-dimethyl-2-oxo-2,3-dihydro-lH- 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 = 7.0 Hz, 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, 4.7 Hz, 1H), 1.04 (dq, J = 9.5, 4.8 Hz, 1H); LCMS: 475.2 [M+H]+and 35.8 mg of N-((4bS,9bS)-l-amino-7-((R)-l-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10- dihydro-4bH-indeno[l,2-b]benzofuran-9b-yl)-l,5-dimethyl-2-oxo-2,3-dihydro-lH- imidazole-4-carboxamide (19C-12) (peak 2, tR 16.43 min.);1H NMR (500 MHz, methanol-d4) δ: 7.38-7.51 (m, 2H), 7.01 (br d, J = 6.9 Hz, 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 = 7.1 Hz, 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, 4.8 Hz, 1H), 0.06 (dq, J = 9.4, 4.8 Hz, 1H); LCMS: 475.2 [M+H]+.

[0582] Example 23: N-(l-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH- indeno[l,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-lH-pyrrole-2-carboxamide

[0583]

[0584] Scheme-19D

[0585]

[0586] 1-[3-(benzyloxy)phenyl]ethan-1-one (19D-1):

[0587] Into a 500 mL round bottom flask was placed a solution of 1-(3- hydroxyphenyl)ethan-1-one (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). The resulting solution was stirred at 80 °C in an oil bath for 2 h. The solids were filtered off. The reaction was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This resulted in 30.5 g (92%) of 1-[3-(benzyloxy)phenyl]ethan-1-one as a yellow oil.

[0588] 2-[3-(benzyloxy)phenyl]butan-2-ol (19D-2):

[0589] Into a 250 mL round bottom flask was placed a solution of 1-[3- (benzyloxy)phenyl]ethan-1-one (5 g, 22.10 mmol, 1.00 equiv) and THF (100 mL), then bromo(ethyl)magnesium (22 mL, 3.00 equiv) was added at 0 °C. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 300 mL of water. The resulting solution was extracted with 3 x 200 mL of chloromethane. The organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1). This resulted in 3.1 g (55%) of 2-[3-(benzyloxy)phenyl]butan-2-ol as a colorless oil.

[0590] 1-(benzyloxy)-3-(butan-2-yl)benzene (19D-3):

[0591] Into a 250 mL 3 necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-[3-(benzyloxy)phenyl]butan-2-ol (6.2 g, 24.19 mmol, 1.00 equiv) in dichloromethane (120 mL), followed by the addition of triethylsilane (18.2 mL, 5.00 equiv) and trifluoroacetic acid (18.05 mL, 1.00 equiv). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 100 mL of water and extracted with 3 x 50 mL of dichloromethane. The organic layers were combined and concentrated in vacuo. The residue was applied onto a silica gel column with petroleum ether (100%) This resulted in 3.8 g (65%) of 1-(benzyloxy)-3-(butan-2-yl)benzene as a yellow oil.

[0592] 3-(Butan-2-yl)phenol (19D-4):

[0593] Into a 100 mL round bottom flask was placed 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 H2at room temperature for 2 h. The solids were filtered off. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 / 20). This resulted in 2.0 g (84%) of 3-(butan-2-yl)phenol as a yellow solid.

[0594] 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):

[0595] Into a 100 mL round bottom flask was placed 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 in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 / 2). This resulted in 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.

[0596] 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-hexene-16-one (19D-6):

[0597] Into a 50 mL round bottom flask was placed a solution 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-hexene-16-one (1.37 g, 3.86 mmol, 1.00 equiv) in dichloromethane (20 mL), oxalyl chloride (1.1 mL, 3.00 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was stirred at 40 °C in an oil bath for 2 h. The reaction was then quenched by the addition of 50 mL of water / ice. The resulting solution was extracted with 3 x 100 mL of dichloromethane. The organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 5). This resulted in 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-hexene-16-one as a brown oil.

[0598] 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-hexene-16-one (19D-7):

[0599] Into a 50 mL round bottom flask was placed 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-hexene-16-one (1.2 g, 3.21 mmol, 1.00 equiv) in tetrahydrofuran (18 mL). Subsequently, NH3 in IPA (4.8 mL, 3.00 equiv) was added at -50 °C. The resulting solution was stirred at -40 °C to 10 °C for 1.5 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 2). This resulted in 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-hexene-16-one as a yellow solid.

[0600] 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 (19D-8):

[0601] A 25 mL round bottom flask was charged with 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-hexen-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 at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This resulted in 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.

[0602] 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):

[0603] Into a 50-mL round-bottom flask, was placed a solution of N-[5-(butan-2-yl)-9- hydroxy-11-nitro-16-oxo-8-oxatetra cyclo[7.7.0.0^[2,7].0^[10,15]] pentadeca-2(7),3,5, 10,12,14-hexaen-1-yl]-4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (140 mg, 0.26 mmol, 1.00 equiv) in ethanol (5 mL), water (0.5 mL), Fe (40.32 mg, 3.00 equiv), and hydrogen chloride (0.05 mL). The resulting solution was stirred at 85 °C in an oil bath for 2 h. The solid was filtered off. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with dichloromethane / methanol (20 / 1). This resulted in 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).

[0604] 1 HNMR (300 MHz, 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 = 6.9 Hz, 3H), 0.90-0.78 (m, 3H); LC-MS: (ES, m / z): [M+H] + :510.1

[0605] 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

[0606]

[0607] This compound was prepared in analogy to Example 18 described above. LCMS: 592.3 [M+H] + .

[0608] 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):

[0609] This compound was prepared in analogy to Example 18 described above. LCMS: 592.3 [M+H]

[0608] 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):

[0609]

[0610] Scheme-20

[0611]

[0612] 2-(hydroxyamino)malonic acid dimethyl ester (104):

[0613] To glacial acetic acid (55 mL) was added malonic acid dimethyl ester 103 (21.7 mL, 190 mmol) followed by dropwise addition of a solution of sodium nitrite (26.2 g, 380 mmol) in 70 mL of water (over ~2 h) with stirring. 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 5% sodium bicarbonate solution until the aqueous solution became weakly basic. The organic layer was dried over Na2S04, the solvent was evaporated to get the product as a solid. The crude was used for the next step without further purification.

[0614] 3,5-dimethyl-lH-pyrrole-2-carboxylic acid methyl ester (106):

[0615] To a solution of acetylacetone 105 (10.3 mL, 100 mmol) in acetic acid (40 mL) at 95 °C was added a solution of 2-(hydroxyimino)malonic acid dimethyl ester 104 (17 g, 105 mmol) in 20 mL of acetic acid and 10 mL of water gradually along with zinc dust (26 g, 400 mmol). 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 off, washed with water, dried in air at room temperature, dissolved in DCM, filtered off from zinc dust residue, concentrated, and dried in air at room temperature. The product was dissolved in DCM and filtered through a pad of silica gel and washed with DCM. The solvent was evaporated to get the product.

[0616] 4-(chlorosulfonyl)-3,5-dimethyl-lH-pyrrole-2-carboxylic acid methyl ester (107):

[0617] 3,5-dimethyl-lH-pyrrole-2-carboxylic acid methyl ester 106 (383 mg, 2.5 mmol) was dissolved in chloroform (0.25 M) and the clear solution was cooled to 0 °C. To this cold solution was added chlorosulfonic acid (2.5 mL, 37.5 mmol) slowly. The reaction was stirred at 0 °C for 2.5 h. The reaction mass was poured slowly into ice-cold water. The product was extracted with DCM (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine solution (50 mL), dried over anhydrous Na2S04, and the solvent was evaporated to get the crude. The crude was dissolved in DCM and filtered through a plug of silica gel and washed with DCM to get the product.

[0618] 3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxylic acid methyl ester (108):

[0619] Methyl 4-(chlorosulfonyl)-3,5-dimethyl-lH-pyrrole-2-carboxylate 107 (377.5 mg, 1.5 mmol) was dissolved in THF (15 mL) and cooled to -10 °C. To this was added a solution of NH3 in THF (5 mL) prepared by bubbling ammonia gas into THF at -20 °C. The reaction mass was slowly warmed to room temperature and stirred for 2 h. THF was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL x 3) and dried over Na2S04. The solvent was evaporated to give a crude product. The residue was purified by trituration with DCM and filtered to give the product.

[0620] 3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxylic acid (109):

[0621] To a solution of methyl 3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxylate 108 (255 mg, 1.1 mmol) in MeOH:H20 (1 : 10) (11 mL) was added LiOH.H20 (461.6 mg, 11 mmol). The reaction mass was stirred at room temperature for 12 h. MeOH was removed in vacuo and the aqueous layer was diluted with water (10 mL) and acidified to pH ~ 1 using 1 N HC1. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water and washed with brine solution, dried over Na2S04and the solvent was evaporated to give a solid product which was used as such in the next step without purification.

[0622] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxamide (110):

[0623] Dissolve 3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxylic acid 109 (200 mg 0.91 mmol) in DMF (9 mL) and cool the resulting solution to 0 °C. Add EDCI (216.7 mg, 1.365 mmol), HOBT (184.5 mg, 1.365 mmol) and DIPEA (0.396 mL, 2.275 mmol) at 0 °C and stir the reaction mass for 30 min. Then add 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran-10-one 37 (312 mg, 0.91 mmol) and stir the reaction mixture at 30 °C for 15 h. Quench the reaction with water (100 mL) and extract with ethyl acetate (3 x 50 mL). Wash the combined organic layer with brine solution and dry over Na2S04and evaporate in vacuum, the crude is purified by column chromatography (methanol:DCM) to get (110).

[0624] N-(l-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxamide (111):

[0625] To a solution of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-lH-pyrrole-2-carboxamide 110 (110 mg, 0.2 mmol) in EtOH-water mixture (1:1, 7 mL) add Fe powder (33.5 mg, 0.6 mmol) and concentrated HC1 (1 drop). Reflux the resulting solution at 90 °C for 3 h. Filter the hot reaction mass through a pad of celite and wash with ethyl acetate. Evaporate the organic layer under vacuum. Dissolve the obtained residue in ethyl acetate (100 mL) and wash with water (50 mL x 2) then with brine solution. Dry the combined organic layer over Na2S04and evaporate the solvent under vacuum to get the crude. Purify the crude by silica gel column chromatography (methanol:DCM) to get the product. (300 MHz, CD3OD) δ 1.2 (dd, J = 6.2 Hz, J = 0.9 Hz, 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] + LCMS: 511.5 [M+H]

[0626] Example 26: N-(l-amino-4b-hydroxy-7-((lR,2S)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)- lH-pyrrole-2-carboxamide

[0627]

[0628] This compound was prepared in analogy to Example 26 above. LCMS: 508.0 [M+H] + .

[0629] Example 27: N-(l-amino-4b-hydroxy-7-((lS,2R)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)- lH-pyrrole-2-carboxamide

[0630]

[0631] This compound was prepared in analogy to Example 26 above. LCMS: 508.2 [M+H] + .

[0632] Example 28: N-((4bR,9bR)-l-amino-4b-hydroxy-7-(lS,2S)-2-methylcyclopropyl)- 10-oxo-4b,10-dihydro-9bH-indeno[l,2-b]benzofuran-9b-yl)-3-methyl-4- (methylsulfonyl)-lH-pyrrole-2-carboxamide

[0633]

[0634] Scheme 22

[0635]

[0636] tert-Butyl ((S)-l-(((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro- 9bH-indeno[l,2-b]benzofuran-9b-yl)amino)-l-oxo-3-phenylpropan-2- yl)carbamate (113):

[0637] (tert-butoxycarbonyl)-L-phenylalanine 112 (4.80 g, 16.4 mmol) was dissolved in DMF (110 mL, 0.15 M) and cooled to 0 °C. EDCI (4.73 g, 24.7 mmol) was then added, followed by HOBt (3.33 g, 24.7 mmol). The mixture was stirred for another 20 minutes, and 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) was added, followed by DIPEA (8.6 mL, 49.3 mmol). The mixture was stirred at 30 °C for another 24 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and then with 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 to obtain the product and other isomers.

[0638] (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-phenylpropionamide (114):

[0639] ((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-phenylpropane-2-yl)tert-butyl carbamate 113 (1.475 g, 2.36 mmol) was dissolved in DCM (47 mL). A dioxane solution of HCl (5.9 mL, 23.6 mmol) was added to the resulting solution, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness, the residue was dissolved in water, and the aqueous layer was alkalized with an aqueous solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (150 mL × 2), and the combined organic layers were washed with water (100 mL) and then with a brine solution. The combined organic layers were dried with Na2SO4 and the solvent was evaporated under vacuum to obtain a crude product, which was used as is in the next step without purification.

[0640] (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-phenylthiourea)propionamide (116):

[0641] Isocyanosulphenylbenzene 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[l,2-b]benzofuran-9b-yl)-3-phenylpropanamide 114 (1.25 g, 2.36 mmol) in DCM (24 mL) at 0 °C. The reaction mass was then 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 a crude product. The crude product was purified by short silica gel column chromatography (ethyl acetate: hexane) to give the product.

[0642] (4bS,9bS)-9b-Amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[l,2- b]benzofuran-10-one (117):

[0643] (S)-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,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 allowed to warm to 50 °C for 12 h. DCM was evaporated and the obtained residue was dissolved in water. The aqueous layer was basified by saturated NaHC03solution and then extracted with ethyl acetate. The combined organic layers were dried over Na2S04and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane) to give the product.

[0644] ((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[l,2- b]benzofuran-9b-yl)carbamic acid tert-butyl ester (118):

[0645] (4bS,9bS)-9b-Amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[l,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 h. The reaction mass was evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate: hexane) to give the product.

[0646] ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2- b]benzofuran-9b-yl)carbamic acid tert-butyl ester (12):

[0647] ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2- b]benzofuran-9b-yl)carbamic acid tert-butyl ester (12):

[0648] ((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester (119):

[0649] To a degassed solution of ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10- dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester 12 (326 mg, 0.73 mmol) in toluene (12.5 mL), water (2.5 mL) was added 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.

[0650] The resulting reaction mixture was purged with N2for 10 min, then the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture 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 Na2SO4and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane) to give the product.

[0651] (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1 S,2S)-2-methylcyclopropyl)- 4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride (120):

[0652] ((4bR,9bR)-1-amino-4b-hydroxy-7-((1 S,2S)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamic acid tert-butyl ester 119 (250 mg 0.59 mmol) was dissolved in DCM (12 mL). To this solution was added HC1 in dioxane (1.5 mL, 5.9 mmol) and the reaction was stirred for 12 h. The reaction was evaporated to dryness to give the product (crude) which was used as such in the next step.

[0653] N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1 S,2S)-2-methylcyclopropyl)-10-oxo- 4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)- 1 H-pyrrole-2-carboxamide (121):

[0654] Dissolve 3-methyl-4-(methylsulfonyl)-lH-pyrrole-2-carboxylic acid 30 (97.6 mg 0.48 mmol) in DMF (8 mL). Cool the resulting solution to 0 °C. Add HATU (28.2 mg, 0.60 mmol) and DIPEA (0.210 mL, 1.2 mmol) at 0 °C and stir the reaction mass for 30 min. Then add (4bR,9bR)-l,9b-diamino-4b-hydroxy-7-((lS,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[l,2-b]benzofuran-10- one hydrochloride 120 (144 mg, 0.4 mmol) and stir the reaction at 30 °C for 15 h. Quench the reaction with water (100 mL) and extract the aqueous layer with ethyl acetate (2 x 100 mL). Wash the combined organic layer with water and brine solution, dry over Na2S04and evaporate the solvent under vacuum. Purify the crude product by silica gel column chromatography (MeOH:DCM) followed by purification by preparative HPLC (ethanol:hexane) to get the product. (300 MHz, MeOD) δ 0.66-0.72 (m, 1H), 0.78-0.84 (m, 1H), 0.95-1.03 (m, 1H), 1.13 (d, J = 6.0 Hz, 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 = 8.1 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 2.27 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 7.43-7.49 (m, 1H). LCMS: 508.1 [M+H] + .

[0655] The biological activity of the compounds of the application was determined using the following methods. The cytopathic effect (CPE) inhibition assay was used Determination of drug efficacy against picornaviruses

[0656] In the assay, HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblast cells) and RD cells (derived from human rhabdomyosarcoma) were used. For comparison, ribavirin (Riv), pleco and BTA-798 (BTA) were used as controls. The reagents were dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 10 mg / ml - 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 a concentration of 3 to 5 times, so that the concentration of dimethyl sulfoxide in each well was between 0.5% and 1%.

[0657] A virus-induced cytopathic effect (CPE) inhibition assay is used to determine drug efficacy. In this regard, after growing cells suitable for the virus in a 96-well plate, a dilution of the virus in DME supplemented with 2% FBS (DME / 2% FBS) or MEM supplemented with 2% FBS (MEM / 2% FBS) is inoculated into each well of the plate in an amount of 1001 at a concentration corresponding to 100 CCID50(50% cell culture infective dose) and incubated at 33°C or 37°C for 30 minutes to 1 hour to allow the virus to adsorb onto the cells. The medium is removed and aliquots of drug dilutions at various concentrations are added to each well in an amount of 100 μl. When HRV (human rhinovirus) is grown at 33°C, the other viruses are incubated in a 37°C CO2incubator for 2 to 3 days. Alternatively, the cells are incubated for 2 to 3 days without removing the medium after adding 50 μl of each drug dilution at a concentration that is 2-fold higher, followed by adding 50 μl of the virus dilution. The virus is incubated in the host HeLa cells in DME / 2% or MEM / 2% FBS at 37°C for 2 to 3 days.

[0658] For HeLa cells, the EC 50 (50% maximum effective concentration) is determined using an MTT assay, which is the drug concentration that induces half of the response between the baseline and the maximum. For RD and MRC-5 cells, the FDA (fluorescein diacetate) or MTT assay CPE is used. To determine the effect of drug toxicity on the efficacy results, mock infections are also included at the time of virus inoculation. Virus-free medium is added to the cell culture and then subjected to the same treatment as the mock infected cells inoculated with the virus. That is, the medium is removed after one hour of incubation and the drug dilution in medium is added again. After 2 to 3 days of incubation, the cells are observed under a microscope and the CC 50 (50% cytotoxic concentration) at which 50% of the cells are killed, where the number of viable cells in the mock infected wells containing the drug is compared to the number of viable cells in the control wells that do not contain the drug. In the FDA hydrolysis assay, FDA is added to each well after the medium is removed and incubated for 20 to 30 min, and then the CPE is determined using a spectrophotofluorimeter in the same manner as MTT to measure the fluorescence intensity.

[0659] That is, the survival rate (survival %) of the mock infected cells for cytotoxicity measurement is calculated using the following mathematical formula 1:

[0660] Cell drug = survival x [A(drug) - A(blank solution) / A(cell control) - A(blank x 100% solution)]

[0661] While 100% cell survival means that the drug is not cytotoxic, the highest cytotoxicity is reflected by 0% cell survival. The 50% cytotoxicity concentration is defined as the concentration required to reduce the cell number by 50%. This concentration of the drug is expressed as CC50. A higher value means lower cytotoxicity.

[0662] Furthermore, the antiviral effect can be calculated using the following mathematical formula 2: Antiviral effect = [A(drug / virus) - A(virus control) / A(cell control) - A(virus control)]

[0663] If the survival rate is 100%, it has an antiviral effect of 100%, while if the survival rate is 0%, it has no antiviral effect. Although the EC 50 The lower the value, the better the antiviral effect, as calculated for the drug concentration at which the cells in the wells infected with the virus can exhibit a 50% survival rate.

[0664] The LC 50 concentrations at which cytotoxicity against the compounds is exhibited in some embodiments, and the EC 50 concentrations at which activity against a variety of rhinoviruses belonging to the picornavirus family is exhibited.

[0665] Determination of drug effect against picornaviruses using a multi-cycle cytopathic effect (CPE) reduction assay

[0666] The multi-cycle CPE reduction assay is used to perform the determination of the efficacy of the drugs against picornaviruses. The antiviral activity of the compounds is initially determined by a CPE reduction assay based on MIS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].

[0667] In particular, 100 50% cell culture infective doses (CCID 50 ) of virus are used to infect cells grown to confluence in 96-well plates. After adsorption for 2 hours at 37°C, the virus is removed and serial dilutions of the compounds are added. The cultures are further incubated for 3 days at 37°C until complete CPE is observed in the infected and untreated virus controls (VC). After removal of the medium, 90 μl of medium and 10 μl of MTS-pheazine methosulfate (Promega, Leiden, The Netherlands) are added to each well. After incubation for 2 hours at 37°C, the optical density (OD) of each well is read in a microplate reader at 498 nm.

[0668] The CPE% value used to assess the antiviral activity is calculated using the following mathematical formula 3:

[0669] CPE% = 100 x [OD(CC) - OD(virus + compound) / OD(CC) - OD(VC)]

[0670] The CPE% value for measuring the cytotoxicity of a drug was calculated by the following mathematical formula 4:

[0671] CPE% = 100 x [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)]

[0672] In the above mathematical formulas 3 and 4,

[0673] OD(CC) represents the OD of a background cell culture which is neither induced by a virus nor chemically treated,

[0674] OD(VC) represents the OD of a control cell culture which is induced by a virus but not chemically treated,

[0675] OD(virus + compound) represents the OD of a cell culture infected by a virus which has been treated with a concentrated compound,

[0676] OD(compound) represents the OD of a cell culture treated only with a concentrated compound, and

[0677] OD(blank) represents the OD of a well to which only a cell culture was added.

[0678] The effective concentration (EC 50 ) represents the drug concentration at which 50% of cells survive the CPE induced by a virus, and the cytotoxic concentration (CC 50 ) represents the drug concentration at which 50% of cells are killed by a compound, and they are calculated by logarithmic interpolation.

[0679] The cytotoxic concentrations (CC 50 ) and the effective concentrations (EC 50 ) of some compounds of Examples against various viruses are listed in Table 1 below.

[0680] Table 1: Table of biological activity data

[0681]

[0682]

[0683] As shown in Table 1 above, most of the compounds according to the present application exhibit high CC 50 concentrations, and thus are found to have low cytotoxicity. In addition, the compounds according to the present application are mostly found to have high antiviral activity against various rhinoviruses (HRV).

[0684] Accordingly, since the compounds in the embodiments according to the present application exhibit low cytotoxicity and high antiviral activity against various rhinoviruses, they can be effectively used in a pharmaceutical composition for preventing or treating a disease caused by the picornaviruses to which they belong.

[0685] Accordingly, since the compounds in the embodiments according to the present application have low cytotoxicity and exhibit antiviral activity against the picornaviruses to which coxsackievirus, poliovirus and rhinovirus belong, they can be effectively used in a pharmaceutical composition for preventing or treating a disease caused by such viruses, for example, a respiratory disease, a circulatory disease of the heart and a nervous system disease, including poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media.

[0686] Since the compounds represented by the chemical formula according to the present application in balance with each other not only have low cytotoxicity but also have high antiviral activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus, they can be effectively used as a pharmaceutical composition for preventing or treating a viral disease such as poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-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

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or an optical isomer thereof: in, G 1 It is a C3-C4 cycloalkyl group, wherein the C3-C4 cycloalkyl group can be substituted by one, two, or three independent substituents selected from straight-chain or branched C1-C3 alkyl groups; or G 1 It is a straight-chain or branched C1-C4 alkyl, or a straight-chain or branched C1-C4 alkoxy, wherein the C1-C4 alkyl and C1-C4 alkoxy are substituted with cyclopropyl; L represents a chemical bond or CH2; E is a)-CH(CHOHCH3)(NMe2); or b) A 4-6 membered heterocyclic group containing one or two nitrogen atoms or a 5-6 membered heteroaryl group containing one nitrogen atom, wherein the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one to three substituents independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl, -OH, =O, -SO2R; wherein each R is independently selected from straight-chain or branched C1-C3 alkyl, a 5-6 membered heterocyclic group containing one or two nitrogen atoms, and NR. 1 R 2 The 5-6 membered heterocyclic group is optionally surrounded by a C1-C3 alkyl group or NR. 3 R 4 replace; Each R 1 and R 2 Independently selected from H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally NR 3 R 4 Replace; and Each R 3 and R 4 It is independently selected from H or methyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the compound has formula (II):

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the compound has formula (III):

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein L is a chemical bond.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein E is -CH(CHOHCH3)(NMe2).

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein E is a 5-6 heteroaryl group containing a nitrogen atom, wherein the 5-6 heteroaryl group is optionally substituted by one to three substituents independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl groups, -OH and -SO2R.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein G 1 It is a straight-chain or branched C1-C4 alkyl group substituted with cyclopropyl group.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein G 1 It is a C3-C4 cycloalkyl group that is optionally substituted by one, two or three independent substituents selected from straight-chain or branched C1-C3 alkyl groups.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein G 1 It is a straight-chain or branched C1-C4 alkoxy group substituted with cyclopropyl group.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the compound has formula (Ia): Where A 1 Choose from the group consisting of: H, straight-chain or branched C1-C3 alkyl groups, and SO2R; and A 2 Choose the group consisting of the following items: H and SO2R.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein A 1 It is either methyl or SO2CH3.

12. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein A 2 The designation is SO2R, and R is selected from the group consisting of: CH3; 5-6 membered heterocyclic groups containing one or two nitrogen atoms and substituted with CH3 or N(CH3)2; and NR. 1 R 2 .

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the compound has the formula (Ib): Where Y is H or CH3.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the compound has the formula (Ic): Where X is cyclopropyl.

15. The compound of claim 13 or claim 14, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein L is a chemical bond.

16. The compound according to claim 13 or claim 14, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein E is –CH(CHOHCH3)(NMe2), or Wherein E is a 5-6 heteroaryl group containing a nitrogen atom, wherein the 5-6 heteroaryl group is optionally substituted by one to three substituents independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl, -OH and -SO2R.

17. A compound of formula (Ib) or a pharmaceutically acceptable salt thereof or an optical isomer thereof: Where Y is H or CH3; L represents a chemical bond or CH2; E is a)-CH(CHOHCH3)(NMe2); or b) A 4-6 membered heterocyclic group containing one or two nitrogen atoms or a 5-6 membered heteroaryl group containing one nitrogen atom, wherein the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are each substituted by one to three independent substituents selected from the group consisting of: Straight-chain or branched C1-C3 alkyl, -OH, =O, -SO2R; wherein each R is independently selected from straight-chain or branched C1-C3 alkyl, 5-6 membered heterocyclic groups containing one or two nitrogen atoms, and NR. 1 R 2 The 5-6 membered heterocyclic group is optionally surrounded by a C1-C3 alkyl group or NR. 3 R 4 replace; Each R 1 and R 2 Independently selected from H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally NR 3 R 4 Replace; and Each R 3 and R 4 It is independently selected from H or methyl.

18. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof or an optical isomer thereof: Where X is cyclopropyl; L represents a chemical bond or CH2; E is a)-CH(CHOHCH3)(NMe2); or b) A 4-6 membered heterocyclic group containing one or two nitrogen atoms or a 5-6 membered heteroaryl group containing one nitrogen atom, wherein the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are each substituted by one to three independent substituents selected from the group consisting of: Straight-chain or branched C1-C3 alkyl, -OH, =O, -SO2R; wherein each R is independently selected from straight-chain or branched C1-C3 alkyl, 5-6 membered heterocyclic groups containing one or two nitrogen atoms, and NR. 1 R 2 The 5-6 membered heterocyclic group is optionally surrounded by a C1-C3 alkyl group or NR. 3 R 4 replace; Each R 1 and R 2 Independently selected from H and C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally NR 3 R 4 Replace; and Each R 3 and R 4 It is independently selected from H or methyl.

19. The compound of claim 17 or claim 18, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein L is a chemical bond.

20. The compound according to claim 17 or claim 18, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein E is –CH(CHOHCH3)(NMe2), or Wherein E is a 5-6 heteroaryl group containing a nitrogen atom, wherein the 5-6 heteroaryl group is optionally substituted by one to three substituents independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl, -OH and -SO2R.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein the compound is selected from...

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein the compound is selected from the group consisting of:

23. Use of the compound or a pharmaceutically acceptable salt thereof or an optical isomer thereof according to any one of claims 1 to 21 in the preparation of a medicament for the prevention or treatment of a viral disease, wherein the viral disease is caused by a microRNA virus.

24. A pharmaceutical composition for the prevention or treatment of viral diseases, said pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

25. A combination comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof or an optical isomer thereof, or a pharmaceutical composition according to claim 24, and one or more therapeutically active agents.

26. Use of the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a pharmaceutical composition of claim 24, or a combination of claims 25, in the preparation of a medicament for treating a viral disease, wherein the viral disease is caused by a microRNA virus.

27. Use of the compound of claim 21 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, or a pharmaceutical composition of claim 24 or a combination of claim 25, in the preparation of a medicament for the prevention or treatment of a viral disease, wherein the viral disease is caused by a microRNA virus.

28. The use according to claim 26 or 27, wherein the viral disease is caused by Coxsackievirus.

29. The use according to claim 26 or 27, wherein the viral disease is caused by poliovirus.

30. The use according to claim 26 or 27, wherein the viral disease is caused by echovirus.

31. The use according to claim 26 or 27, wherein the viral disease is caused by an enterovirus.

32. The use according to claim 26 or 27, wherein the viral disease is caused by a rhinovirus.

33. The use according to claim 26 or 27, wherein the viral disease is poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, herpetic pharyngitis, foot-and-mouth disease, pneumonia, sinusitis, or otitis media.

34. Use of the compound of claim 22 or a pharmaceutically acceptable salt thereof or an optical isomer thereof in the preparation of a medicament for the prevention or treatment of a viral disease, wherein the viral disease is caused by a microRNA virus.

35. A pharmaceutical composition for the prevention or treatment of viral diseases, said pharmaceutical composition comprising the compound of claim 22 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

36. A combination comprising the compound of claim 22 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, and one or more therapeutically active agents.

37. Use of the compound of claim 22 or a pharmaceutically acceptable salt thereof or an optical isomer thereof in the preparation of a medicament for treating a viral disease, wherein the viral disease is caused by a microRNA virus.

38. Use of the compound of claim 22 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, or a pharmaceutical composition of claim 35 or a combination of claim 36, in the preparation of a medicament for the prevention or treatment of a viral disease, wherein the viral disease is caused by a microRNA virus.

39. The use according to claim 37 or 38, wherein the viral disease is caused by Coxsackievirus.

40. The use according to claim 37 or 38, wherein the viral disease is caused by poliovirus.

41. The use according to claim 37 or 38, wherein the viral disease is caused by echovirus.

42. The use according to claim 37 or 38, wherein the viral disease is caused by an enterovirus.

43. The use according to claim 37 or 38, wherein the viral disease is caused by a rhinovirus.

44. The use according to claim 37 or 38, wherein the viral disease is poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, herpetic pharyngitis, foot-and-mouth disease, pneumonia, sinusitis, or otitis media.