Antiviral 1, 3-dioxoindene compounds

Abstract

The present invention provides compounds of formula (I) as described herein, as well as pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions in the treatment of viral infections.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on April 20, 2021, with application number 202180029147.1 and invention title "Antivirin 1,3-dioxoindene Compound". Technical Field

[0002] This invention relates to novel 1,3-dioxoindene compounds, which are inhibitors of picornaviruses (including Coxsackievirus, Enterovirus, Echovirus, Poliovirus, and Rhinovirus), and are therefore useful for 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, colds, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. This invention provides novel tetracyclic pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions to treat and prevent viral diseases. Background Technology

[0003] Picornaviridans are non-enveloped, positive, single-stranded RNA viruses with an RNA genome of 7.2 kb–8.5 kb in length. These viruses are very small and spherical, measuring approximately 22 nm in size. ~ 30nm, and was first identified a long time ago. Viruses belonging to the Picornaviridae family are enteroviruses, including rhinovirus, poliovirus, Coxsackievirus A, Coxsackievirus B, echovirus, and hepatitis A virus.

[0004] Diseases caused by picornaviruses are diverse, ranging from respiratory, digestive, circulatory, and skin diseases. Examples include poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpetic pharyngitis, and foot-and-mouth disease. However, there are no cures for these diseases. Most drugs under development are uncoated inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory illnesses, which cause health, social, and economic problems. Picornaviridae are major causative agents of waterborne diseases. Because RNA viruses are very stable and difficult to disinfect, they continue to cause related diseases.

[0005] Human rhinovirus (hRV) has recently been associated with most asthma exacerbations and is known to be present even in the bronchial tissue of many patients with stable asthma. Comparisons of corresponding bronchial mucosal biopsy samples obtained from asthmatic and non-asthmatic patients have shown a significantly higher frequency of hRV detection in the lower respiratory tract of asthmatic patients compared to non-asthmatic patients. A correlation has also been reported between the presence of hRV and the clinical severity of asthma. Furthermore, rhinovirus causes chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, and asthma.

[0006] Rhinoviruses are a major cause of the common cold, while enteroviruses induce illnesses including meningitis and respiratory infections. Extensive efforts to provide vaccination against poliovirus have significantly reduced polio outbreaks worldwide, but cases are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is now potentially under control to some extent thanks to vaccines against the hepatitis A virus. However, vaccines against Coxsackievirus, Echovirus, or Rhinovirus have not yet been developed.

[0007] Specifically, Coxsackievirus B is a major cause of myocarditis, and in severe cases, it can develop into idiopathic dilated cardiomyopathy requiring a heart transplant.

[0008] Enviroxime derivatives are considered promising candidates with broad-spectrum anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with the synthesis of positive-sense RNA by binding to viral protein 3A, which is required for the formation of RNA intermediates during viral replication (Heinz BA and Vance LM: J Virol, 1995, 69(7), 4189-97). However, in clinical studies, this compound has been observed to have little or no therapeutic effect, along with adverse pharmacokinetics and undesirable side effects (Miller FD et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

[0009] Based on knowledge of the fine structure and function of viral protease 2C, the protease inhibitor AG7088 has been developed. In cell cultures at nanomolar concentrations, AG7088 has activity against 48 rhinovirus types and Coxsackievirus A21, B3, Enterovirus 70, and Echovirus 11 (Pattick AK et al.: Antimicrobila Agents Chemother, 1999, 43(10), 2444-50).

[0010] The clarification of the molecular structure of the viral capsid has provided the preconditions for the targeted design of capsid blocking agents, known as "WIN substances" (Diana GD: Curr Med Chem 2003, 2, 1-12). These substances inhibit the adsorption and / or uncoating of rhinoviruses and enteroviruses. Some WIN substances exhibit high specificity against a single genus or type of piconemavirus. Other derivatives inhibit the replication of rhinoviruses and enteroviruses. For example, arilide, disoxaril, and pirodavir belong to the WIN substance family. These compounds have shown very good antiviral activity in cell culture. However, poor solubility (arilide), low bioavailability (arilide and disoxaril), rapid metabolism and excretion (disoxaril and WIN 54954), and side effects such as rash (WIN 54954) make clinical application impractical.

[0011] Pleconaril, a WIN substance, has very good oral bioavailability and, after binding to the hydrophobic sac in the viral capsid, inhibits the penetration of rhinovirus, echovirus, and coxsackievirus (Pevear D C et al.: Antimicrob Agents Chemother 1999, 43(9), 2109-15; McKinlay MA et al.: Annu Rev Microbiol 1992, 46, 635-54). Therefore, pleconaril may be effective against a broad spectrum of viral diseases, ranging from the common cold to viral meningitis or myocarditis. Resistance to rhinovirus, enterovirus 71, and coxsackievirus B3 has been observed (Ledford RM et al.: J Virol 2004, 78(7), 3663-74; Groarke JM et al.: J Infect Dis 1999, 179(6), 1538-41). However, the proven therapeutic efficacy was insufficient to register Picovir (Viropharma, USA) as a treatment for rhinovirus infections in the United States. In March 2002, the Food and Drug Administration (FDA) rejected the application due to the low success rate and observed side effects.

[0012] BTA-798 was found to have higher antiviral activity than plencolnazide, as evaluated in vitro and in vivo with rhinovirus, and is now undergoing clinical trials (Ryan, J. et al., Antiviral Res [18th Intl ConfAntiviral Res (April 11-14, Barcelona) 2005] 2005, 65(3): Abst LB-11).

[0013] However, to date, no antiviral drugs have been developed and approved for the treatment of enteroviruses or rhinoviruses. New treatments and therapies targeting enteroviruses or rhinoviruses are still needed.

[0014] In this invention, an in-depth and thorough study was conducted on effective antiviral drugs against microRNA viruses (including Coxsackievirus, Enterovirus, Echovirus, Poliovirus, and Rhinovirus), and it was ultimately discovered that a novel 1,3-dioxanone derivative exhibits high inhibitory activity against microRNA viruses (including Coxsackievirus, Enterovirus, Echovirus, Poliovirus, and Rhinovirus). Summary of the Invention

[0015] This invention provides novel compounds with effective antiviral activity in vitro. The invention also provides pharmaceutical compositions containing novel compounds and methods for using said compounds and compositions to inhibit viral replication or reactivation and to treat symptoms of virus-related or virus-induced diseases. Other objects of the invention are described in the following description and examples.

[0016] In one aspect, the present invention provides compounds of formula (I): or pharmaceutically acceptable salts thereof: in, G 1 Selected from straight-chain or branched C1-C4 alkyl, C3-C4 cycloalkyl, or straight-chain or branched C1-C4 alkoxy; wherein the C1-C4 alkyl, C3-C4 cycloalkyl and C1-C4 alkoxy can be substituted by one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl; L represents a chemical bond or CH2; E is a) -CH(CHOHCH3)(NMe2); or b) A monocyclic 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 monocyclic 5-6-membered heterocyclic group containing one or two nitrogen atoms, and NR. 1 R 2 The monocyclic 5-6 membered heterocyclic group is optionally surrounded by a C1-C3 alkyl group or NR. 3 R 4 replace; Each R 1 and R2 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 The compound is independently selected from H or methyl. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers. In yet another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of the compound of the present invention and one or more therapeutically active agents. Detailed Implementation

[0017] 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.

[0018] Unless the context clearly indicates otherwise, the terms used in this specification have the following meanings: As used herein, the term "subject" refers to an animal. In some respects, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some implementations, a subject is a human. As used herein, "patient" refers to a human subject. As used herein, a subject "needs" treatment if they would benefit biologically, medically, or in terms of quality of life.

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

[0020] As used herein, the term "treating" or "treatment" in one embodiment refers to improving a disease or condition (i.e., slowing or stopping or reducing the development of a disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to reducing or improving at least one bodily parameter, including those that the patient may not be able to discern. In yet another embodiment, "treating" or "treatment" refers to regulating a disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing bodily parameters), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset, development, or progression of a disease or condition.

[0021] As used herein, unless otherwise stated herein or obviously contradicted by the context, the terms “a,” “an,” “the,” and similar terms used in the context of this invention (especially in the context of the claims) shall be construed as encompassing both the singular and the plural.

[0022] Unless otherwise stated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the otherwise claimed invention.

[0023] "Optionally substituted" means that the referred group may be substituted at one or more positions by any one or any combination of groups listed below. The number, position, and selection of substituents should be understood to cover only those substitutions that a skilled chemist would reasonably expect to be stable; therefore, 'oxo' is not a substituent on an aryl or heteroaryl ring, for example, and no single carbon atom has three hydroxyl or amino substituents. Unless otherwise specified, optional substituents are generally up to four selected from halogens, oxo groups, CN, amino, hydroxyl, -C 1-3 alkyl, , , -SO2 , and The groups, wherein each Independently H or C 1-3 alkyl.

[0024] Unless otherwise specified, "aryl" as used herein refers to a phenyl or naphthyl group. Unless otherwise specified, the aryl group may optionally be composed of up to four groups selected from halogen, CN, amino, hydroxyl, C... 1-3 alkyl, , , -SO2 , and The groups are substituted, wherein each of the groups is replaced by Independently H or C 1-3 alkyl.

[0025] As used in this article, "halogen" or "halogen" can be fluorine, chlorine, bromine or iodine.

[0026] As used in this article, "C" 1-6"Alkyl" or "C1-C6 alkyl" indicates a straight-chain or branched alkyl group having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition will be modified accordingly, such as "C 1-4 "alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0027] As used in this article, "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group (-O-alkyl) having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition will be modified accordingly, such as "C 1-4 "Alkoxy" will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0028] As used in this article, "C" 1-4 "Halogenated alkyl" or "C1-C4 halogenated alkyl" refers to a straight-chain or branched alkyl group having 1-4 carbon atoms, wherein at least one hydrogen atom has been substituted by a halogen. The number of halogen substitutions can be one to at most the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms, such as C6 or C3, is specified, the definition will be modified accordingly. Therefore, "C 1-4 "Halogenated alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, wherein at least one hydrogen atom is substituted by a halogen, such as fluorine: CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-.

[0029] As used in this article, "C" 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring with 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.

[0030] "4- to 8-membered heterocyclic groups," "5- to 6-membered heterocyclic groups," "3- to 10-membered heterocyclic groups," "3- to 14-membered heterocyclic groups," and "5- to 14-membered heterocyclic groups" 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 heterocycles, respectively. Unless otherwise specified, such rings contain 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 rings may be saturated or partially saturated, but not aromatic. A heterocyclic group may be attached to another group at a nitrogen or carbon atom. The term "heterocyclic group" includes monocyclic groups, fused-ring groups, and bridging groups. Examples of such heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiaran, tetrahydropyran, 1,4-dioxane, 1,4-oxothiacyclohexane, 8-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, azabicyclobutane, ethylenedioxo, oxacyclobutane, or thiazole. In some embodiments, unless otherwise specified, the heterocyclic group has 1-2 heteroatoms selected from N, O, and S as ring members and 4-7 ring atoms, and optionally is composed of up to four groups selected from halogen, oxo, CN, amino, hydroxyl, C 1-3 alkyl, , , -SO2 , and The groups are substituted, wherein each of the groups is replaced by Independently H or C 1-3 Alkyl group. Specifically, the heterocyclic group containing a sulfur atom is optionally replaced by one or two oxo groups on the sulfur atom.

[0031] "Heteroaryl" is a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, heteroaryls are 5-10 membered rings or ring systems (e.g., 5-7 membered monocyclic groups or 8-10 membered bicyclic groups), usually 5-6 membered rings 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-furanyl or 3-furanyl, 2-pyrroleyl or 3-pyrroleyl, 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, and 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-pyrazinyl or 4-pyrazinyl, 3-pyrazinyl, 4-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl and 2-pyrimidineyl, 4-pyrimidineyl or 5-pyrimidineyl. The heteroaryl group is optionally surrounded by up to four groups selected from halogen, CN, amino, hydroxyl, C. 1-3 alkyl, , , -SO2 , and The groups are substituted, wherein each of the groups is replaced by Independently H or C 1-3 alkyl.

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

[0033] This document describes various embodiments of the invention. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The embodiments listed below represent the invention: Implementation Scheme 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof: in, G 1Selected from straight-chain or branched C1-C4 alkyl, C3-C4 cycloalkyl, or straight-chain or branched C1-C4 alkoxy; wherein the C1-C4 alkyl, C3-C4 cycloalkyl and C1-C4 alkoxy can be substituted by one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl; L is a chemical bond or a C1-C4 straight-chain or branched alkylene linkage; E is a) -CH(CHOHCH3)(NMe2); or b) A monocyclic 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 monocyclic 5-6-membered heterocyclic group containing one or two nitrogen atoms, and NR. 1 R 2 The monocyclic 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.

[0034] Implementation Scheme 2. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): .

[0035] Implementation Scheme 3. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III): .

[0036] Implementation Scheme 4. The compound according to any one of the foregoing implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a straight-chain or branched C1-C4 alkyl group.

[0037] Implementation Scheme 5. The compound according to any one of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a C3-C4 cycloalkyl group.

[0038] Implementation Scheme 6. The compound according to any one of the foregoing implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a straight-chain or branched C1-C4 alkoxy group.

[0039] Implementation Scheme 7. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the C1-C4 alkyl, C3-C4 cycloalkyl and C1-C4 alkoxy groups may be substituted with one, two or three substituents.

[0040] Implementation Scheme 8. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the substituents are independently selected from cyclopropyl and straight-chain or branched C1-C3 alkyl groups.

[0041] Implementation Scheme 9. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is a C1-C4 straight-chain or branched alkylene group. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is CH2.

[0042] Implementation Scheme 10. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein E is -C(CHOHCH3)(NMe2).

[0043] Implementation Scheme 11. The compound according to any one of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof, wherein E is a monocyclic 4-6 membered heterocyclic group.

[0044] Implementation Scheme 12. The compound according to any one of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof, wherein E is a monocyclic 4-6 membered heteroaryl group.

[0045] Implementation Scheme 13. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 4-6-membered heterocyclic group contains one or two nitrogen atoms.

[0046] Implementation Scheme 14. The compound according to any one of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof, wherein the 5-6-membered heteroaryl group contains a nitrogen atom.

[0047] Implementation Scheme 15. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one, two or three substituents.

[0048] Implementation Scheme 16. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the substituent is independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl, -OH, =O, -SO2R.

[0049] Implementation Scheme 17. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from straight-chain or branched C1-C3 alkyl groups, monocyclic 5-6 membered heterocyclic groups, and NR. 1 R 2 .

[0050] Implementation Scheme 18. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 5-6 membered heterocyclic group is optionally surrounded by a C1-C3 alkyl group or NR. 3 R 4 replace.

[0051] Implementation Scheme 19. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Independently selected from H and C1-C3 alkyl groups. A compound according to any one of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein the C1-C3 alkyl group is optionally NR- 3 R 4 replace.

[0052] Implementation Scheme 20. The compound according to any one of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 4 It is independently selected from H or methyl.

[0053] Implementation Scheme 21. The compound according to any one of the foregoing implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1 A straight-chain or branched C1-C4 alkyl group, optionally substituted with one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl groups.

[0054] Implementation Scheme 22. The compound according to any one of the foregoing implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a C3-C4 cycloalkyl group that is optionally substituted by one, two or three substituents independently selected from straight-chain or branched C1-C3 alkyl groups.

[0055] Implementation Scheme 23. The compound according to any one of the foregoing implementation schemes, or a pharmaceutically acceptable salt thereof, wherein G 1It is a straight-chain or branched C1-C4 alkoxy group that is optionally substituted with one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl groups.

[0056] Implementation Scheme 24. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, said compound having 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.

[0057] Implementation Scheme 25. The compound according to the foregoing implementation scheme, wherein A 1 It is either methyl or SO2CH3.

[0058] Implementation Scheme 26. The compound according to the foregoing implementation scheme, wherein A 2 The designation is SO2R, and R is selected from the group consisting of: CH3; a monocyclic 5-6 membered heterocyclic group containing one or two nitrogen atoms and substituted with CH3 or N(CH3)2; and NR. 1 R 2 .

[0059] Implementation Scheme 27. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, said compound having formula (Ib): Where Y is H or CH3.

[0060] Implementation Scheme 28. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, said compound having formula (Ic): X is selected from the group consisting of the following: methyl, ethyl, and cyclopropyl.

[0061] Implementation Scheme 29. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments of any example, said compound being 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-(methanesulfonyl)-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)-3-methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxamide; [2-b]benzofuran-9b-yl)-2-(azacyclobut-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-hydroxypyridine amide; N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(N-(2-(2-(dimethylamino)ethyl)aminosulfonyl)-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-(azacyclobut-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; [-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-hydroxypyridine amide; 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-hydroxybutyramide; 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)pyrrolidine-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-hydroxybutyramide; N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-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-(azacyclobut-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-imidazol-4-carboxamide;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; N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)- 1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo N-(1-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)) N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-aminosulfonyl-1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxamide and N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxamide. This embodiment includes each of the embodiments shown in the bioactivity data sheet herein.

[0062] Implementation Scheme 30. A compound comprising each or any one of the embodiments shown in the bioactivity data sheet herein.

[0063] Implementation Scheme 31. A compound of Formulas I to III or a compound according to any one of the embodiments herein, a pharmaceutically acceptable salt thereof or an optical isomer thereof, for the prevention or treatment of viral diseases.

[0064] Implementation Scheme 32. A pharmaceutical composition for the prevention or treatment of viral diseases, said pharmaceutical composition comprising a compound of the chemical formulas I to III or any compound 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.

[0065] Embodiment 33. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by Coxsackievirus. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by poliovirus. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by echovirus. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by enterovirus. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by rhinovirus. A pharmaceutically acceptable salt of the compound described in this embodiment or an optical isomer thereof, or a pharmaceutical composition described in this embodiment, wherein the viral disease is caused by piconemavirus. The compounds described in the embodiments herein, their pharmaceutically acceptable salts or optical isomers thereof, or the pharmaceutical compositions described in the embodiments herein, wherein the viral diseases are poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0066] Implementation Scheme 34. Use of compounds of Formulas 1 to III or any compound according to any one of the embodiments herein, or pharmaceutically acceptable salts thereof or optical isomers thereof, for the prevention or treatment of viral diseases.

[0067] Implementation Scheme 35. The use described in this implementation scheme, wherein the viral disease is caused by Coxsackievirus.

[0068] Implementation Scheme 36. The use described in the implementation scheme herein, wherein the viral disease is caused by the poliovirus.

[0069] Implementation Scheme 37. The use described in this implementation scheme, wherein the viral disease is caused by echovirus.

[0070] Implementation Scheme 38. The use described in the implementation scheme herein, wherein the viral disease is caused by an enterovirus.

[0071] Implementation Scheme 39. The use described in this implementation scheme, wherein the viral disease is caused by a rhinovirus.

[0072] Implementation Scheme 40. The use as described in the implementation scheme herein, wherein the viral disease is caused by a microRNA virus.

[0073] Implementation Scheme 41. According to the use described in this implementation scheme, the viral disease is poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0074] These compounds are novel and can be used as intermediates for the preparation of compounds of formulas (I) to (III) described herein.

[0075] Another embodiment of the invention provides a compound as described above or a pharmaceutically acceptable salt thereof as a medicine.

[0076] The use of compounds of formula (I) or

[0078] pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment or prevention of viral diseases and / or infections in humans is also within the scope of this invention.

[0077] Included within the scope of this invention are pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.

[0078] According to another aspect of this embodiment, the pharmaceutical composition according to the invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0079] The present invention also provides the use of the pharmaceutical composition described above for treating viral infections or other viruses in persons who are infected or at risk of infection.

[0080] The present invention also provides the use of the pharmaceutical compositions described above for treating viral diseases or other viral infections in persons who have or are at risk of having a disease.

[0081] Another aspect of the invention relates to a method for treating or preventing viral diseases and / or infections in humans by administering an antivirally effective amount of the compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, either separately or together.

[0082] Another aspect of the invention refers to an article comprising a composition effective in treating herpes virus diseases and / or infections; and packaging material comprising a label indicating that the composition may be used to treat diseases and / or infections caused by a virus; wherein the composition comprises a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof.

[0083] Another aspect of the invention relates to a method for inhibiting viral replication, the method 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 may be performed in vitro or in vivo.

[0084] The scope of this invention also includes the use of compounds of formula (I) or salts thereof to inhibit viral replication.

[0085] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may 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.

[0086] These additional agents can be combined with the compounds of the present invention to produce a single pharmaceutical dosage form. Alternatively, these additional agents can be administered to a patient alone as part of a multi-dosage form, for example, using a kit. Such additional agents can be administered to a patient before, during, or after administration of the compounds of the present invention or their pharmaceutically acceptable salts.

[0087] The daily applicable dosage range of the compounds of the present invention is typically from 0.01 mg / kg to 100 mg / kg of body weight, for example, from 0.1 mg / kg to 50 mg / kg of body weight. Each dosage unit conveniently contains 5% to 95% (w / w) of the active compound. Sometimes such formulations contain 20% to 80% of the active compound.

[0088] The actual pharmaceutically effective dose or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and disease severity. In any case, the combination will be administered in a dosage and manner that allows for the delivery of a pharmaceutically effective dose based on the patient's unique condition.

[0089] When the compositions of the present invention comprise a combination of the compounds of the present invention and one or more additional therapeutic or preventative agents, both the compounds and the additional agents shall be present at dose levels between about 10% and 100% of the dose normally administered in a single therapy regimen, and sometimes between about 10% and 80%.

[0090] Antiviral agents intended for use in such combination therapies include agents (compounds or biologics) that effectively inhibit viral formation and / or replication in humans, including but not limited to agents that interfere with host or viral mechanisms necessary for viral formation and / or replication in humans.

[0091] Many of the compounds of this invention contain one or more chiral centers. These compounds can be prepared and used as a single isomer or as a mixture of isomers. Methods for isolating isomers (including diastereomers and enantiomers) are known in the art, and examples of suitable methods are described herein. In some embodiments, the compounds of this invention are used as a single, substantially pure isomer, meaning that at least 90% of the sample of the compound is the specified isomer, and less than 10% of the sample is any other isomer or mixture of isomers. In some embodiments, at least 95% of the sample is a single isomer. The selection of suitable isomers is within the range of ordinary technical levels, as an isomer will generally be more active in the in vitro assay of herpesvirus DNA polymerase described herein and will be a single isomer. In cases where the difference in in vitro activity between isomers is relatively small, for example less than about 4-fold, a single isomer can be selected based on the level of activity against viral replication in cell cultures, such as as described herein: for example, an isomer with a lower IC-50 or EC-50.

[0092] The compounds of the present invention can be synthesized via the following general synthetic route, specific examples of which are described in more detail in the embodiments.

[0093] This invention also provides a method for preparing compounds of formula (I) as described herein, and intermediates that can be used to prepare compounds of formula (I). Therefore, this invention also includes a method for preparing compounds of formula (I). This invention also includes any variations of this method, wherein an intermediate product available at any stage is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure materials.

[0094] The invention also relates to those forms of the method in which a compound available as an intermediate at any stage of the method is used as a starting material and the remaining method steps are carried out, or in which the starting material is formed under reaction conditions or used as a derivative, for example, in a protective form or in the form of a salt, or in which a compound obtainable by the method according to the invention is prepared under process conditions and further processed in situ.

[0095] The terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomer configurations that can exist for a given compound of the invention and include geometrical isomers. It should be understood that substituents may be attached to the chiral center of a carbon atom. The term "chiral" refers to a molecule that is non-overlapping on its mirror-image counterpart, while the term "chiral" refers to a molecule that is overlapping on its mirror-image counterpart. Therefore, the invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to denote racemic mixtures where appropriate. A "diastereomer" is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon may be specified by R or S. Compounds with unsplit absolute configurations can be designated as (+) or (-) based on the direction (right-handed or left-handed) of their rotational plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-.

[0096] Depending on the choice of starting materials and procedures, compounds may exist in one possible isomer or as a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. This invention aims to include all such possible stereoisomers, including racemic 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 compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0097] Based on the physicochemical differences of the components, such as by chromatography and / or fractional crystallization, any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers or diastereomers.

[0098] Any resulting racemic mixture of the final product or intermediate can be resolved into optical enantiomers by known methods, such as by separating the diastereosal salts obtained from them with optically active acids or bases and releasing the optically active acidic or basic compounds. Specifically, the basic moiety can therefore be used to resolve the compounds of the present invention into their optical enantiomers, for example by fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). Racemic products can also be resolved by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents.

[0099] Furthermore, the compounds of the present invention (including their salts) may also be obtained as their hydrates, or may include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover both solvated and non-solventized forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field that are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0100] The compounds of the present invention (including their salts, hydrates and solvates) can be inherently or by design to form polymorphs.

[0101] As used herein, the term "salt" or "salts" refers to the acid addition salt or base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" refers to a salt that retains the bioavailability and properties of the compounds of the present invention and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts by means of amino and / or carboxyl groups or similar groups.

[0102] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids, such as acetates, aspartic acid, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonates, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonic acids, propionates, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0103] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0104] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0105] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0106] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and aminobutanetriol.

[0107] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from a basic or acidic portion. Typically, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate, etc.), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, where feasible, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0108] Any formula given herein is intended to represent the unlabeled and isotopically labeled forms of the compounds of the invention, having at most three atoms with a non-natural isotopic distribution, such as those rich in deuterium or... 13 C or 15 The site of N. The isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number rather than a natural abundance mass distribution. Examples of isotopes that can be usefully overdoped into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I. This invention includes various isotope-labeled compounds of the invention, such as those containing radioactive isotopes such as... 3 H and 14 C, or non-radioactive isotopes thereof, such as 2 H and 13 Those compounds in which C exists at levels substantially higher than the normal isotopic distribution. Compounds labeled with this type of isotope can be used for metabolic studies (e.g., using...). 14C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including methods for determining the tissue distribution of drugs or substrates, or those applicable to the patient's radiation therapy. Specifically, 18 F-labeled compounds of the present invention may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using appropriate isotope-labeled reagents instead of the commonly used unlabeled reagents. Labeled samples can be used for relatively low isotope incorporation, such as in cases where radiolabeling is used to detect trace amounts of the compound.

[0109] In addition, heavier isotopes, especially deuterium (i.e., 2 More extensive substitution of H or D can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, or improved therapeutic index. It should be understood that deuterium as used herein is considered a substituent in the compounds of this invention, and samples of compounds having deuterium as a substituent typically have at least 50% deuterium incorporation at the labeled site. The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its native abundance. If the substituent in the compound of the present invention is deuterium, then such compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doped at each specified deuterium atom), at least 4000 (60% deuterium doped), at least 4500 (67.5% deuterium doped), at least 5000 (75% deuterium doped), at least 5500 (82.5% deuterium doped), at least 6000 (90% deuterium doped), at least 6333.3 (95% deuterium doped), at least 6466.7 (97% deuterium doped), at least 6600 (99% deuterium doped), or at least 6633.3 (99.5% deuterium doped).

[0110] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with an isotope, such as D₂O, d 6 -Acetone, d 6 -DMSO.

[0111] Compounds of the present invention containing groups capable of acting as hydrogen bond donors and / or acceptors can form cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from the compounds of the present invention using known cocrystal formation procedures. Such procedures include grinding, heating, co-sublimating, co-melting, or contacting the compounds of the present invention with the cocrystal forgings in solution under crystallization conditions, and separating the resulting cocrystals. Suitable cocrystal forgings include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising the compounds of the present invention.

[0112] Unless otherwise stated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the otherwise claimed invention.

[0113] The compounds of the present invention can be administered by known methods, including oral, parenteral, and inhalation. In some embodiments, the compounds of the present invention are administered orally in the form of pills, lozenges, tablets, capsules, solutions, or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is usually performed intravenously, typically over a period of about 15 minutes to 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation; the inhalation method is particularly suitable for treating respiratory infections. The compounds of the present invention exhibit oral bioavailability, therefore, in some embodiments, the compounds can be administered orally.

[0114] The compounds of the present invention can also be used in combination with other agents (combination partners) for treating viral infections in subjects (e.g., other antiviral agents of formula I or not).

[0115] The term "combination" refers to a fixed combination of dosage units, as a single dosage form suitable for simultaneous or sequential use, or as a kit for combined administration, wherein the compounds of the present invention and the combination partners can be administered simultaneously or separately at time intervals, which in particular allow the combination partners to exhibit synergy, such as synergy, effect, or any combination thereof.

[0116] In some embodiments of the invention, the compounds of the invention are used in combination with a second antiviral agent (such as those named herein).

[0117] The second antiviral agent may be administered in combination with the compounds of the present invention, wherein the second antiviral agent is administered before, simultaneously with, or after one or more compounds of the present invention. When it is necessary to administer the compounds of the present invention and the second agent simultaneously via the same route of administration, the compounds of the present invention and the second agent may be formulated into the same dosage form. Examples of dosage forms containing the compounds of the present invention and the second agent are tablets or capsules.

[0118] In some embodiments, the combination of the compound of the present invention and the second antiviral agent can provide synergistic activity. The compound of the present invention and the second antiviral agent can be administered together, alone, simultaneously, or sequentially.

[0119] The “effective amount” of a compound is an amount necessary or sufficient to treat or prevent the viral infection and / or disease or condition described herein. In one example, the effective amount of a viral inhibitor of Formula I is an amount sufficient to treat a subject’s viral infection. In another example, the effective amount of the inhibitor is an amount sufficient to treat a subject requiring such treatment for a viral infection. The effective amount can vary depending on factors such as the subject’s body type and weight, the type of disease, or the specific compound of the invention. For example, the choice of the compound of the invention can affect the composition of the “effective amount.” Those skilled in the art will be able to examine the factors contained herein and determine the effective amount of the compounds of the invention without excessive experimentation.

[0120] The administration regimen can affect the composition of the effective dose. The compounds of the present invention can be administered to subjects before or after the onset of a viral infection. Furthermore, several separate doses can be administered daily or sequentially, as well as alternating doses, or the dose can be administered via continuous infusion or bolus injection. Additionally, the dosage of the compounds of the present invention can be increased or decreased proportionally as indicated by the urgency of the treatment or prevention situation.

[0121] The compounds of the present invention can be used to treat the conditions, symptoms, or diseases described herein, or to manufacture pharmaceutical compositions for treating these diseases. The present invention provides methods for treating these diseases using the compounds of the present invention or for preparing pharmaceutical compositions containing the compounds of the present invention for treating these diseases.

[0122] The term "pharmaceutical composition" includes formulations suitable for administration to mammals, such as humans. When the compounds of the present invention are administered as pharmaceuticals to mammals (e.g., humans), they may be given on their own or as a pharmaceutical composition comprising, 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 with a pharmaceutically acceptable carrier, or optionally a combination of two or more pharmaceutically acceptable carriers.

[0123] The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or media suitable for administering the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials relating to carrying or transporting the subject reagent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and without harm to the patient. Some examples of materials that 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 gum; 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 glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. Generally, pharmaceutically acceptable carriers are sterile and / or substantially pyrogen-free.

[0124] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may also be present in the composition.

[0125] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as palmitic acid ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0126] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations are readily available in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount will range from about 1% to about 99% of the active ingredient, sometimes from about 5% to about 70%, and sometimes from about 10% to about 30%.

[0127] Methods for preparing these formulations or compositions include the step of associating the compounds of the present invention with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by uniformly and tightly associating the compounds of the present invention with a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product.

[0128] Formulations of the present invention suitable for oral administration may be in the form of capsules, sachets, pills, tablets, lozenges (using a flavoring matrix, such as sucrose and gum arabic or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, or elixirs or syrups, or lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic) and / or mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as large pills, granules, or pastes.

[0129] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) of the present invention for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol.

[0130] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0131] The tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to provide the desired release profile, other polymer matrices, liposomes, and / or microspheres to provide a slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial retention filter, or by incorporation with a sterilizing agent in the form of a sterile solid composition that can be immediately dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions that optionally release the active ingredient only, or for example, in a portion of the gastrointestinal tract, in a delayed manner. Examples of encapsulation compositions that may be used include polymeric substances and waxes. Where appropriate, the active ingredient may also be in the form of microencapsulated forms having one or more of the excipients described above.

[0132] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranyl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, as well as mixtures thereof.

[0133] In addition to inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0134] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0135] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal application may be presented in suppository form, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax or salicylate, and are solid at room temperature but liquid at body temperature, and thus will dissolve in the rectal or vaginal cavity and release the active compound.

[0136] Preparations of the present invention suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing suitable carriers as known in the art.

[0137] Dosage forms for topical or transdermal application of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under sterile conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0138] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0139] In addition to the compounds of this invention, the powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0140] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate of such flux can be controlled by providing a rate-controlled membrane or by dispersing the active compounds in a polymer matrix or gel.

[0141] Ophthalmic preparations, ointments, powders, solutions, etc., are also contemplated to be within the scope of this invention.

[0142] Pharmaceutical compositions of the present invention suitable for parenteral administration may comprise a combination of one or more compounds of the present invention with one or more pharmaceutically acceptable carriers, such as sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0143] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0144] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents in these compositions, such as sugars and sodium chloride. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0145] In some cases, to prolong the action of a drug, it may be necessary to slow its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the drug in parenteral administration can be achieved by dissolving or suspending it in an oil-based medium.

[0146] Injectable, long-acting formulations are prepared by forming microcapsule matrices of the subject compound within biodegradable polymers, such as polylactide-polyglycolic acid. The drug release rate can be controlled based on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Long-acting injectable formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0147] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they are administered in tablet or capsule form via injection, inhalation, eye wash, ointment, suppository, etc.; via injection, infusion, or inhalation; topically via lotion or ointment; and rectally via suppository.

[0148] As used herein, the phrases “parenteral administration” and “administered via a parenteral route” refer to administration methods other than enteral and local administration (typically by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Intravenous infusion is sometimes a method of delivering the compounds of the present invention. Infusion can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion over intervals of 15 minutes to 4 hours, typically between 0.5 hours and 3 hours. Such infusions may be used once daily, twice daily, or up to three times daily.

[0149] As used in this article, the phrases “systemic administration,” “administered in a systemic manner,” “administered peripherally,” and “administered in a peripheral manner” mean that a compound, drug, or other material is not directly administered to the central nervous system, but rather enters the patient’s system and is thus subjected to metabolism and other similar processes, such as subcutaneous administration.

[0150] These compounds can be administered to humans and other animals for treatment via any suitable route of administration, including oral, nasal (e.g., via spray), rectal, vaginal, parenteral, intracerebrospinal, and topical, such as via powder, ointment, or drops, including buccal and sublingual.

[0151] Regardless of the chosen route of administration, the compounds and / or pharmaceutical compositions of the present invention, which can be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0152] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed in order to obtain an amount of active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition and administration mode without toxicity to the patient.

[0153] The selected dosage level will depend on a variety of factors, including the activity of the specific compound of the invention or its ester, salt or amide; the route of administration; the time of administration; the excretion rate of the specific compound; the duration of treatment; other drugs, compounds and / or materials used in combination with the specific compound; the age, sex, weight, condition, general health and medical history of the patient being treated; and similar factors well known in the medical field.

[0154] A physician or veterinarian with ordinary skill in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the compound of the invention used in the pharmaceutical composition below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0155] Generally, the appropriate daily dose of the compounds of the present invention will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose will generally depend on the factors described above. Typically, when used to indicate efficacy, the intravenous and subcutaneous doses of the compounds of the present invention for a patient will range from about 0.0001 to about 100 mg / kg body weight / day, sometimes from about 0.01 to about 50 mg / kg / day, and still sometimes from about 0.1 to about 20 mg / kg / day. An effective dose is an amount for the prevention or treatment of viral infections.

[0156] If necessary, the effective daily dose of the active compound may be administered as a single daily dose or, optionally, as two, three, four, five, six, or more sub-dose administered individually at appropriate intervals throughout the day, in unit dosage form. Compounds delivered orally or by inhalation are typically administered in doses one to four times daily. Compounds delivered by injection are typically administered once daily or every other day.

[0157] Compounds delivered by infusion are typically administered in doses one to three times daily. When multiple doses are administered in a day, the doses may be administered at intervals of approximately 4 hours, 6 hours, 8 hours, or 12 hours.

[0158] While the compounds of the present invention can be administered alone, they are sometimes administered as pharmaceutical compositions, such as those described herein. Therefore, methods of using the compounds of the present invention include administering the compound as a pharmaceutical composition, wherein at least one compound of the present invention is mixed with a pharmaceutically acceptable carrier prior to administration.

[0159] general synthetic procedures The compounds described herein can be synthesized via the following general synthetic routes, specific examples of which are described in more detail in the embodiments.

[0160] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of this invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21).

[0161] abbreviated list Acetyl group ACN or MeCN acetonitrile AcOEt / EtOAc Ethyl Acetate AcOH (acetic acid) aq water-based Bn benzyl Bu butyl (nBu = n-butyl, tBu = tert-butyl) CDI carbonyl diimidazole CH3CN Acetonitrile DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene Boc2O ditert-butyl dicarbonate DCE 1,2-Dichloroethane DCM dichloromethane DIAD (Diisopropyl Azodicarbonate) DiBAl-H diisobutylaluminum hydride DIPEA or DIEA N-ethyldiisopropylamine DMA N,N-dimethylacetamide DMAP dimethylaminopyridine DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EI electrospray ionization Et2O diethyl ether Et3N Triethylamine Ether diethyl ether EtOAc (ethyl acetate) EtOH (ethanol) FC rapid chromatography h hours HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate HCl hydrochloric acid HMPA (Hexamethylphosphoramide) HOBt 1-hydroxybenzotriazole HPLC (High Performance Liquid Chromatography) H2O water IPA isopropanol L rise LC-MS (Liquid Chromatography-Mass Spectrometry) LiHMDS bis(trimethylsilyl)aminolithium MgSO4 Magnesium sulfate Me methyl MeI iodomethane MeOH (methanol) mg min minutes mL MS mass spectrometry MsCl methanesulfonyl chloride NaHCO3 (Sodium bicarbonate) Na2SO4 Sodium sulfate NH2OH Hydroxylamine Pd / C Palladium / Carbon Pd(OH)₂ Palladium hydroxide PG protection base Ph phenyl Ph3P Triphenylphosphine Prep preparation type Rf shift value RP inversion Rt retention time RT room temperature SFC Supercritical Fluid Chromatography SiO2 silica gel SOCl2 thionyl chloride T3P ® Propylphosphonic anhydride TBAF Tetrabutylammonium Fluoride TBDMS tert-butyldimethylsilyl TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate TEA Triethylamine TFA (trifluoroacetic acid) THF Tetrahydrofuran TLC (Thin Layer Chromatography) TsCl Toluenesulfonyl chloride TsOH Toluenesulfonic acid In view of the embodiments and schemes provided herein, the compounds of the present invention are prepared from commonly available compounds using procedures known to those skilled in the art.

[0162] Within the scope of this text, unless the context otherwise requires, only readily removable groups that are not components of the specific desired end product of the compounds of this invention are designated as “protecting groups”. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in, for example, standard reference works such as Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 (URL: http: / / www.science-of-synthesis.com (electronic version, Vol. 48)); JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, 3rd ed., Wiley, New York 1999, “The Peptides”; Vol. 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der Organischen Chemie” (Methods of Organic Chemistry), Houben-Weyl Methods of Molecular Transformation. Weyl, 4th edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, “Amino acids, Peptides, Proteins” (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 by their ease of removal, for example by solvent decomposition, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage), without undesirable side effects.

[0163] Salts of the compounds of the present invention having at least one salifying group can be prepared in ways known per se. For example, salts of the compounds of the present invention having an acidic group can be formed, for example, by treating the compound with a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, such as a 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 hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate, sodium bicarbonate or potassium bicarbonate, with the corresponding calcium compound, or with ammonia or a suitable organic amine, sometimes using a stoichiometric amount or only a small excess of the salifying agent. Acid addition salts of the compounds of the present invention are obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchanger. Internal salts of the compounds of the present invention containing acidic and basic salifying groups (e.g., free carboxyl groups and free amino groups) can be formed, for example, by neutralizing the salt (such as an acid addition salt) to its isoelectric point with a weak base, or by treating it with an ion exchanger.

[0164] Salts can be converted into free compounds by conventional means; metal salts and ammonium salts can be converted, for example, by treatment with a suitable acid, and acid addition salts can be converted, for example, by treatment with a suitable basic reagent.

[0165] The mixture of isomers obtainable according to the invention can be separated into individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning, recrystallization and / or chromatographic separation (e.g. on silica gel) between multiphase solvent mixtures or by medium-pressure liquid chromatography, for example, on a reversed-phase column, and racemic mixtures can be separated, for example, by forming a salt with an optically purified salting agent and separating the thus obtainable diastereomer mixture, for example by fractional crystallization or by chromatography on an optically active column material.

[0166] Intermediates and final products can be processed and / or purified according to standard methods, such as chromatographic methods, partitioning methods, (re)crystallization, etc.

[0167] LC-MS High-resolution mass spectrometry ESI-MS data were recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The MS system had a resolution of approximately 30,000. Candidate drugs were infused into the mass spectrometer from the sample probe via UPLC (Acquity, Waters). Separation was performed on an Acquity UPLC BEH C18 1×50 mm column at a flow rate of 0.15 mL / min, with a gradient of 5% to 95% over 3 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 system's mass accuracy was found to be <5 ppm.

[0168] example The invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the embodiments are well established in the art: efficacy evidence in these assays is generally considered a predictor of efficacy in subjects.

[0169] The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, with reference to the following reaction schemes and examples. A general method for synthesizing compounds of formula (I) is provided in the following schemes.

[0170] Example 1 : N-((4bR, 9bR)-1- amino -4b- hydroxyl -7-((1R,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide (33) : Option-1 4- Nitroisobenzofuran -1,3- diketone (2) : The initial suspension of 1 (1.0 kg, 4.7 mol) of 3-nitrophthalic acid in Ac₂O (1 Ltr) was refluxed at 140 °C for 2.5 h. It was then cooled to 80 °C and slowly added to diethyl ether (4 Ltr) with vigorous stirring. The precipitate was collected by filtration through a Buchner funnel and washed with Et₂O to give the product.

[0171] 4- Nitro -1,3- Dioxane -2,3- Dihydrogen -1H- Indene -2- Ethyl carboxylate (3) : At ambient temperature, ethyl acetoacetate (42 mL, 0.31 mol) and Ac₂O (48.5 mL, 0.52 mol) were added to a suspension of anhydride 2 (50 g, 0.26 mol) in anhydrous DCM (260 mL). Et₃N (108 mL, 0.78 mol) was added dropwise to the suspension over a period of 30 minutes at room temperature (exothermic). A few mL of TEA were added. The suspension was stirred for another 15 minutes at the same temperature, and then the DCM was evaporated. The resulting crude product was then dissolved in 2 L of water and cooled to 0 °C. The solution was fixed with a top stirrer, and 300 mL of 2N HCl was added dropwise under vigorous stirring, maintaining the temperature below 0 °C. A precipitate began to form slowly. The solution was stirred for another 15 minutes at 0 °C, then filtered through a Buchner funnel and washed with ice-cold water (500 mL). The solution was then air-dried for three days to obtain a solid product.

[0172] 4- Nitro -1H- Indene -1,3(2H)- diketone (4) : Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate 3 (272.5 g, 1.04 mol) was dissolved in 1 L of MeCN:water (20:1, 1.0 M). TFA (60 mL, 1.14 mol) was slowly added to the suspension at room temperature, and the mixture was then heated at 50 °C. After 4 hours, the reaction mixture was concentrated on a rotary evaporator until approximately 100 mL of solvent remained. The precipitated solid was then filtered through a Buchner funnel and washed with (1:1) CHCl3:hexane. This yielded the product, and the filtrate was concentrated again to obtain more product in a second batch.

[0173] 2,2- dihydroxy -4- Nitro -1H- Indene -1,3(2H)- diketone (5) : 10.0 g (52.3 mmol) of 4-nitro-1H-indene-1,3(2H)-dione was dissolved in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added, and the mixture was refluxed at 105 °C–110 °C for 5 hours. The reaction mixture was then filtered through diatomaceous earth under thermal conditions, and the volatiles were concentrated to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione.

[0174] 7- bromine -4b,9b- dihydroxy -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (7) : The crude product 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 was then dissolved in ice-cold AcOH (210 mL, 0.25 mmol), and 3-bromophenol 6 (9.96 g, 57.5 mmol) was added and refluxed for another 12 hours. The reaction mixture was concentrated and dissolved in EA (500 mL–600 mL). It was filtered through diatomaceous earth and the residue was washed with EA. The filtrate was washed with water (200 mL × 2) and brine (100 mL). It was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified twice by silica gel column chromatography (35%–40% EA in hexane solution) to obtain the pure product.

[0175] 7- bromine -9b- chlorine -4b- hydroxyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (8) : 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 7 (39.5 g, 0.105 mol) was dissolved in DCM (520 mL, 0.2 M), and oxalyl chloride (11 mL, 0.13 mol) was added at room temperature. DMF (40 mL, 0.53 mol) was slowly added (0.05 mL / min for 30 min, then 0.1 mL / min for 30 min, then rapidly), and the mixture was stirred at ambient temperature (30 °C). The reaction mixture was then stirred at room temperature (20 °C) for another 12 hours. The reaction mixture was diluted with water (~300 mL). The aqueous layer was extracted with DCM (~500 mL × 2). The combined organic layers were washed with water (~300 mL) and brine (~300 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (10%-30% EA in hexane solution) to obtain the pure product.

[0176] 9b- amino -7- bromine -4b- hydroxyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (9) : 21.2 g (53.4 mmol) of 9b-chloro-4b-hydroxy-4-nitro-8-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 8 was dissolved in THF (530 mL, 0.1 M) and cooled to -40 °C. At the same temperature, 54 mL (0.11 mmol) of 2.0 M NH3 IPA solution was added, and the mixture was stirred for another 3 h. The reaction mixture was diluted with water (~150 mL) and brine (150 mL). The aqueous layer was extracted with EA (~300 mL × 2). The combined organic layers were washed with brine (~100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (using 20%-30% EA in hexane and 20% DCM as a co-solvent) to obtain the pure product.

[0177] (7- bromine -4b- hydroxyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (10) : Boc anhydride (8.74 g, 40 mmol) and molecular I2 (0.69 g, 2.67 mmol) were added to a racemic mixture (10.1 g, 31 mmol) of 9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 9 in THF (5.0 mL, 5.0 M) and stirred at 30 °C for 72 h. The reaction mixture was concentrated and purified. The crude product was purified by silica gel column chromatography (10%–30% EA in hexane solution and 5%–10% DCM) to obtain the pure product.

[0178] (1- amino -7- bromine -4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (11) : A racemic mixture of tert-butyl carbamate 10 (10.3 g, 21.5 mmol) was dissolved in EtOH:water (10:1, 110.0 mL, 0.20 M), and Fe powder (3.57 g, 63.9 mmol) was added, followed by concentrated HCl (0.8 mL, catalyst). The mixture was refluxed at 90 °C for 3 hours. The reaction mixture was filtered through diatomaceous earth using hot EA (50 mL–100 mL) under 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). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10%-30% EA / hx) to obtain the pure product.

[0179] ((4bR,9bR)-1- amino -7- bromine -4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (12) and ((4bS,9bS)-1- amino -7- bromine -4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene[1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (13) : (1-Amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)tert-butyl carbamate (11) (7000 mg) was purified by chiral chromatography using (AD column, HPLC = 20 mL / min, heptane / EtOH = 70 / 30, 724 psi) to obtain 3010 mg of ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)tert-butyl carbamate (12) (peak 2, tR 15.59 min.); 1H NMR (500 MHz, methanol-d4) δ: 7.48 (br t, J = 7.7 Hz, 1H). 7.37 (br s, 1H), 7.11 (brs, 1H), 7.02 (br d, J=7.1Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s,5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M + H] + And 3060 mg of ((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl) tert-butyl carbamate (13) (peak 1, tR 8.97 min.); 1H NMR (500 MHz, methanol-d4) δ: 7.48 (br t, J=7.6 Hz, 1H), 7.37 (br s, 1H), 7.11 (br s, 1H), 7.02 (br d, J=6.9 Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s, 5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M + H] + .

[0180] Option 2 Intermediates (14 and 18) according to J. Am. Chem. Soc. 2013, 135 The literature preparation reported in 82-85.

[0181] ((1S,2S)-2- methylcyclopropyl) Boric acid (15) : A solution of (4S,5S)-N4,N4,N5,N5-tetramethyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,2-dioxoboronide-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 × 3), the combined ether layers were washed with water and dried over Na2SO4, and the solvent was evaporated at low temperature to give the product. The crude product was used in the next step without purification.

[0182] 6- methyl -2-((1S,2S)-2- methylcyclopropyl )-1,3,6,2- Dioxazoniborone heterocyclic octane -4,8- diketone (17) : 15% (800 mg, 8.0 mmol) of ((1S,2S)-2-methylcyclopropyl)boronic acid in toluene:DMSO (80 mL) was added to 16% (1.766 mg, 12 mmol) of diacetic acid. The resulting reaction mixture 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 × 3). The combined organic layers were washed with water and dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was ground with diethyl ether, the solid was filtered off and washed with diethyl ether to obtain the final product.

[0183] ((1R,2R)-2- methylcyclopropyl ) Boric acid (19) : A solution of (4R,5R)-N4,N4,N5,N5-tetramethyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,2-dioxoboronide-4,5-dicarboxamide 18 (11.3 g, 31.7 mmol, based on the starting material from the previous step) in distilled water (317 mL, 0.1 M) was stirred at room temperature for 12 h. The reaction mixture was extracted with diethyl ether (500 mL × 3), the combined organic layers were washed with water (× 1), dried over anhydrous Na₂SO₄, and concentrated at low temperature to give a crude product. This crude product was used in the next step without purification.

[0184] 6- methyl -2-((1R,2R)-2- methylcyclopropyl )-1,3,6,2- Dioxazoniborone heterocyclic octane -4,8- diketone (20) : 2,2'-(methylcyclopropyl)borate 19 (6.03 g, 60.3 mmol) was added to a solution of ((1R,2R)-2-methylcyclopropyl)boronic acid 19 in toluene / DMSO (10 / 1, 300 mL / 30 mL), and the mixture was refluxed for 3 hours under Dean-Stark conditions. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The organic layer was washed with water (200 mL × 4), dried over anhydrous Na₂SO₄, filtered, and concentrated. Diethyl ether was added to the residue, yielding the desired product. 1 H NMR (300MHz, CDCl3) δ 3.92 (d, J = 16.6Hz, 2H), 3.72 (dd, J =16.6, 4.8Hz, 2H), 3.04 (s, 3H), 1.10 (d, J = 5.8Hz, 3H), 0.70 (dt, J = 11.3,5.7Hz, 1H), 0.47 - 0.35 (m, 1H), 0.34 - 0.22 (m, 1H), -0.61 (dt, J = 9.2, 6.1 Hz, 1H).

[0185] Option 3 Toluenesulfonylglycine methyl ester (23) : 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 slowly added. The reaction mixture was cooled to 0 °C. Then, DIPEA (208 mL, 1194.7 mmol) was slowly added, and the reaction was stirred at 0 °C for 10 min. The reaction was heated to 30 °C and stirred for 18 h. The reaction was quenched with 1 N HCl, and the aqueous layer was extracted with DCM (500 mL × 3). The combined organic layers were washed with water (500 mL) and then with brine (200 mL). The organic layers were dried over Na₂SO₄, and the solvent was evaporated to give the crude product. The crude product was purified by grinding with DCM:Hex to obtain the product.

[0186] 3- hydroxyl -3- methyl -1- Toluenesulfonylpyrrolidine -2- Methyl carboxylate (25) : Toluenesulfonyl 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), followed by the slow addition of DBU (79 mL, 529.0 mmol), and the reaction mixture 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 HCl solution. Once the pH of the aqueous phase became acidic, the organic phase was washed with 5% Na₂CO₃ solution and then with water until the pH was neutral. The organic phase was dried over anhydrous Na₂SO₄ and evaporated under vacuum to give the product. The crude product was used in the next step without purification.

[0187] 3- methyl -1- Toluenesulfonyl -4,5- Dihydrogen -1H- Pyrrole -2- Methyl carboxylate (26) : 25g (69g, 220mmol) of 3-hydroxy-3-methyl-1-toluenesulfonylpyrrolidine-2-carboxymethyl ester was dissolved in anhydrous pyridine (550mL), and POCl3 (61mL, 660mmol) was slowly added. The reaction mixture was stirred at room temperature (30°C) for 12h. The reaction mixture was poured into ice water, and the aqueous layer was extracted with diethyl ether (5 times). The combined organic layers were washed with 5% HCl solution. Once the pH of the aqueous layer became acidic, the organic layer was washed with 5% Na2CO3 solution, followed by washing with water until the pH was neutral. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by silica gel column chromatography.

[0188] 3- methyl -1H- Pyrrole -2- Methyl carboxylate (27) : Methyl 3-methyl-1-toluenesulfonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid ester 26 (30 g, 102 mmol) was dissolved in THF (204 mL), and DBU (46 mL, 306 mmol) was slowly added. The resulting reaction mixture was stirred at 50 °C for 20 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with 1N HCl, then with 5% NaHCO3, and then with water. The organic layer was dried over Na2SO4 and evaporated to obtain the crude product. The crude product was filtered through a silica gel stopper, and the solvent was evaporated to obtain the final product.

[0189] 3- methyl -4-( Methylthio )-1H- Pyrrole -2- Methyl carboxylate(28) : Methyl 3-methyl-1H-pyrrole-2-carboxylic acid ester 27 (460 mg, 3.3 mmol) and CuI (314 mg, 0.5 mmol) were dissolved in DMSO (3.3 mL, 1.0 M). Dimethyl disulfide (0.531 mL, 6.0 mmol) was then added, and the mixture was heated at 110 °C for 48 hours. The reaction was quenched with water (50 mL) and EA (50 mL). The layers were filtered through diatomaceous earth 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). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10%–15% EA in hexane solution) to obtain the final product.

[0190] 3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- Methyl carboxylate (29) : Methyl 3-methyl-5-(methylthio)-1H-pyrrole-2-carboxylic acid ester 28 (185 mg, 1.0 mmol) was dissolved in MeOH (10 mL), and a solution of OXONE (1.85 g, 2.0 mmol) in water (10 mL) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature (25 °C) for 3 hours. Volatile substances were removed under reduced pressure, and the suspension of the solids in water was extracted with EA (70 mL × 2) using a certain amount of water to dissolve only the inorganic matter. The combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (30%-40% EA in hexane solution) to obtain the pure product.

[0191] 3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- carboxylic acid (30) : LiOH·H₂O (353 mg, 8.4 mmol) was added to a solution of ethyl 3-methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxylate 29 (390 mg, 1.68 mmol) in H₂O:THF (17 mL). The resulting reaction mixture was then stirred at 80 °C for 12 hours. The reaction mixture was acidified with 1N HCl, and the precipitated solid was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with water and then with a brine solution. The organic layers were dried over anhydrous Na₂SO₄, and the solvent was evaporated to give the product, which was used as is in the next step without purification.

[0192] Option 4 ((4bR, 9bR)-1- amino -4b- hydroxyl -7-((1R,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (31) : 12 tert-butyl carbamate ((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (112 mg, 0.25 mmol) was dissolved in nitrogen-purged toluene:water (5 mL). Pd(OAc)₂ (6 mg, 0.03 mmol), RuPhos (24 mg, 0.05 mmol), K₃PO₄ (213 mg, 1.0 mmol), and 6-methyl-2-((1R,2R)-2-methylcyclopropyl)-1,3,6,2-dioxazaborane-4,8-dione 20 (79 mg, 0.38 mmol) were added. The reaction mixture was refluxed at 100 °C for 2 h, and the reaction was filtered through a diatomaceous earth bed. The filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product.

[0193] (4bR,9bR)-1,9b- Diamino -4b- hydroxyl -7-(1R,2R)-2- methylcyclopropyl )-4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- Ketone hydrochloride (32) : 70 mg (0.21 mmol) of tert-butyl carbamate ((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 31 was dissolved in DCM (2 mL). A solution of 1,4-dioxane (0.6 mL, 2.1 mmol) in 4N HCl was added. The reaction mixture was stirred at room temperature (30 °C) for 12 h. The solvent was evaporated under vacuum to obtain the crude product. The crude product was used without purification.

[0194] N-(4bR,9bR)-1- amino -4b- hydroxyl -7-(1R,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide (33) : 3-Methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxylic acid 30 (48 mg, 0.23 mmol) was dissolved in DMF (4 mL, 0.05 M). HATU (111 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) were added and the mixture was 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 the mixture was 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 then dried over Na2SO4 and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography and then purified again by ADH chiral column chromatography to obtain the final product. 1 H-NMR (300MHz, MeOD) δ 0.66-0.72 (m, 1H), 0.78-0.84 (m, 1H), 0.95-1.03 (m, 1H), 1.13 (d, J = 6.0Hz, 3H), 1.49-1.55 (m, 1H), 2.48 (s, 3H),3.05 (s, 3H), 6.45 (s, 1H), 6.63-6.67 (m, 1H), 6.76 (d, J = 8.1Hz, 1H), 7.02(d, J = 7.2Hz, 1H), 2.27 (d, J = 8.1Hz, 1H), 7.38 (s, 1H), 7.43-7.49 (m, 1H). LCMS: 508.4 [M+H] + .

[0195] Example 2 : N-((4bR,9bR)-1- amino -4b- hydroxyl -7-((1S,2R)-2- methylcyclopropyl )-10- Oxygenation - 4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( Nitrogen heterocyclic butyl -1- base) Acetamide This compound was prepared similarly to the compounds described above. LCMS: 420.2 [M+H] + .

[0196] Example 3 : N-((4bR,9bR)-1- amino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-6- Hydroxypyridine amide The compound was prepared similarly to that in Example 1 above. LCMS: 458.2 [M+H] + .

[0197] Example 4 : N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-5-(N-(2-( dimethylamino ) Ethyl ) Aminosulfonyl )-3,4- dimethyl -1H- Pyrrole -2- formamide (51) : Option 5 4b,9b- dihydroxy -7- Isopropyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (35) : 250 g (1.31 mol) of 4-nitro-1H-indene-1,3(2H)-dione (4) was dissolved in 2 L of 1,4-dioxane and 200 mL of AcOH. 291 g (2.62 mol) of SeO2 was added at room temperature and the mixture was refluxed at 110 °C for 4 hours. The mixture was then stirred at room temperature for 12 hours. 500 g–600 g of diatomaceous earth was then added. The mixture was stirred and filtered through a diatomaceous earth mat. The residue was washed with 300 mL–500 mL of ethyl acetate. The filtrate was concentrated to give crude product 5, which was used as is. 2,2-Dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude, 1.31 mol) was dissolved in 2 L of ice-cold AcOH and 3-isopropylphenol 34 (196 g, 1.44 mol) was added, and the mixture was refluxed for 10 hours. The solution was then concentrated and purified by silica gel column chromatography (30% EA in hexane solution) to obtain the pure product.

[0198] 9b- chlorine -4b- hydroxyl -7- Isopropyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (36) : 35g (50g, 0.147mol) of 4b,9b-dihydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one was dissolved in DCM (500mL), and oxalyl chloride (1.2 equivalents) was added to the suspension in a single batch. DMF (50mL) was then slowly added. The reaction mixture was then stirred at room temperature for another 6 hours. The mixture was quenched with water (500mL) and the layers were separated. The aqueous layer was extracted with DCM (300mL × 2). The combined organic layers were washed with water (300mL) and brine (300mL). The mixture was dried over sodium sulfate and concentrated to obtain a crude product, which was then purified using a short silica pad (30% ethyl acetate in hexane solution) to obtain the pure product. 1 H-NMR (300MHz, CDCl3): δ1.18 (dd, J = 3.6Hz, J = 6.9Hz, 6H), 2.84 (septet peak, J = 6.9Hz, 1H), 6.34 (s, 1H), 6.70 (s, 1H), 6.94 (dd, J = 1.0Hz, J = 7.8Hz, 1H), 7.45 (d,J = 7.8Hz, 1H), 7.81-7.83 (m, 1H), 8.21 (m, 1H), 8.52 (m, 1H).

[0199] 9b- amino -4b- hydroxyl -7- Isopropyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran - 10- ketone (37) : 36 g (0.1 mol) of 9b-chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one was dissolved in 350 mL of THF and cooled to -40 °C. A 2.0 M solution of NH3 in 100 mL (0.20 mol) of IPA was added to the clear solution using a dropping funnel, and the temperature was maintained below -20 °C. The reaction mixture was monitored at -20 °C for one hour, then allowed to warm to room temperature. The mixture was stirred at room temperature until the reaction was complete, and then completely concentrated. The crude product was dissolved in 500 mL of ethyl acetate and washed with water (200 mL × 2) and brine (100 mL). The solution was dried over anhydrous Na2SO4 and then concentrated to obtain a crude product. This crude product was purified using a short silica pad to obtain the pure product. 1 H-NMR (300MHz, CDCl3) δ 1.18 (d, J = 6.9Hz, 6H), 2.84 (septet peak, J = 6.9Hz, 1H), 3.46 (s,1H), 6.25 (s, 1H), 6.74 (s, 2H), 6.90 (dd, J = 1.2Hz, J = 7.8Hz, 1H), 7.55 (d, J =7.8Hz, 1H), 7.77 (t, J = 8.1Hz, 1H), 8.22 (dd, J = 1.2Hz, J = 8.4Hz, 1H), 8.52 (dd, J = 1.2Hz, J = 8.1Hz, 1H).

[0200] Option 6 Acetic acid 3- Nitrobutane -2- ester (39) : 3-Nitrobut-2-ol 38 (7.5 g, 63 mmol) was dissolved in DCM (37.5 mL, 1.7 M), and acetic anhydride (11.3 mL, 120 mmol) was added, followed by DMAP (305 mg, 2.52 mmol). After stirring at room temperature (20 °C) for 24 hours, the reactants were quenched with MeOH (8 mL) and stirred for another hour. The mixture was then dissolved in DCM (250 mL) and washed with saturated NaHCO3 (100 mL × 2), water (100 mL), and brine (~100 mL). The solution was dried over anhydrous Na2SO4 and concentrated to obtain a pure product as an oil.

[0201] Ethyl formylglycine (41) : pTSA (1.36 g, 7.2 mmol) was added to a solution of glycine ester hydrochloride 40 (20.0 g, 0.143 mol) in ethyl formate (90 mL, 1.6 M). The mixture was refluxed, and TEA (22.0 mL, 0.157 mol) was added dropwise at this temperature. The reaction mixture was refluxed again for 24 hours or monitored by TLC. The mixture was then cooled to room temperature (20 °C) and concentrated. The crude product was then filtered through a short silica pad using a 50% EA solution in hexane (3000 mL). This was subsequently concentrated to give the product, which was used unchanged in the next step. NMR indicated the presence of TEA in the product. When excess TEA is used in the next step, it is used unchanged in the next step.

[0202] 2- Ethyl isocyanate (42) : POCl3 (7.5 mL, 80 mmol) was slowly added dropwise to a solution of ethyl formyl glycinate 41 (9.40 g, 80 mmol) and TEA (28 mL, 0.2 mol) in DCM (80 mL, 1.0 M) at 0 °C. The solution turned red, and after the addition was complete, the mixture was allowed to reach room temperature and stirred for another 4 hours. The reaction mixture was then slowly quenched on Na2CO3 solution and solid Na2CO3 and stirred for another 30 minutes at room temperature. The organic layer was separated, and the aqueous layer was extracted with DCM (200 mL × 2). The combined organic layers were then washed with water (100 mL) and brine (100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated to obtain a pure product in liquid form.

[0203] 3,4- dimethyl -1H- Pyrrole -2- Ethyl carboxylate (43) : 39g (8.9g, 55.0mmol) of 3-nitrobutyl-2-yl acetate and 42g (8.1g, 71.5mmol) of 2-isocyanoethyl ester were dissolved in THE:water (1:1, 110mL, 0.5M), and anhydrous K₂CO₃ (12.2g, 88.0mmol) was slowly added in portions under vigorous stirring, and the reaction mixture was stirred at room temperature for another 3 days. The reaction mixture was then concentrated into a thick slurry. It was then diluted with ice-cold water (100mL) and slowly neutralized with 5% HCl (2N, pH=5) at 0°C. It was then extracted with EA (150mL × 3). The combined organic layers were washed with 5% brine (100mL × 2). The mixture was then dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0%-10% EA in hexane solution) to obtain the pure product.

[0204] 5-( Chlorosulfonyl )-3,4- dimethyl -1H- Pyrrole -2- Ethyl carboxylate (44) : Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate 43 (1.67 g, 10.0 mmol) was dissolved in CHCl3 (40 mL, 0.25 M), and chlorosulfonic acid (10.0 mL, 150.0 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for another 3 hours. The reaction mixture was quenched with crushed ice (120 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated to give a crude product. The crude product was passed through a short silica gel pad with DCM, and the filtrate was concentrated to give a pure product.

[0205] 5-(N-(2-(( tert-butoxycarbonyl ) amino ) Ethyl ) Aminosulfonyl )-3,4- dimethyl -1H- Pyrrole -2- Ethyl carboxylate (46) : Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 44 (530 mg, 2.0 mmol) was dissolved in DCM (20 mL, 0.1 M) at room temperature, and tert-butyl (2-aminoethyl)carbamate 45 (385 mg, 2.4 mmol) was added, followed by DIPEA (0.52 mL, 3.0 mmol). The reaction mixture was then stirred at room temperature (25 °C) for 2 hours. The reaction mixture was quenched with water (50 mL) and then extracted with DCM (70 mL × 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (30% EA in hexane solution) to obtain the pure product.

[0206] 5-(N-(2-(( tert-butoxycarbonyl ) amino ) Ethyl ) Aminosulfonyl )-3,4- dimethyl -1H- Pyrrole -2- carboxylic acid (47) : Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)aminosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 46 (682 mg, 1.75 mmol) was dissolved in THF:MeOH:H2O (1:1:10, 18.0 mL, 0.1 M) and LiOH·H2O (367 mg, 5.0 mmol) was added. The reaction mixture was refluxed at 80 °C for 5 hours. The reaction mixture was concentrated to remove volatiles. It was then acidified with 1N HCl (pH < 2-3). The precipitated solid was then filtered off, washed with cold water, and dried to give the pure product.

[0207] Plan-7 (2-((5-((4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) carbamoyl )-3,4- dimethyl -1H- Pyrrole )-2- sulfonamide group ) Ethyl ) tert-butyl carbamate (48) : 452 mg (1.25 mmol) of 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)aminosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid 47 was dissolved in DMF (5 mL, 0.25 M) and cooled to 0 °C. EDCI (360 mg, 1.88 mmol) was added, followed by HOBt (254 mg, 1.88 mmol). After 10 minutes, 425 mg (1.25 mmol) of 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 was added, followed by DIPEA (0.55 mL, 3.13 mmol), and the mixture was allowed to reach room temperature (35 °C) for 18 hours. The reactants were then quenched with water (60 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with water (50 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (40% EA in hexane solution) to obtain the product.

[0208] 5-(N-(2- aminoethyl ) Aminosulfonyl )-N-(4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -1H- Pyrrole -2- formamide (49) : (275 mg, 0.4 mmol) of tert-butyl carbamate 48 was dissolved in DCM (8 mL, 0.05 M) and a solution of 4 M HCl in dioxane (1.0 mL, 4.0 mmol) was added. The mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was diluted with DCM (20 mL) and stirred with saturated NaHCO3 (20 mL) for 10 minutes. Free amine was not released well, and therefore 0.5 mL of TEA was added. The mixture was then diluted with DCM (100 mL), and the layers were separated. The organic layer was washed with saturated NaHCO3 (20 mL), water (30 mL), and brine (30 mL). It was then dried over anhydrous Na2SO4 and concentrated to obtain a solid.

[0209] 5-(N-(2-( dimethylamino ) Ethyl ) Aminosulfonyl )-N-(4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -1H- Pyrrole -2- formamide (50) : 5-(N-(2-aminoethyl)aminosulfonyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 49 (88 mg, 0.15 mmol) was dissolved in MeCN:ice AcOH (2:1, 3 mL, 0.05 M) cooled to 0 °C. A 35% HCHO aqueous solution (0.125 mL, 1.5 mmol) was added, followed by NaBH3CN (33 mg, 0.53 mmol). The mixture was stirred at 0 °C for another 0.5 h. The reaction mixture was quenched with water (40 mL) and extracted with EA (40 mL × 2). The combined organic layers were washed with water (30 mL) and brine (10 mL). The crude product was obtained by drying with anhydrous Na2SO4 and concentrating. The crude product was then purified by column chromatography (0.05% TEA / 0-10% MeOH / DCM) to obtain the pure product.

[0210] N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-5-(N-(2-( dimethylamino ) Ethyl ) Aminosulfonyl )-3,4- dimethyl -1H- Pyrrole -2- formamide (51) : 5-(N-(2-aminoethyl)aminosulfonyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 50 (46 mg, 0.075 mmol) was dissolved in EtOH:water (10:1, 5.0 mL, 0.015 M), and iron powder (13 mg, 0.23 mmol) was added, followed by 1 M HCl (3 drops). The mixture was refluxed at 90 °C for 1.5 hours. The reaction mixture was cooled to 50 °C and then neutralized with TEA (1 drop). The reaction mixture was then filtered through diatomaceous earth under hot conditions 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 Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (10% MeOH in DCM solution) to obtain the pure product. 1 H-NMR (300MHz, CD3OD) δ 1.19 (d, J = 6.9Hz, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 2.43 (s, 6H), 2.65 (t, J = 6.6Hz, 2H), 2.82 (septet peak, J = 6.9Hz, 1H), 3.06 (t, J = 6.6Hz, 2H),6.69 (s, 1H), 6.77 (d, J = 7.8Hz, 1H), 6.85 (d, J = 7.8Hz, 1H), 7.03 (d, J = 7.2Hz, 1H), 7.36 (d, J =7.8Hz, 1H), 7.45-7.50 (m, 1H). LCMS: 582.3 [M+H] + .

[0211] Example 5 : N-((4bR,9bR)-1- amino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( Azacyclobutane -1- base )Acetamide (62) Option 8 2-(1- Cyclopropyl vinyl )-4,4,5,5- Tetramethyl -1,3,2- dioxoborane heterocyclopentane (54) : Anhydrous lithium chloride (7.06 g, 166.5 mmol), CuCl (16.5 g, 166.5 mmol), and anhydrous N,N-dimethylformamide (500 mL) were added to a reaction flask under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. Then, potassium acetate (16.4 g, 166.5 mmol), B2Pin253 (42.3 g, 166.5 mmol), and cyclopropylacetylene 52 (10 g, 151.3 mmol) were added sequentially, and stirring was continued at room temperature for 20 h. The reaction mixture was quenched with saturated NH4Cl solution (100 mL), ethyl acetate (100 mL) was added, and the mixture was filtered through a diatomaceous earth bed. The filtrate was extracted with hexane (200 mL × 3), and the combined organic layers were collected, washed with water (100 mL × 3), washed with brine (100 mL), dried over Na2SO4, and the solvent was evaporated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (hexane) to obtain an oily product.

[0212] Plan-9 2-( Azacyclobutane -1- base ) tert-butyl acetate (57) : Azacyclobutane hydrochloride 56 (73 g, 78 mmol) was dissolved in THF:water (4:1, 170 mL, 0.3 M) and cooled to 0 °C. 2N NaOH aqueous solution (78 mL, 157 mmol) was added and stirred for 10 min. Then, 2-bromoacetic acid tert-butyl 55 (7.2 mL, 49 mmol) was added dropwise at 0 °C, and the mixture was stirred at 30 °C for another 1 h. The reaction mixture was then extracted with EA (150 mL × 2), and the combined organic layers were washed with saturated brine (~50 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to give a crude product in liquid form.

[0213] 2-( Nitrogen heterocyclic butyl -1- base ) Acetate hydrochloride (58) : 57g (6.7g, 39mmol) of 2-(azacyclobutan-1-yl)tert-butyl acetate was cooled to 0°C and a solution of 4M HCl in dioxane (98mL, 0.4M) was slowly added. The reaction mixture was then stirred at room temperature (30°C) for 24 hours. The precipitated solid was then filtered off, washed with cold 1,4-dioxane (~20mL-30mL), and dried to give the pure product.

[0214] Plan-10 ((4bR,9bR)-1- amino -7-(1- Cyclopropyl vinyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (59) : (1-Amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) tert-butyl 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), which had been purged with nitrogen, was added. The reaction mixture was purged again with N2 (10 min), and then 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentane 54 (2.15 g, 11.3 mmol) was added and maintained at 90 °C for another 3 h. The reaction mixture was passed through a diatomaceous earth bed and concentrated. It was dissolved in EA and water, and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (20%-30% EA in hexane solution) to obtain the pure product.

[0215] ((4bR,9bR)-1- amino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen - 9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (60) : Under nitrogen atmosphere, 59 g (5.43 g, 12.5 mmol) of tert-butyl carbamate (1-amino-7-(1-cyclopropylvinyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate was dissolved in DCM (125 mL, 0.10 M) and [((4 S 5 S [Cy2-UBaphox)Ir(COD)]BARF (433 mg, 0.25 mmol). It was then washed with H2 gas and maintained at room temperature (20 °C) under an H2 atmosphere (60 psi) for 4 hours. The reaction mixture was then concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (using 0%-10%-30% EA in hexane solution and 10% DCM as a co-solvent) to obtain the pure product.

[0216] (4bR,9bR)-1,9b- Diamino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (61) : ((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)tert-butyl carbamate 60 (2.18 g, 5.00 mmol) was dissolved in DCM (50 mL, 0.1 M), and immediately a dioxane solution of 4.0 M HCl (12.5 mL, 50.0 mmol) was added. The reaction mixture was then stirred at room temperature (20 °C) for another 6 hours. The reaction mixture was diluted with EA (~150 mL) and stirred with saturated NaHCO3 (~100 mL) for 5-10 minutes.

[0217] Separate the layers and extract the aqueous layer with EA (~100 mL). Wash the combined organic layer with water (100 mL) and brine (~100 mL). Dry the mixture with anhydrous Na2SO4 and concentrate to obtain the product, which is used as is in the next step without further purification.

[0218] N-((4bR,9bR)-1- amino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen - 9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( Nitrogen heterocyclic butyl-1- base ) Acetamide (62) : At 0 °C, HATU (2.57 g, 6.75 mmol) and DIPEA (2.35 mL, 13.5 mmol) were added to 45 mL of anhydrous DMF (0.1 M) solution of 2-(azacyclobut-1-yl)acetate hydrochloride 58 (1.02 g, 6.75 mmol). After 10 minutes, (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) were added and the mixture was stirred at room temperature (20 °C) for 15 h. The reaction mixture was quenched with water (~100 mL) and saturated NaHCO3 (~100 mL). It was then extracted with EA (100 mL × 3). The combined organic layers were washed with water (100 mL × 2) and brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0%-10% MeOH in DCM solution) to obtain the pure product. 1 H-NMR (500MHz, MeOD) δ 7.50 - 7.39(m, 1H), 7.29 (d, J = 8.0Hz, 1H), 6.99 (d, J = 7.3Hz, 1H), 6.85 (dd, J = 8.0, 1.3Hz, 1H), 6.72 (d, J = 8.5Hz, 1H), 6.69 (d, J = 1.3Hz, 1H), 3.37 (t, J = 7.3Hz,4H), 3.18 (s, 2H), 2.09 (p, J = 7.1Hz, 2H), 1.91-1.83 (m, 1H), 1.25 (d, J =7.0Hz, 3H), 0.94 – 0.79 (m, 1H), 0.55-0.47 (m, 1H), 0.40 – 0.26 (m, 1H), 0.17-0.13 (m, 1H), 0.07-0.03 (m, 1H). LCMS: 432.3 [M - H] - LCMS: 434.2 [M+H] + .

[0219] Example 6 :N-(1- amino -7-((1R,2S)-1,2- Dimethylcyclopropyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- Formamide.

[0220] The compound was prepared similarly to that in Example 5 above. LCMS: 522.2 [M+H] + .

[0221] Example 7 : N-(1- amino -4b- hydroxyl -7-(2- methylcyclobutyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- Formamide.

[0222] The compound was prepared similarly to that in Example 5 above. LCMS: 522.2 [M+H] + .

[0223] Example 8 : N-((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-6- Hydroxypyridine amide The compound was prepared similarly to that in Example 5 above. LCMS: 458.1 [M+H] + .

[0224] Example 9 : N-(1- amino -4b- hydroxyl -7-(( trans)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen - 9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (83) : Plan-11 3-(( tert-butyldimethylsilyl ) Oxygen ) benzaldehyde (64) : At 0 °C, tert-butylchlorodimethylsilane (44.4 g, 0.30 mol) was slowly added to a solution of 3-hydroxybenzaldehyde (30 g, 0.25 mol) and imidazole (21.7 g, 0.32 mol) in anhydrous dichloromethane (250 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and washed with DCM. The organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified on a silica gel column by elution with EA / hexane (0 / 100 -> 1 / 10) to give the desired product. 1 HNMR (300MHz, CDCl3) δ 9.95 (s, 1H), 7.40 (tdd, J = 21.4, 12.8, 9.5Hz, 3H), 7.11(ddd, J = 7.9, 2.5, 1.2Hz, 1H), 1.00 (s, 9H), 0.23 (d, J = 3.0Hz, 6H).

[0225] (E)- tert-butyldimethyl (3-( C -1- olefins -1- base ) phenoxy ) silane (66) : Acetic acid (13.7 mL, 0.24 mol) was added dropwise 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) at room temperature. The reaction mixture was stirred for 10 min, and then ammonium acetate (12.2 g, 0.16 mol) was added. The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered, concentrated, and purified on a silica gel column by elution with n-Hex to give the desired product. 1 H NMR (300MHz, CDl3) δ 7.14 (td, J = 7.8, 2.8Hz, 1H), 6.92 (d, J = 7.5Hz, 1H), 6.81 (s, 1H), 6.68 (d, J = 8.0Hz, 1H), 6.35(d, J = 15.9Hz, 1H), 6.22 (m, 1H), 1.88 (d, J = 6.1Hz, 3H), 0.99 (d, J = 2.6Hz, 9H), 0.20 (d, J = 2.6Hz, 6H).

[0226] tert-butyldimethyl (3-(( trans )-2- methylcyclopropyl ) phenoxy ) silane (67) : Diethylzinc (50 mL, 1.0 M hexane solution, 0.05 mol) was added dropwise to anhydrous dichloromethane (150 mL) with stirring at -40 °C. After 10 min, a solution of diiodomethane (8 mL, 0.1 mol) in anhydrous dichloromethane (25 mL) was added dropwise to the reaction mixture at -40 °C. The reaction mixture was stirred at -40 °C for 1 h. Trichloroacetic acid (0.82 g, 0.005 mol) and DME (2.59 mL, 0.025 mol) in anhydrous dichloromethane (25 mL) were added dropwise to the reaction mixture at -40 °C. The reaction mixture was stirred at -15 °C for 1 h. At -15°C, 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) was added dropwise to the reaction mixture. After 10 min, the reaction mixture was heated to room temperature and stirred overnight at room temperature. 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 MgSO4, concentrated, and purified on a silica gel column. Elution with n-Hex / EA (100 / 0 -> 50 / 1) yielded the desired racemic product with an oily trans geometry. 1 H NMR (300MHz, CDCl3) δ 7.08 (t, J = 7.8Hz, 1H), 6.60 (m, 2H), 6.48 (t, J = 2.0Hz, 1H), 1.87 (dd, J = 6.4, 1.3Hz, 0.20H), 1.51 (dt, J =8.9, 3.3Hz, 1H), 1.19 (dd, J = 15.5, 5.8Hz, 3H), 1.01 (m, 9H), 0.81 (m, 2H), 0.71 (m, 1H), 0.18 (m, 6H).

[0227] 3-(( trans )-2- methylcyclopropyl ) phenol (68) : Concentrated HCl (30 mL) was added dropwise to a solution of racemic tert-butyldimethyl(3-((trans)-2-methylcyclopropyl)phenoxy)silane 67 (32.93 g, 0.12545 mol) in ethanol (300 mL) with stirring. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified on a silica gel column, eluted with EA / Hex (1 / 20 -> 1 / 15) to give 3-((1S,2S)-2-methylcyclopropyl)phenol (product). 1 H NMR (300MHz, CDCl3) δ 7.10 (t, J = 7.9Hz,1H), 6.59 (m, 2H), 6.49 (m, 1H), 4.66 (d, J = 8.7Hz, 1H), 1.52 (dt, J = 8.9, 4.6 Hz, 1H), 1.15 (t, J = 10.4Hz, 3H), 1.04 (tdd, J = 10.3, 5.7, 4.5Hz, 1H), 0.86(m, 1H), 0.72(m, 1H).

[0228] 4b,9b- dihydroxy -7-(( trans )-2- methylcyclopropyl )-4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2- b] Benzofuran -10- ketone (69) : Selenium dioxide (19 g, 0.17 mol) was added 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). The reaction mixture was refluxed at 130 °C for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, filtered through a diatomaceous earth mat, and concentrated to give crude product 5, which was used in the next step without purification. A racemic mixture of 3-((trans)-2-methylcyclopropyl)phenol (12.7 g, 0.085 mol) was added to a solution of 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (crude product) in glacial acetic acid (140 mL). The reaction mixture was refluxed at 80 °C for 3 hours, cooled to room temperature, diluted with EA, filtered, and concentrated. The residue was purified on a silica gel column and eluted with EA / hexane (1 / 2 -> 2 / 3) to obtain the desired product. 1H NMR (300MHz, CDCl3) δ 8.48 (dd, J = 8.0, 0.9Hz, 1H), 8.16 (dd, J = 7.6, 1.0Hz, 1H), 7.77 (t, J =7.8Hz, 1H), 7.40 (d, J = 7.9Hz, 1H), 6.72 (ddd, J = 7.9, 3.9, 1.4Hz, 1H), 6.45(m, 1H), 1.50 (m, 1H), 1.12 (m, 3H), 0.98 (m, 1H), 0.81 (dt, J = 14.8, 5.5Hz,1H), 0.75 (m, 1H).

[0229] 9b- chlorine -4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2- b] Benzofuran -10- ketone (70) : 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) was added dropwise to a solution of anhydrous dichloromethane (143 mL) at room temperature, followed by the addition of oxaloyl chloride (2.90 mL, 0.03 mol). Anhydrous DMF (10 mL) was added dropwise to the reaction mixture with stirring at room temperature (~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 MgSO4, filtered, concentrated, and purified on a silica gel column, eluted with EA / Hex (1 / 4 -> 1 / 2) to give the desired product. 1 H NMR (300MHz, CDCl3) δ 8.49 (dd, J = 8.0, 1.1Hz, 1H), 8.19 (dd, J =7.7, 1.1Hz, 1H), 7.80 (t, J = 7.9Hz, 1H), 7.38 (d, J = 8.0Hz, 1H), 6.75 (dt, J=8.1, 1.6Hz, 1H), 6.44 (t, J = 1.4Hz, 1H), 6.29 (s, 1H), 1.50 (m, 1H), 1.13 (dd, J = 5.7, 1.2Hz, 3H), 0.99 (m, 1H), 0.82 (dt, J = 12.4, 4.4Hz, 1H), 0.76 (m, 1H).

[0230] 9b- amino -4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -4b,9b- Dihydrogen -10H- Indene [1, 2-b] Benzofuran -10- ketone (71) : At -40 °C, a solution of racemic 9b-chloro-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (6.47 g, 0.017 mol) in anhydrous THF (90 mL) was added dropwise with ammonia solution (26.1 mL, 0.052 mol, 2.0 M IPA solution) for ~10 min. The reaction mixture was stirred at -40 °C for 1 h, then at -20 °C for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine and water. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a silica gel column, eluted with EA / Hex (1 / 2 -> 2 / 3) to give the desired product. 1 HNMR (300MHz, CDCl3) δ 8.48 (m, 1H), 8.10 (d, J = 7.6Hz, 1H), 7.73 (dd, J = 13.5, 5.6 Hz, 1H), 7.27 (d, J = 7.4Hz, 1H), 6.68 (m, 1H), 6.45 (d, J = 2.7Hz, 1H), 1.48(d, J = 5.1Hz, 1H), 1.13 (t, J = 5.0Hz, 3H), 0.98 (d, J = 6.7Hz, 1H), 0.81 (dd, J=5.0, 1.9Hz, 1H), 0.73 (dd, J = 7.3, 4.9Hz, 1H).

[0231] Option-12 3- methyl -1-( phenylsulfonyl )-1H- Pyrrole -2- Methyl carboxylate (73) : At 0 °C, NaH (1.51 g, 37.8 mmol) was added to a solution of methyl 3-methyl-1H-pyrrole-2-carboxylate 27 (3.5 g, 25.2 mmol) in anhydrous DMF (63 mL), followed by the addition of benzenesulfonyl chloride 72 (4.82 mL, 37.8 mmol). The reaction mixture was stirred at 0 °C to room temperature for 15 h. The reaction was quenched with ice water (300 mL), the aqueous layer was extracted with ethyl acetate (3 × 100 mL), and the combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane), and the obtained product was recrystallized using DCM and HX.

[0232] 5-( methoxycarbonyl )-4- methyl -1-( phenylsulfonyl )-1H- Pyrrole -2- sulfinic acid (74) : Methyl 3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylic acid ester 73 (5.03 g, 18 mmol) was dissolved in THF (180 mL). The resulting solution was cooled to -78 °C, and lithium diisopropylamino (18 mL, 36 mmol) was added dropwise at -78 °C, while the reaction mixture was stirred at -78 °C for 1 h. Sulfur dioxide (gas) was slowly bubbled into the cold solution at -78 °C for 30 min. The resulting reaction mixture was slowly heated to room temperature and stirred at room temperature for 12 h. THF was removed under vacuum, and the resulting residue was dissolved in water and washed with ethyl acetate (50 mL × 2). The aqueous layer was acidified to pH ~ 1 with 1N HCl, extracted with ethyl acetate (200 mL × 3), and the combined organic layers were washed with water and brine solution. The organic layers were dried over Na2SO4, and the solvent was evaporated to obtain the product, which was used as is in the next step without purification.

[0233] 5-( Chlorosulfonyl )-3- methyl -1-( phenylsulfonyl )-1H- Pyrrole-2- Methyl carboxylate (75) : 3.9 g (11.4 mmol) of 5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-sulfinic acid 74 was dissolved in 115 mL of THF and cooled to 0 °C. 1.83 g (13.7 mmol) of NCS was added. The reaction mixture was stirred at room temperature for 15 h. THF was removed under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product.

[0234] 4-((5-( methoxycarbonyl )-4- methyl -1-( phenylsulfonyl )-1H- Pyrrole -2- base ) sulfonyl ) Piperazine -1- tert-butyl carboxylate (77) : Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylic acid 75 (491.2 mg, 1.3 mmol) was dissolved in DCM (13 mL). Piperazine-1-carboxylic acid tert-butyl ester 76 (290.6 mg, 1.56 mmol) was added, followed by DIPEA (0.340 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL × 3), dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the final product.

[0235] 4-((5-( methoxycarbonyl )-4- methyl -1H- Pyrrole -2- base ) sulfonyl ) Piperazine -1- tert-butyl carboxylate (78) : 77 (660 mg, 1.25 mmol) of 4-((5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in MeOH:H2O (13 mL). K2CO3 (518.3 mg, 3.75 mmol) was added to this solution. The reaction mixture was stirred at 50 °C for 12 h. Methanol was evaporated, and the resulting residue was dissolved in water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with water and then with a brine solution. The organic layers were dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the final product.

[0236] 5-((4-( tert-butoxycarbonyl ) Piperazine -1- base ) sulfonyl )-3- methyl -1H- Pyrrole -2- carboxylic acid (79) : 78 (360 mg, 0.93 mmol) of 4-((5-(methoxycarbonyl)-4-methyl-1H-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in MeOH:H2O (1:10) (10 mL) and LiOH·H2O (195 mg, 4.65 mmol) was added. The reaction mixture was heated at 70 °C for 8 h. The MeOH was removed under vacuum, and the aqueous layer was diluted with water (10 mL) and acidified with 1N HCl to pH ~ 1. The product was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water and then with brine, dried over Na2SO4, and the solvent was evaporated to give product (79), which was used as is in the next step without purification.

[0237] Plan-13 4-((5-((4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -10- Oxygenation -4b,10- Dihydrogen - 9bH- Indene [1,2-b] Benzofuran -9b- base ) carbamoyl )-4- methyl -1H- Pyrrole -2- base ) sulfonyl ) Piperazine-1- tert-butyl carboxylate (80) : 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.

[0238] N-(4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-( Piperazine -1- sulfonyl )-1H- Pyrrole -2- formamide (81) : Racemic 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 (250 mg, 0.35 mmol) was added to a solution of 1,4-dioxane in 4N HCl (0.9 mL, 3.5 mmol) in DCM (7 mL, 0.05 M), and the reaction mixture 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 alkalized with 10% NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and then with brine. The organic layer was dried with Na2SO4 and the solvent was evaporated to obtain a solid product, which was used as is in the next step without further purification.

[0239] N-(4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (82) : At 0 °C, a racemic solution of N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 81 (100 mg, 0.16 mmol) in ice-cold AcOH:MeCN (1:1) (4 mL) was reacted with an aqueous solution of formaldehyde (35%) (0.15 mL, 1.6 mmol), followed by the addition of NaBH3CN (36 mg, 0.6 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, and the aqueous layer was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography to give a solid product.

[0240] N-(1- amino -4b- hydroxyl -7-(( trans )-2-methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (83) : 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) was added to an EtOH:H2O (10:1) (6 mL) solution, and Fe powder (10 mg, 0.2 mmol) and concentrated HCl (1 drop) were added. The reaction was stirred at 90 °C for 3 h. The hot reactants were filtered through a diatomaceous earth bed. 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 then with brine. The organic layers were dried over Na2SO4, and the solvent was evaporated. The crude product was purified by silica gel column chromatography to give a solid product. 1 H-NMR (300MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.81-0.89 (m, 1H), 0.98-1.02(m, 1H), 1.16 (d,J= 5.7Hz, 1H), 1.53-1.59 (m, 1H), 2.29 (s, 3H), 2.30 (s,3H), 2.50-2.53 (m, 4H), 2.99-3.12 (m, 4H), 6.48 (s, 1H), 6.54 (s, 1H), 6.69-6.78 (m, 2H), 7.04 (d, J = 7.2Hz, 1H), 7.33 (d, J = 6.3Hz, 1H), 7.46-7.51 (m,1H). LCMS: 592.2 (M+H] + .

[0241] Example 10 : (2S,3S)-N-(1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene[1,2-b] Benzofuran -9b- base )-2-( dimethylamino )-3- Hydroxybutyramide The compound was prepared similarly to that in Example 9 above. LCMS: 466.4 [M+H] + .

[0242] Example 11 : N-(1- amino -4b- hydroxyl -7-(1S,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-5-(((S)-3-( dimethylamino ) pyrrolidine -1- base ) sulfonyl )- 3- methyl -1H- Pyrrole -2- formamide (89) Plan-14 (S)-5-((3-(( tert-butoxycarbonyl ) amino ) pyrrolidine -1- base ) sulfonyl )-3- methyl -1-( phenylsulfonyl )-1H- Pyrrole -2- Methyl carboxylate (84) : Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylic acid 75 (985 mg, 2.6 mmol) was dissolved in DCM (26 mL). (S)-pyrrolidine-3-ylcarbamate tert-butyl ester (583 mg, 3.1 mmol) was added, followed by DIPEA (0.7 mL, 3.9 mmol). The reaction mixture was stirred at 30 °C for 15 h. The reactants were diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous 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.

[0243] (S)-5-((3-(( tert-butoxycarbonyl ) amino ) pyrrolidine-1- base ) sulfonyl )-3- methyl -1H- Pyrrole -2- carboxylic acid (85) : LiOH·H₂O (855 mg, 20.8 mmol) was added to a solution of (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidine-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), and the reaction was stirred at 80 °C for 15 h. The organic solvent was evaporated. The reaction mixture was acidified with 1N HCl solution, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine. The organic layers were dried over Na₂SO₄, and the solvent was evaporated under vacuum to give the solid product.

[0244] ((3S)-1-((5-((4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) carbamoyl )-4- methyl -1H- Pyrrole -2- base ) sulfonyl ) pyrrolidine -3- base ) tert-butyl carbamate (86) : At 0 °C, EDCI (212 mg, 1.1 mmol) was added to a solution of (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 85 (276 mg, 0.7 mmol) in DMF (7 mL), followed by HOBt (149 mg, 1.1 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 (260 mg, 0.7 mmol) was added, followed by DIPEA (0.4 mL, 2.2 mmol). The reaction mixture was stirred at room temperature (30 °C) for 20 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and then with brine, and dried over Na2SO4. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product.

[0245] 5-(((S)-3- aminopyrrolidine -1- base ) sulfonyl )-N-(4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )- 4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -1H- Pyrrole -2- formamide (87) : A racemic mixture (170 mg, 0.24 mmol) of ((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-pyrrolo-2-yl)sulfonyl)pyrrolidine-3-yl)carbamate tert-butyl ester 86 was added to a stirred solution in DCM (5 mL, 0.05 M) with 1,4-dioxane solution of 4N HCl (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 alkalized with 10% NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and then with brine. The organic layers were dried over Na₂SO₄. The solvent was evaporated under vacuum to obtain the product.

[0246] 5-(((S)-3-( dimethylamino ) pyrrolidine -1- base ) sulfonyl )-N-(4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -1H- Pyrrole -2- formamide (88) : At 0 °C, a racemic mixture (120 mg, 0.2 mmol) of 5-(((S)-3-aminopyrrolidine-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 was added to a stirred solution in ice-cold AcOH:MeCN = 1:1 (7 mL, 0.03 M) with formaldehyde (35% aqueous solution) (0.34 mL, 3.9 mmol), followed by the addition of NaBH3CN (62 mg, 1.0 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, and the aqueous layer was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography to obtain the final product.

[0247] N-(1- amino -4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-5-(((S)-3-( dimethylamino ) pyrrolidine -1- base ) sulfonyl )-3- methyl -1H- Pyrrole -2- formamide (89) : Fe powder (8 mg, 0.2 mmol) and concentrated HCl (1 drop) were added to a racemic mixture (32 mg, 0.05 mmol) of 5-(((S)-3-(dimethylamino)pyrrolidine-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 in EtOH:H2O (10:1) (5 mL) with stirring. The reaction mixture was stirred at 90 °C for 3 h. The hot reaction mixture was filtered through a diatomaceous earth bed. The filtrate was evaporated under vacuum, and the resulting residue was dissolved in ethyl acetate, washed with water and then with brine. The organic layer was dried over Na2SO4, and the solvent was evaporated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a solid product. 1 H-NMR (300MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.82-0.89(m, 1H), 0.97-1.07 (m, 1H), 1.16 (d, J = 5.7Hz, 3H), 1.53-1.59 (m,1H), 1.62-1.72 (m, 1H), 2.02-2.08 (m, 1H), 2.22 (s, 6H), 2.31 (s, 3H), 2.64-2.75 (m,1H), 2.98- 3.05 (m, 1H), 3.16-3.27 (m, 1H), 3.41-3.53 (m, 2H), 6.48 (s, 1H), 6.58 (s, 1H), 6.69-6.77 (m, 2H), 7.04 (d, J = 7.2Hz, 1H), 7.33 (d, J = 7.2Hz, 1H), 7.47-7.52 (m, 1H). LCMS: 606.3 (M+H] + .

[0248] Example 12 : N-((4bR,9bR)-1- amino -4b- hydroxyl -7-(( trans )-2- methylcyclopropyl )-10- Oxygenation - 4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -5-((4- Methylpiperazine -1- base ) sulfonyl)-1H- Pyrrole -2- formamide Plan-15 4-((5-( ethoxycarbonyl )-3,4- dimethyl -1H- Pyrrole -2- base ) sulfonyl ) Piperazine -1- tert-butyl carboxylate (123) : Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (530 mg, 2.0 mmol) was dissolved in DCM (20 mL, 0.1 M) at room temperature, and piperazine-1-carboxylate tert-butyl ester (448 mg, 2.4 mmol) was added, followed by DIPEA (0.52 mL, 3.0 mmol). The reaction mixture was then stirred at room temperature (25 °C) for 18 hours. The reaction mixture was quenched with water (50 mL) and then extracted with DCM (70 mL × 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (10%–20% EA in hexane solution) to obtain the pure product.

[0249] 5-((4-( tert-butoxycarbonyl ) Piperazine -1- base ) sulfonyl )-3,4- dimethyl -1H- Pyrrole -2- carboxylic acid (124) : 4-((5-(ethoxycarbonyl)-3,4-dimethyl-1H-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (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. The reaction mixture was refluxed at 80 °C for 5 hours. The reaction mixture was concentrated to remove volatiles. It was then acidified with 1 N HCl (pH < 2-3). The precipitated solid was then filtered off, washed with cold water, and dried to give the product.

[0250] 4-(5-((4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene[1,2-b] Benzofuran -9b- base ) carbamoyl )-3,4- dimethyl -1H- Pyrrole -2- carbonyl ) Piperazine -1- tert-butyl carboxylate (125) : 5-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (264 mg, 0.75 mmol) was dissolved in DMF (4 mL, 0.2 M) and cooled to 0 °C. EDC.HCl (216 mg, 1.125 mmol) and HOBt (152 mg, 1.125 mmol) were added. After 10 minutes, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (255 mg, 0.75 mmol) was added, followed by DIPEA (0.33 mL, 1.875 mmol), and allowed to reach room temperature (35 °C). The mixture was stirred for another 18 h. The reaction mixture was then quenched with water (30 mL) and extracted with EA (50 mL × 2). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography (20%-50% EA:MeOH (4:1) in hexane solution) to obtain an impure product, which was then purified again using a MeOH / DCM system to obtain the pure product.

[0251] N-(4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -5-( Piperazine -1- carbonyl )-1H- Pyrrole -2- formamide (126) : 135 mg (0.2 mmol) of 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-carboxylic acid tert-butyl ester was dissolved in DCM (2.0 mL, 0.1 M), and a dioxane solution of 4 M HCl (0.50 mL, 2.0 mmol) was added. The mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was concentrated, and the residue was dissolved in EA (20 mL–30 mL) and stirred with saturated NaHCO3 (approximately 20 mL) for 5–10 minutes. The mixture was then extracted with EA (50 mL × 2).

[0252] The combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated to obtain a crude product. The crude product was used in the next step without further purification.

[0253] N-(4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -5-(4- Methylpiperazine -1- carbonyl )-1H- Pyrrole -2- formamide (127) : N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(piperazin-1-carbonyl)-1H-pyrrole-2-carboxamide (90 mg, 0.15 mmol) was dissolved in MeCN:ice AcOH (2:1, 3 mL, 0.05 M) cooled to 0 °C. A 35% HCHO aqueous solution (0.13 mL, 1.5 mmol) was added, followed by NaBH3CN (33 mg, 0.525 mmol). The mixture was stirred at 0 °C for another 2 hours. The reaction mixture was quenched with water (20 mL), saturated NaHCO3 (20 mL), and extracted with EA (40 mL × 2). The combined organic layers were washed with water (30 mL) and brine (10 mL). The crude product was obtained by drying with anhydrous Na2SO4 and concentrating. The crude product was then purified by thin-layer silica gel column chromatography (0%-5% MeOH in DCM solution) to obtain the pure product.

[0254] N-(1- amino-4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,4- dimethyl -5-(4- Methylpiperazine -1- carbonyl )-1H- Pyrrole -2- formamide (128) : 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-methylpiperazin-1-carbonyl)-1H-pyrrole-2-carboxamide (60 mg, 0.1 mmol) was dissolved in EtOH:water (10:1, 5.0 mL, 0.02 M), and Fe powder (17 mg, 0.3 mmol) was added, followed by 1 drop of 6.0 M HCl. The mixture was refluxed at 90 °C for 2.0 h. The reaction mixture was filtered through diatomaceous earth using EA (30 mL) under warm conditions. The filtrate was concentrated and dissolved in EA (100 mL), and washed with saturated NaHCO3 (20 mL × 2), water (20 mL × 2), and brine (20 mL). The crude product was obtained by drying with anhydrous Na2SO4 and concentrating. The crude product was then purified by silica gel column chromatography (0%-10% MeOH in DCM solution) to obtain the pure product.

[0255] 1H NMR (500MHz, methanol-d4) δ: 7.48 (br s, 2H), 7.05 (br s, 1H), 6.89 (brs, 1H), 6.70 (br s, 2H), 3.10 (br s, 4H), 2.87 (dt, J=13.4, 6.6Hz, 1H), 2.51(br t, J=4.4Hz, 4H), 2.29 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.21 (d, J=6.9Hz, 6H); LCMS: 594.2 (M+H] + Example 13 : N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2- b] Benzofuran -9b- base)-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide The above compounds were prepared using the following method.

[0256] Plan-16 4-((5-((4b- hydroxyl -7- Isopropyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) carbamoyl )-4- methyl -1H- Pyrrole -2- base ) sulfonyl ) Piperazine -1- tert-butyl carboxylate (122) : 79 (384 mg, 1.0 mmol) of 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid) was dissolved in DMF (10 mL, 0.1 M) and cooled to 0 °C. EDCI (288 mg, 1.5 mmol) was added, followed by HOBt (203 mg, 1.5 mmol). After 10 minutes, 37 (340 mg, 1.0 mmol) of 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one) was added, followed by DIPEA (0.43 mL, 2.5 mmol), and the mixture was allowed to reach room temperature (35 °C) for another 12 hours. The reaction mixture was then quenched with water (30 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography (25%-30% EA in hexane solution) to obtain the final product.

[0257] N-(4-((11- Nitrogenyl ) peroxide )-4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran-9b- base )-3- methyl -5-( Piperazine -1- sulfonyl )-1H- Pyrrole -2- formamide (122-1) At room temperature, a dioxane solution of 4N HCl (1.2 mL, 4.9 mmol) was added to a stirred solution of 340 mg (0.49 mmol) of 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-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (DCM) in 10 mL. The resulting reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated to dryness, and the resulting residue was dissolved in water (50 mL) and alkalized with saturated NaHCO3 solution. The product was extracted with EA (50 mL × 3), and the combined organic layers were washed with water and brine solution. The organic layers were dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:20) to obtain the desired product.

[0258] N-(4-((11- Nitrogenyl ) peroxide )-4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (122-2) At 0 °C, 35% formaldehyde solution (0.15 mL, 1.7 mmol) was added to a stirred solution of N-(4-((l1-azenyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 122-1 (100 mg, 0.17 mmol) in ice-cold AcOH:MeCN (4 mL), followed by the addition of NaBH3CN (36 mg, 0.6 mmol). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water, and the desired product was extracted with EA (50 mL × 3). The combined organic layers were washed with water and brine. The organic layers were dried over anhydrous NaSO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:20) to obtain the desired product.

[0259] N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (122-3) Fe powder (14 mg, 0.25 mmol) was added to a stirred solution of N-(4-((l1-azenyl)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (51 mg, 0.08 mmol) in EtOH:H2O (3 mL), followed by the addition of concentrated HCl (1 drop). The resulting reaction mixture was refluxed at 90 °C for 3 h. The hot reaction mixture was filtered through a diatomaceous earth bed and washed with EA. The organic layer was evaporated to dryness, and the resulting residue was dissolved in EA (100 mL) and washed with water (50 mL × 2) and a brine solution. The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography to obtain the desired product. 1H NMR (300MHz, MeOD) δ 7.42-7.33(m, 1H), 7.03 (d, J=7.4Hz, 1H), 6.87 (d, J=7.9Hz, 1H), 6.81-6.72 (m, 1H), 6.69 (s, 1H), 6.52 (s, 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=6.9Hz, 6H). Quality:[M+H] + 580.1 Example 14 : N-((4bR,9bR)-1- amino -4b- hydroxyl -7-((1S,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide Plan-17 Similar to Example 12, the compound was prepared using a 3,4-dimethylpyrrole derivative according to the above scheme. (300MHz, MeOD) δ 0.70-0.76 (m, 1H), 0.81-0.89 (m, 1H), 0.98-1.02 (m, 1H), 1.16 (d, J= 5.7Hz, 1H), 1.53-1.59 (m, 1H), 2.29 (s, 3H), 2.30 (s, 3H), 2.50-2.53 (m, 4H), 2.99-3.12 (m, 4H), 6.48 (s, 1H), 6.54 (s, 1H), 6.69-6.78 (m,2H), 7.04 (d, J = 7.2Hz, 1H), 7.33 (d, J = 6.3Hz, 1H), 7.46-7.51 (m, 1H). LCMS: 592.1 (M+H]+, HPLC purity: 95.4% Example 15 : (2S,3S)-N-((4bR,9bR)-1- amino-7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( dimethylamino )-3- Hydroxybutyramide The compound was prepared similarly to that in Example 12 above. LCMS: 466.3 [M+H] + .

[0260] Example 16 : N-(1- amino -4b- hydroxyl -7-((1R,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide The compound was prepared similarly to that in Example 12 above. LCMS: 508.3 [M+H] + .

[0261] Example 17 : N-((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( Azacyclobutane -1- base ) Acetamide (92) Plan-18 ((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen - 9bH- Indene [1,2-b] Benzofuran-9b- base ) tert-butyl carbamate (90) : Under nitrogen atmosphere, tert-butyl carbamate 59 (174 mg, 0.40 mmol) was dissolved in DCM (8.0 mL, 0.05 M) and [(( 4R, 5 R [Cy2-UBaphox)Ir(COD)]BARF (13.9 mg, 0.008 mmol). It was then washed with H2 gas and maintained at room temperature (20 °C) under H2 atmosphere (60 psi) for 4 hours. The reaction mixture was then concentrated and passed through a short silica stopper. The crude product was obtained by concentration. The crude product was purified by silica gel column chromatography, followed by preparative HPLC (ADH column (Diacel 250 × 20 mm), EtOH:MeOH:hexane = 36:4:60).

[0262] (4bR,9bR)-1,9b- Diamino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (91) : Enantiomeric purity of 90 mg (70 mg, 0.16 mmol) of 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 was dissolved in DCM (1.6 mL, 0.1 M), and immediately followed by the addition of a 4.0 M HCl solution in dioxane (0.40 mL, 1.60 mmol). The reaction mixture was then stirred at room temperature (20 °C) for 6 hours. The reaction mixture was diluted with EA (~50 mL) and stirred with saturated NaHCO3 (~30 mL) for 5-10 minutes. The layers were separated, and the aqueous layer was extracted with EA (~30 mL × 2). The combined organic layers were washed with water (30 mL) and brine (~30 mL). The product was dried and concentrated with anhydrous Na2SO4 to obtain a crude solid product, which was used as is in the next step without further purification.

[0263] N-((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen- 9bH- Indene [1,2-b] Benzofuran -9b- base )-2-( Azacyclobutane -1- base ) Acetamide (92) : At 0 °C, HATU (87.5 mg, 0.23 mmol) and DIPEA (79 µL, 0.23 mmol) were added to 1.5 mL of anhydrous DMF (0.1 M) solution of 2-(azacyclobut-1-yl)acetate hydrochloride 58 (34 mg, 0.23 mmol). 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) were added and the mixture was stirred at room temperature (20 °C) for 15 h. The reaction mixture was quenched with water (~20 mL) and saturated NaHCO3 (~30 mL). It was then extracted with EA (50 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0%-10% MeOH in DCM solution) to obtain the solid product. 1 H-NMR (300MHz, MeOD) δ 7.51 - 7.39 (m, 1H),7.28 (d, J = 7.9Hz, 1H), 6.99 (d, J = 7.0Hz, 1H), 6.85 (dd, J = 7.9, 1.3Hz, 1H),6.78 - 6.65 (m, 2H), 3.38 (t, J = 7.2Hz, 4H), 3.19 (s, 2H), 2.14 - 2.03 (m,2H), 1.91-1.84 (m, 1H), 1.25 (d, J = 7.0Hz, 3H), 0.96 - 0.80 (m, 1H), 0.54-0.49 (m, 1H), 0.37-0.32 (m, 1H), 0.23 - 0.12 (m, 1H), 0.10-0.02 (m, 1H). LCMS:432.2 [M - H] - LCMS: 434.3 [M+H] + .

[0264] Example 18: N-((4bR,9bR)-1- amino -7-((S)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide The compound was prepared similarly to that in Example 15 above. LCMS: 475.1 [M+H] + .

[0265] Example 19 and Examples 20 : N-((4bR,9bR)-1- amino -4b- hydroxyl -7- Isopropoxy -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b]- Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )- 1H- Pyrrole -2- formamide (101) and N-((4bS,9bS)-1- amino -4b- hydroxyl -7- Isopropoxy -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (102) : Plan-19 4b,9b- dihydroxy -7- Isopropoxy -4- Nitro -4b,9b- Dihydrogen-10H- Indene [1,2-b] Benzofuran -10- ketone (94) : 10.0 g (52.3 mmol) of 4-nitro-1H-indene-1,3(2H)-dione 4 was dissolved in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added, and the mixture was refluxed at 105-110 °C for 5 hours. The reaction mixture was then filtered through diatomaceous earth under thermal conditions, and the volatiles were concentrated to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5. This crude product was dissolved in acetic acid (106 mL), and 8.1 g (53 mmol) of 3-isopropoxyphenol 93 was added. The resulting reaction mixture was heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain a solid product.

[0266] 9b- chlorine -4b- hydroxyl -7- Isopropoxy -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran - 10- ketone (95) : 4b,9b-dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 94 (5.4 g, 15 mmol) was dissolved in DCM (75 mL). Oxaloyl chloride (2.6 mL, 30 mmol) was added, followed by dropwise addition of DMF (5.4 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (300 mL), and the organic layer was washed with water (200 mL × 2) and a brine solution, and then dried over Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to give the solid product.

[0267] 9b- amino -4b- hydroxyl -7- Isopropoxy -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran - 10- ketone (96) : This compound was prepared in a manner similar to that of compound 37 described above.

[0268] 4-((5-((4b- hydroxyl -7- Isopropoxy -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) carbamoyl )-4- methyl -lH- Pyrrole -2- base ) sulfonyl ) Piperazine -1- tert-butyl carboxylate (97) : 79 mmol (240 mg, 0.65 mmol) of 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid was dissolved in 6.5 mL of DMF. The resulting solution was cooled to 0 °C, and EDCI (187 mg, 0.975 mmol), HOBT (132 mg, 0.975 mmol), and DIPEA (0.283 mL, 1.625 mmol) were added at 0 °C. The reaction mixture was stirred for 30 min. Then, 96 mmol (232 mg, 0.65 mmol) of 9b-amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one was added, and the reaction mixture was stirred at 30 °C for 15 h. The reaction mixture was quenched with water (100 mL), and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water and then with a brine solution, and dried over Na₂SO₄. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (methanol:DCM) to give a solid product.

[0269] N-(4b- hydroxyl -7- Isopropoxy -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-( Piperazine -1- sulfonyl )-1H- Pyrrole -2- formamide (98) : 97 (145 mg, 0.2 mmol) of 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrolo-2-yl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4 mL). A solution of 4 M HCl in dioxane (0.5 mL) was added to this solution. The clear solution was stirred at room temperature for 15 h. The DCM was evaporated under vacuum. The residue was dissolved in water (100 mL), and the aqueous solution was neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (100 mL × 2), and the combined organic layers were washed with water and then with a brine solution. The organic layers were dried over Na2SO4, and the solvent was evaporated to give a crude solid product. The crude product was used as is in the next step without purification.

[0270] N-(4b- hydroxyl -7- Isopropoxy -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (99) : N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazin-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 98 (115 mg, 0.188 mmol) was dissolved in glacial acetic acid:MeCN (1:1) (5 mL). The solution was cooled to 0 °C, and formaldehyde (0.161 mL, 1.88 mmol) was added, followed by NaBH3CN (41 mg, 0.658 mmol). The resulting suspension was stirred at 0 °C to 5 °C for 1.5 h. Acetonitrile was evaporated, and the residue was quenched with water, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water, followed by a brine solution. The organic layers were dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (methanol:DCM) to obtain a solid product.

[0271] N-(1- amino -4b- hydroxyl -7- Isopropoxy -10- Oxygenation-4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (100): N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide 99 (66 mg, 0.105 mmol) was dissolved in an EtOH-water mixture (1:1, 3.5 mL), and Fe powder (18 mg, 0.315 mmol) and concentrated HCl (1 drop) were added. The clear solution was refluxed at 90 °C for 3 h. The hot reactants were filtered through a diatomaceous earth mat and washed with ethyl acetate. The organic layer was evaporated under vacuum. The obtained residue was dissolved in ethyl acetate (200 mL) and washed with water (75 mL × 2), followed by washing with a brine solution. The combined organic layers were dried over Na2SO4 and evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (methanol:DCM) to obtain a solid product. 1 H-NMR (300MHz, CD30D) δ 1.28 (dd, J= 6Hz, J = 1.6Hz, 6H), 2.29 (s, 6H), 2.51 - 2.54 (m, 4H), 3.06 (br, 4H),4.51- 4.59 (m, 1H) 6.38 (d, J = 1.9Hz, 1H), 6.54 (br, 2H), 6.79(br, 1H), 7.04 (d,J = 7.2Hz, 1H), 7.34 (br, 1H), 7.47 - 7.52 (m, 1H). LCMS: 596.5[M+1] + .

[0272] N-((4bR,9bR)-1- amino -4b- hydroxyl -7- Isopropoxy -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1, 2-b]- Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base) sulfonyl )-1H- Pyrrole -2- formamide (101) and N-((4bS,9bS)-1- amino -4b- hydroxyl -7- Isopropoxy -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole -2- formamide (102) : N-(1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (100) (90 mg) in racemic form was administered by chiral chromatography (IA column, HPLC = 20 mL / min, heptane / Et). Purification (OH=30 / 70, 2562psi) yielded 37.5 mg of N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]-benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (101) (peak 2, tR) 16.32min.), 1H NMR (methanol-d4) δ: 7.43-7.53 (m, 1H), 7.39 (br d,J=12.3Hz, 1H), 7.02 (br s, 1H), 6.72 (br s, 1H), 6.55 (s, 2H), 6.36 (br s,1H), 4.54 (dt, J=12.0, 5.9Hz, 1H), 3.11 (br s, 4H), 2.75 (br s, 4H), 2.45 (brs, 3H), 2.29 (s, 3H), 1.25-1.28 (m, 6H); LCMS: 596.6 [M+H] +And 36.4 mg of N-((4bS,9bS)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide (102) (peak 1, tR 5.70 min.); 1H NMR (methanol-d4) δ: 7.48 (br s, 1H), 7.24-7.42 (m, 1H), 7.03 (br d, J=5.9 Hz, 1H), 6.67-6.82 (m, 1H), 6.53 (s, 2H), 6.36 (br s, 1H), 4.54 (dt, J=11.9, 6.1Hz, 1H), 3.07 (br s, 4H), 2.59 (br s, 4H), 2.33 (s, 3H), 2.28 (s,3H), 1.24-1.31 (m, 6H); LCMS: 596.0 [M + H] + .

[0273] Example 21 : N-(1- amino -4b- hydroxyl -7-((1S,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-( Methylsulfonyl )-1H- Pyrrole -2- formamide Plan-19B N-[9- hydroxyl -5-[(1S,2R)-2- methylcyclopropyl ]-11- Nitro -16- Oxygenation -8- Oxatetracycline [7.7.0.0 ^[2,7].0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -1- base ]-5- methanesulfonyl -3- methyl -1H- Pyrrole - 2- formamide (19B-1) : Add 5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxylic acid (259 mg, 1.27 mmol, 1.50 equivalent), HOBt (172 mg, 1.27 mmol, 1.50 equivalent), and EDCI (243 mg, 1.27 mmol, 1.50 equivalent) to a 50 mL round-bottom flask. N,N - Dimethylformamide (5 mL), 1-amino-9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-l1-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one (300 mg, 0.85 mmol, 1.00 equivalent) and triethylamine (257 mg, 2.54 mmol, 3.00 equivalent). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This yielded 250 mg (55%) of a yellow solid. N -[9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-1-yl]-5-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxamide (19B-1).

[0274] N-[14- amino -9- hydroxyl -5-[(1S,2R)-2- methylcyclopropyl ]-16- Oxygenation -8- Oxatetracycline [7.7.0.0 ^[2,7].0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -1- base ]-5- methanesulfonyl -3- methyl -1H- Pyrrole - 2- formamide (19B-2) : Add to a 50mL round-bottom flask N-[9-hydroxy-5-[(1S,2R)-2-methylcyclopropyl]-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-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 equivalent), Fe (78 mg, 3.00 equivalent), ethanol (10 mL), water (1 mL), hydrogen chloride (0.1 mL). The resulting solution was stirred in an oil bath at 85 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing dichloromethane / methanol (20 / 1). This yielded 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-(methanesulfonyl)-1H-pyrrole-2-carboxamide (19B-2).

[0275] 1 H NMR (300MHz, CD3OD) δ 7.54-7.43 (m, 1H), 7.41-7.35 (m, 1H), 7.08-7.00 (m, 1H), 6.90-6.80 (m, 1H), 6.80-6.75 (m, 1H), 6.69-6.60 (m, 2H), 3.13(s, 3H), 2.29 (s, 3H), 2.12-1.98 (m, 1H), 1.23-1.05 (m, 1H), 1.03 -0.88 (m,1H), 0.81-0.72 (m, 3H), 0.64-0.52 (m, 1H); LC-MS (ES, m / z [M+H] + 508.0 (The stereochemistry of cyclopropane is relative to absolute unknown) Example 22 Examples 29 and Examples 30 : N-(1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl - 10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide (29) , N-((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide (22) and N-((4bS,9bS)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b, 10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide (30) Solution-19C (1R)-1-[3-( benzyloxy ) Phenyl ] Second -1- alcohol (19C-1) : Add 1-[3-(benzyloxy)phenyl]ethyl-1-one (10 g, 44.19 mmol, 1.00 equivalent), MeCN (30 mL), triethylamine (6.7 g, 66.21 mmol, 1.50 equivalent), [Ru(p-cymene)Cl2]2 (136 mg, 0.22 mmol, 0.01 equivalent), (1R,2R)-TsDpen (330 mg, 0.89 mmol, 0.02 equivalent), and HCO2H (6.1 g, 3.00 equivalent) to a 100 mL three-necked round-bottom flask. Stir the resulting solution at room temperature for 12 h. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (20 / 80). This yields 4 g (40%) of (1R)-1-[3-(benzyloxy)phenyl]ethyl-1-ol as a colorless oil.

[0276] (1R)-1-[3-( benzyloxy ) Phenyl] Ethyl N,N- pair ( C -2- base ) Carbamate (19C-2) : Add (1R)-1-[3-(benzyloxy)phenyl]ethyl-1-ol (3.5 g, 15.33 mmol, 1.00 equivalent), CH3CN (15 mL), N,N-bis(propyl-2-yl)carbamoyl chloride (2.9 g, 17.72 mmol, 1.15 equivalent), and TEA (1.9 g, 18.78 mmol, 1.20 equivalent) to a 50 mL round-bottom flask. Stir the resulting solution at 80 °C for 12 h. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (15 / 85). This yields 5.3 g (97%) of (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propyl-2-yl)carbamoyl ester as a yellow oil.

[0277] 2-[(1R)-1-[3-( benzyloxy ) Phenyl ]-1- Cyclopropylethyl ]-4,4,5,5- Tetramethyl -1,3,2- dioxoborane heterocyclopentane (19C-3) : To a 500 mL three-necked round-bottom flask, add (1R)-1-[3-(benzyloxy)phenyl]ethyl N,N-bis(propyl-2-yl)carbamate (5.3 g, 14.91 mmol, 1.00 equivalent), diethyl ether (100 mL), and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (5 g, 29.75 mmol, 2.00 equivalent). Then, add LDA (14.9 mL, 2 mol / L, 2.00 equivalent) dropwise at -20 °C. Stir the resulting solution at room temperature for 12 h. Then quench the reaction by adding methanol. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (15 / 85). This yielded 4.1 g (73%) of 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboronylpentane, a yellow oil.

[0278] 1-( benzyloxy )-3-[(1R)-1- Cyclopropylethyl ] benzene (19C-4) : Add 2-[(1R)-1-[3-(benzyloxy)phenyl]-1-cyclopropylethyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (4 g, 10.57 mmol, 1.00 equivalent), n-pentane (50 mL), and TBAF-3H2O (5 g, 15.87 mmol, 1.50 equivalent) to a 100 mL round-bottom flask. Stir the resulting solution at 45 °C for 12 h. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (10 / 90). This yields 2.4 g (90%) of 1-(benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene as a yellow oil.

[0279] 3-[(1R)-1- Cyclopropylethyl ] phenol (19C-5) : Add 2.1 g (benzyloxy)-3-[(1R)-1-cyclopropylethyl]benzene, 8.32 mmol, 1.00 equivalent, methanol (20 mL), and palladium on carbon (200 mg) to a 100 mL round-bottom flask. Stir the resulting solution at room temperature under a H2 atmosphere for 2 h. Filter off the solid. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (15 / 85). This yields 1.3 g (96%) of 3-[(1R)-1-cyclopropylethyl]phenol as a colorless oil.

[0280] 5-[(1R)-1- Cyclopropylethyl ]-1,9- dihydroxy -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7].0^ [10,15]] sixteen -2(7),3,5,10,12,14- Hexene -16- ketone (19C-6) : Add 3-[(1R)-1-cyclopropylethyl]phenol (1.3 g, 8.01 mmol, 1.00 equivalent), acetic acid (20 mL), and 2,2-dihydroxy-4-nitro-2,3-dihydro-1-phenylene oxide to a 100 mL round-bottom flask. H 1,3-indene (1.8 g, 8.07 mmol, 1.00 equivalent). The resulting solution was stirred at 120 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (30 / 70). This yielded 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]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a yellow solid.

[0281] 1- chlorine -5-[(1R)-1- Cyclopropylethyl ]-9- hydroxyl -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7].0 ^][10,15]] sixteen -2(7),3,5,10,12,14- Hexene -16- ketone (19C-7) : Add 4.1 g (11.16 mmol, 1.00 equivalent) of 5-[(1R)-1-cyclopropylethyl]-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one and 20 mL of dichloromethane to a 100 mL round-bottom flask. N,N - Dimethylformamide (2 mL) and oxaloyl chloride (16.7 mL, 3.00 equivalents). The resulting solution was stirred at 45 °C for 2 h. The reaction was then quenched by adding water / ice. The resulting solution was extracted with dichloromethane. The organic layers were combined and concentrated under vacuum. This yielded 4.5 g (crude) of 1-chloro-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a brown oil.

[0282] 1- amino -5-[(1R)-1- Cyclopropylethyl ]-9- hydroxyl -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7] .0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -16- ketone (19C-8) : Add 30 mL of a THF solution of 1-chloro-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2.7].0^[10.15]]hexadec-2(7).3.5.10.12.14-hexen-16-one (4.5 g, 11.66 mmol, 1.00 equivalent) to a 250 mL round-bottom flask, and dropwise add 17.5 mL of an IPA solution of NH3 (3.00 equivalent) at -50 °C. Stir the resulting solution at -50 °C for 2 h. Concentrate the resulting mixture under vacuum. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (35 / 65). This yielded 3.5 g (82%) of 1-amino-5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a yellow solid.

[0283] N-[5-[(1R)-1- Cyclopropylethyl ]-9- hydroxyl -11- Nitro -16- Oxygenation -8- Oxatetracycline [7.7.0.0^ [2,7].0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -1- base ]-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen - 1H- imidazole -4- formamide (19C-9) : Add 1,5-dimethyl-2-oxo-2,3-dihydro-1-dimethyl-2-oxo-2,3-dihydro-1-dimethyl-2-oxo-2-oxo-2,3-dihydro-1-oxo-2 ... H -Imidazole-4-carboxylic acid (1.3g, 8.33mmol, 1.20 equivalent), EDCI (1.6g, 8.35mmol, 1.20 equivalent), HOBt (1.1g, 8.14mmol, 1.20 equivalent). 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]]hexadec-2(7),3,5,10,12,14-hexen-16-one (2.5 g, 6.82 mmol, 1.00 equivalent) and triethylamine (2.3 mL, 3.00 equivalent). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (20 / 1). This yielded 1.4 g (41%) of a yellow solid. N-[5-[((1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-1-yl]-1,5-dimethyl-2-oxo-2,3-dihydro-1 H -Imidazole-4-carboxamide.

[0284] N-(1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1, 2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide (19C-10) : Add N-[5-[(1R)-1-cyclopropylethyl]-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-1-yl]-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazolium-4-carboxamide (120 g, 237.86 mmol, 1.00 equivalent), ethanol (10 mL), iron (40 mg, 0.72 mmol, 3.00 equivalent), water (1 mL), and concentrated hydrogen chloride (0.01 mL) to a 25 mL round-bottom flask. Stir the resulting solution at 85 °C for 2 h. Concentrate the resulting mixture under vacuum. Purify the residue by rapid chromatography using DCM / MeOH (25 / 1). This yielded 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-imidazol-4-carboxamide (19C-10, Example 29).

[0285] 1H NMR (300MHz, CD3OD) 7.55-7.39 (m, 2H), 7.05-7.01 (m, 1H), 6.93-6.70(m, 3H), 3.21 (s, 3H), 2.35 (s, 3H), 2.04-1.84 (m, 1H), 1.30-1.27 (m, 3H),0.94-0.89 (m, 1H), 0.57-0.52 (m, 1H), 0.38-0.34 (m, 1H), 0.22-0.16 (m, 1H),0.09-0.02 (m, 1H); LCMS: (ES, m / z ):[M+H] + 475.2 N-((4bR,9bR)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation -9b,10- Dihydrogen - 4bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole -4- formamide ( 19C-11 , Example 22 )and N-((4bS,9bS)-1- amino -7-((R)-1- Cyclopropylethyl )-4b- hydroxyl -10- Oxygenation - 9b,10- Dihydrogen -4bH- Indene [1,2-b] Benzofuran -9b- base )-1,5- dimethyl -2- Oxygenation -2,3- Dihydrogen -1H- imidazole - 4- formamide ( 19C-12 , Example 30 ): N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazolium-4-carboxamide (19C-10) (103.9 mg) in its racemic form was administered by chiral chromatography (IA column, HPLC = 20 mL / min). n, heptane / IPA = 60 / 40) purification yielded 42.8 mg of N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazolium-4-carboxamide (19C-11) (peak 1, tR) 7.76min.), 1H NMR (400MHz, methanol-d4) δ: 8.32-8.47 (m, 2H), 7.97(br d, J=7.2Hz, 1H), 7.86 (br d, J=7.8Hz, 1H), 7.62-7.71 (m, 2H), 4.17 (s,3H), 3.31 (s, 3H), 2.80-2.93 (m, 1H), 2.24 (d, J=7.0Hz, 3H), 1.81-1.90 (m,1H), 1.46-1.55 (m, 1H), 1.28-1.36 (m, 1H), 1.15 (dq, J=9.4, 4.7Hz, 1H), 1.04(dq, J=9.5, 4.8Hz, 1H); LCMS: 475.2 [M + H]+ and 35.8 mg of N-((4bS,9bS)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazolium-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=6.9Hz, 1H), 6.85–6.94 (m, 1H). 6.70 (br s, 2H), 3.20 (s, 3H), 2.34 (s, 3H), 1.86-1.94 (m, 1H), 1.27(d, J=7.1Hz, 3H), 0.85-0.93 (m, 1H), 0.50-0.55 (m, 1H), 0.31-0.38 (m, 1H), 0.18 (dq, J=9.8, 4.8Hz, 1H), 0.06 (dq, J=9.4, 4.8Hz, 1H); LCMS: 475.2 [M + H]+. .

[0286] Example 23 : N-(1- amino -7-( sec-butyl )-4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1, 2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide Plan-19D 1-[3-( benzyloxy ) Phenyl ] Second -1- ketone (19D-1) : A solution of 1-(3-hydroxyphenyl)ethyl-1-one (20 g, 146.90 mmol, 1.00 equivalent), CH3CN (180 mL), (bromomethyl)benzene (20 mL, 1.20 equivalent), and potassium carbonate (40.8 g, 2.00 equivalent) was placed in a 500 mL round-bottom flask. The resulting solution was stirred in an oil bath at 80 °C for 2 h. The solid was filtered off. The reaction mixture was concentrated under vacuum. The residue was fed onto a silica gel column containing ethyl acetate / petroleum ether (1:10). This yielded 30.5 g (92%) of 1-[3-(benzyloxy)phenyl]ethyl-1-one as a yellow oil.

[0287] 2-[3-( benzyloxy ) Phenyl ] Man -2- alcohol (19D-2) : A solution of 1-[3-(benzyloxy)phenyl]ethyl-1-one (5 g, 22.10 mmol, 1.00 equivalent) and THF (100 mL) was added to a 250 mL round-bottom flask, followed by the addition of magnesium bromo(ethyl)magnesium (22 mL, 3.00 equivalent) at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 300 mL of water. The resulting solution was extracted with 3 × 200 mL of chloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1 / 1). This yielded 3.1 g (55%) of 2-[3-(benzyloxy)phenyl]but-2-ol as a colorless oil.

[0288] 1-( benzyloxy )-3-( Man -2- base ) benzene (19D-3) : A solution of 2-[3-(benzyloxy)phenyl]but-2-ol (6.2 g, 24.19 mmol, 1.00 equivalent) in dichloromethane (120 mL) was added to a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Triethylsilane (18.2 mL, 5.00 equivalent) and trifluoroacetic acid (18.05 mL, 1.00 equivalent) were then added. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 100 mL of water and extracted with 3 × 50 mL dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied to a silica gel column containing petroleum ether (100%). This yielded 3.8 g (65%) of 1-(benzyloxy)-3-(but-2-yl)benzene as a yellow oil.

[0289] 3-( Man -2- base ) phenol (19D-4) : A solution of 1-(benzyloxy)-3-(but-2-yl)benzene (3.8 g, 15.81 mmol, 1.00 equivalent) in methanol (38 mL) and palladium on carbon (380 g) were added to a 100 mL round-bottom flask. The resulting solution was stirred at room temperature under H2 for 2 h. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1 / 20). This yielded 2.0 g (84%) of 3-(but-2-yl)phenol as a yellow solid.

[0290] 5-( Man -2- base )-1,9- dihydroxy -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7].0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -16- ketone(19D-5) : A solution of 3-(but-2-yl)phenol (1.5 g, 9.99 mmol, 1.00 equivalent) 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 equivalent) were added to a 100 mL round-bottom flask. The resulting solution was stirred in an oil bath at 120 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1 / 2). This yielded 1.37 g (39%) of 5-(but-2-yl)-1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a yellow solid.

[0291] 5-( Man -2- base )-1- chlorine -9- hydroxyl -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7].0^[10,15]] sixteen -2(7),3,5,10,12,14- Hexene -16- ketone (19D-6) : Add 5-(but-2-yl)1,9-dihydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one (1.37 g, 3.86 mmol, 1.00 equivalent) to a 50 mL round-bottom flask along with 20 mL of dichloromethane, 1.1 mL of oxaloyl chloride, and... N,N The solution was prepared in dimethylformamide (2 mL). The resulting solution was stirred in an oil bath at 40 °C for 2 h. The reaction was then quenched by adding 50 mL of water / ice. The resulting solution was extracted with 3 × 100 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column containing ethyl acetate / petroleum ether (1 / 5). This yielded 1.2 g (83%) of 5-(but-2-yl)-1-chloro-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a brown oil.

[0292] 1- amino -5-( Man -2- base )-9- hydroxyl -11- Nitro -8- Oxatetracycline [7.7.0.0^[2,7].0^[10,15]] sixteen-2(7),3,5,10,12,14- Hexene -16- ketone (19D-7) : A solution of 5-(but-2-yl)-1-chloro-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one (1.2 g, 3.21 mmol, 1.00 equivalent) in tetrahydrofuran (18 mL) was added to a 50 mL round-bottom flask. Subsequently, an IPA solution of NH3 (4.8 mL, 3.00 equivalent) 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 under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1 / 2). This yielded 630 mg (55%) of 1-amino-5-(but-2-yl)-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one as a yellow solid.

[0293] N-[5-( butane -2- base )-9- hydroxyl -11- Nitro -16- Oxygenation -8- Oxatetracycline [7.7.0.0^[2,7].0^ [10,15]] sixteen -2(7),3,5,10,12,14- Hexene -1- base ]-4- methanesulfonyl -3- methyl -1H- Pyrrole -2- formamide (19D-8) : Add 122 mg (0.60 mmol, 1.50 equivalent) of 4-methanesulfonyl-3-methyl-1H-pyrrole-2-carboxylic acid to a 25 mL round-bottom flask. N,NA solution of dimethylformamide (2 mL), EDCI (115 mg, 0.60 mmol, 1.50 equivalence), HOBt (81 mg, 0.60 mmol, 1.50 equivalence), 1-amino-5-(but-2-yl)-9-hydroxy-11-nitro-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-16-one (150 mg, 0.42 mmol, 1.00 equivalence), and triethylamine (121 mg, 1.20 mmol, 2.50 equivalence). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (25 / 1). This yielded 140 mg (61%) of a yellow solid. N -[5-(but-2-yl)-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7]0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-1-yl]-4-methanesulfonyl-3-methyl-1 H -Pyrrole-2-carboxamide.

[0294] N-[14- amino -5-( Man -2- base )-9- hydroxyl -16- Oxygenation -8- Oxatetracycline [7.7.0.0^[2,7].0^[10, 15]] sixteen -2(7),3,5,10,12,14- Hexene -1- base ]-4- methanesulfonyl -3- methyl -1H- Pyrrole -2- formamide (19D- 9) : Add to a 50mL round-bottom flask N -[5-(but-2-yl)-9-hydroxy-11-nitro-16-oxo-8-oxatetracyclo[7.7.0.0^[2,7].0^[10,15]]hexadec-2(7),3,5,10,12,14-hexen-1-yl]-4-methanesulfonyl-3-methyl-1 HA solution of pyrrolo-2-carboxamide (140 mg, 0.26 mmol, 1.00 equivalent) in ethanol (5 mL), water (0.5 mL), Fe (40.32 mg, 3.00 equivalent), and hydrogen chloride (0.05 mL) was prepared. The resulting solution was stirred in an oil bath at 85 °C for 2 h. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing dichloromethane / methanol (20 / 1). This yielded 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-(methanesulfonyl)-1H-pyrrolo-2-carboxamide (19D-9).

[0295] 1 HNMR (300MHz, CD3OD) δ 7.61-7.35 (m, 3H), 7.18-7.05 (m, 1H), 6.90-6.63 (m, 3H), 3.01 (s, 3H), 2.62-2.40 (m, 4H), 1.65-1.50 (m, 2H), 1.19 (d, J =6.9Hz, 3H), 0.90-0.78 (m, 3H); LC-MS: (ES, m / z ): [M+H] + 510.1 Example 24 : N-(1- amino -4b- hydroxyl -7-((1S,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-((4- Methylpiperazine -1- base ) sulfonyl )-1H- Pyrrole - 2- formamide The compound was prepared similarly to that in Example 18 above. LCMS: 592.3 [M+H] + .

[0296] Example 25 : N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen-9bH- Indene [1,2- b] Benzofuran -9b- base )-3,5- dimethyl -4- Aminosulfonyl -1H- Pyrrole -2- formamide (111) : Plan-20 2-( Hydroxyamino ) Dimethyl malonate (104) : Dimethyl malonate 103 (21.7 mL, 190 mmol) was added to glacial acetic acid (55 mL) with stirring, followed by dropwise addition of a solution of sodium nitrite (26.2 g, 380 mmol) in 70 mL of water (continuously for ~2 h). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate. The combined extracts were washed with water and a 5% sodium bicarbonate solution until the aqueous solution became weakly alkaline. The organic layer was dried over Na₂SO₄, and the solvent was evaporated to give a solid product. The crude product was used in the next step without further purification.

[0297] 3,5- dimethyl -1H- Pyrrole -2- Methyl carboxylate (106) : At 95 °C, a solution of dimethyl 2-(hydroxyimino)malonate 104 (17 g, 105 mmol) in 20 mL acetic acid and 10 mL water was gradually added simultaneously to a solution of acetylacetone 105 (10.3 mL, 100 mmol) in acetic acid (40 mL) and zinc powder (26 g, 400 mmol). The reaction mixture was stirred at the same temperature for 2 h. The hot reaction mixture 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 the zinc powder residue, concentrated, and dried in air at room temperature. The product was dissolved in DCM, filtered through a silica gel pad, and washed with DCM. The solvent was evaporated to give the product.

[0298] 4-( Chlorosulfonyl )-3,5- dimethyl -1H- Pyrrole -2- Methyl carboxylate (107) : Methyl 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ester 106 (383 mg, 2.5 mmol) was dissolved in chloroform (0.25 M) and the clear solution was cooled to 0 °C. Chlorosulfonic acid (2.5 mL, 37.5 mmol) was slowly added to the cold solution. The reaction was stirred at 0 °C for 2.5 h. The reactants were slowly poured into ice-cold water. The product was extracted with DCM (50 mL × 2). The combined organic layers were washed with water (50 mL) and a brine solution (50 mL), dried over anhydrous Na₂SO₄, and the solvent was evaporated to give the crude product. The crude product was dissolved in DCM, filtered through a silica gel stopper, and washed with DCM to give the final product.

[0299] 3,5- dimethyl -4- Aminosulfonyl -1H- Pyrrole -2- Methyl carboxylate (108) : Methyl 4-(chlorosulfonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ester 107 (377.5 mg, 1.5 mmol) was dissolved in THF (15 mL) and cooled to -10 °C. A solution of NH3 in THF (5 mL) was added (prepared by purging THF with ammonia at -20 °C). The reaction mixture was slowly heated to room temperature and stirred for 2 h. THF was removed under vacuum to obtain a residue. The residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL × 3), and dried over Na2SO4. The solvent was evaporated to obtain a crude product. The residue was purified by grinding with DCM and filtered to obtain the product.

[0300] 3,5- dimethyl -4- Aminosulfonyl -1H- Pyrrole -2- carboxylic acid (109) : LiOH·H₂O (461.6 mg, 11 mmol) was added to a solution of methyl 3,5-dimethyl-4-aminosulfonyl-1H-pyrrole-2-carboxylate 108 (255 mg, 1.1 mmol) in MeOH:H₂O (1:10) (11 mL). The reaction mixture was stirred at room temperature for 12 h. The MeOH was removed under vacuum, and the aqueous layer was diluted with water (10 mL) and acidified to pH ~ 1 with 1N HCl. The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water and then with a brine solution, dried over Na₂SO₄, and the solvent was evaporated to give a solid product, which was used as is in the next step without purification.

[0301] N-(4b- hydroxyl -7- Isopropyl -4- Nitro-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,5- dimethyl -4- Aminosulfonyl -1H- Pyrrole -2- formamide (110) : 3,5-Dimethyl-4-aminosulfonyl-1H-pyrrole-2-carboxylic acid 109 (200 mg, 0.91 mmol) was dissolved in DMF (9 mL), and the resulting solution was cooled to 0 °C. EDCI (216.7 mg, 1.365 mmol), HOBT (184.5 mg, 1.365 mmol), and DIPEA (0.396 mL, 2.275 mmol) were added at 0 °C, and the reaction mixture was stirred for 30 min. Then, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (312 mg, 0.91 mmol) was added, and the reaction mixture was stirred at 30 °C for 15 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with a salt solution and dried with Na2SO4, and then evaporated under vacuum. The crude product was purified by column chromatography (methanol:DCM) to obtain (110).

[0302] N-(1- amino -4b- hydroxyl -7- Isopropyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3,5- dimethyl -4- Aminosulfonyl -1H- Pyrrole -2- formamide (111) : Fe powder (33.5 mg, 0.6 mmol) and concentrated HCl (1 drop) were added to a solution of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-aminosulfonyl-1H-pyrrole-2-carboxamide 110 (110 mg, 0.2 mmol) in an EtOH-water mixture (1:1, 7 mL). The resulting solution was refluxed at 90 °C for 3 h. The hot reactants were filtered through a diatomaceous earth mat and washed with ethyl acetate. The organic layer was evaporated under vacuum. The obtained residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL × 2), followed by washing with a brine solution. The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (methanol:DCM) to obtain the final product. (300MHz, CD30D) δ 1.2 (dd, J = 6.2Hz, J = 0.9Hz, 6H), 2.44 (s, 3H), 2.49 (s, 3H), 2.84 - 2.87 (m, 1H), 6.70 (m, 2H), 6.89 (m 1H), 7.04 (m 1H), 7.48 (m, 2H). LCMS: 510.78 [M+1] + LCMS: 511.5 [M+H] + .

[0303] Example 26 : N-(1- amino -4b- hydroxyl -7-((1R,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -5-( Methylsulfonyl )-1H- Pyrrole -2- formamide The compound was prepared similarly to that in Example 26 above. LCMS: 508.0 [M+H] + .

[0304] Example 27 : N-(1- amino -4b- hydroxyl -7-((1S,2R)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b]Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide The compound was prepared similarly to that in Example 26 above. LCMS: 508.2 [M+H] + .

[0305] Example 28 : N-((4bR, 9bR)-1- amino -4b- hydroxyl -7-(1S,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole -2- formamide Option 22 ((S)-1-(((4bS,9bS)-7- bromine -4b- hydroxyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1, 2-b] Benzofuran -9b- base ) amino )-1- Oxygenation -3- Phenylacetane -2- base ) tert-butyl carbamate (113) : (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 min, 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 h. 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.

[0306] (S)-2- amino -N-((4bS,9bS)-7- bromine -4b- hydroxyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- Phenylacetamide (114) : ((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)carbamate tert-butyl ester 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.

[0307] (S)-N-(4bS,9bS)-7- bromine -4b- hydroxyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2- b] Benzofuran-9b- base )-3- Phenyl -2-(3- Phenylacetyl ) propionamide (116) : At 0 °C, isocyanothiobenzene 115 (0.425 mL, 3.54 mmol) was added to a solution of (S)-2-amino-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenylpropionamide 114 (1.25 g, 2.36 mmol) in DCM (24 mL). The reaction mixture was then heated to room temperature and stirred at 28 °C for 24 h. The reaction mixture was evaporated to dryness to give a crude product. The crude product was purified by short silica gel column chromatography (ethyl acetate:hexane) to obtain the product.

[0308] (4bS,9bS)-9b- amino -7- bromine -4b- hydroxyl -4- Nitro -4b,9b- Dihydrogen -10H- Indene [1,2-b] Benzofuran -10- ketone (117) : (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 (1.70 g, 2.58 mmol) was dissolved in DCM (260 mL). TFA (8.8 mL, 77.4 mmol) was added to this solution at room temperature. The reaction mixture was then heated to 50 °C for 12 h. The DCM was evaporated, and the resulting residue was dissolved in water. The aqueous layer was alkalized with saturated NaHCO3 solution and then extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the final product.

[0309] ((4bS,9bS)-7- bromine -4b- hydroxyl -4- Nitro -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (118) : (4bS,9bS)-9b-amino-7-bromo-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 117 (472 mg, 1.25 mmol) was dissolved in THF (1.25 mL). Boc anhydride (546 mg, 2.5 mmol) was added, followed by iodine (32 mg, 0.125 mmol). The reaction mixture was stirred at room temperature for 36 h. The mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product.

[0310] ((4bR,9bR)-1- amino -7- bromine -4b- hydroxyl -10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (12) : ((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)tert-butyl carbamate 118 (460 mg, 0.96 mmol) was dissolved in an EtOH-water mixture (1:1, 10 mL). Fe powder (161 mg, 2.88 mmol) and concentrated HCl (2 drops) were added. The clear solution was refluxed at 90 °C for 3 h. The hot reactants were filtered through a diatomaceous earth mat and washed with ethyl acetate. The organic layer was evaporated under vacuum. The obtained residue was dissolved in ethyl acetate (250 mL) and washed with water (100 mL × 2), followed by washing with a brine solution. The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to give the product.

[0311] ((4bR,9bR)-1- amino -4b- hydroxyl -7-((1S,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base ) tert-butyl carbamate (119) : 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)carbamate tert-butyl ester 12 (326 mg, 0.73 mmol) in toluene (12.5 mL) and water (2.5 mL), Pd(OAc)2 (16.4 mg, 0.073 mmol), RuPhos (68 mg, 0.146 mmol), and K3PO4 (620 mg, 2.92 mmol) were added. Then, 6-methyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,6,2-dioxazaborhecyl-4,8-dione 17 (231 mg, 1.095 mmol) was added.

[0312] The obtained reaction mixture was purged with N2 for 10 min, and then 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 × 2), dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the final product.

[0313] (4bR,9bR)-1,9b- Diamino -4b- hydroxyl -7-((1S,2S)-2- methylcyclopropyl )-4b,9b- Dihydrogen - 10H- Indene [1,2-b] Benzofuran -10- Ketone hydrochloride (120) : 250 mg (0.59 mmol) of tert-butyl carbamate ((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 119 was dissolved in DCM (12 mL). A dioxane solution of HCl (1.5 mL, 5.9 mmol) was added to this solution, and the reaction mixture was stirred for 12 h. The reaction mixture was evaporated to dryness to obtain the product (crude product), which was used as is in the next step.

[0314] N-((4bR,9bR)-1- amino -4b- hydroxyl -7-((1S,2S)-2- methylcyclopropyl )-10- Oxygenation -4b,10- Dihydrogen -9bH- Indene [1,2-b] Benzofuran -9b- base )-3- methyl -4-( Methylsulfonyl )-1H- Pyrrole-2- formamide (121) : 3-Methyl-4-(methanesulfonyl)-1H-pyrrole-2-carboxylic acid 30 (97.6 mg, 0.48 mmol) was dissolved in DMF (8 mL). The resulting solution was cooled to 0 °C. HATU (28.2 mg, 0.60 mmol) and DIPEA (0.210 mL, 1.2 mmol) were added at 0 °C, and the reaction mixture was stirred for 30 min. Then (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one hydrochloride 120 (144 mg, 0.4 mmol) was added, and the reaction mixture was stirred at 30 °C for 15 h. The reaction mixture was quenched with water (100 mL), and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water and then with a brine solution, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was purified by silica gel column chromatography (MeOH:DCM) and then by preparative HPLC (ethanol:hexane) to obtain the final product. (300MHz, MeOD) δ 0.66-0.72 (m, 1H), 0.78-0.84 (m, 1H), 0.95-1.03 (m, 1H), 1.13 (d, J = 6.0Hz, 3H), 1.49-1.55 (m, 1H), 2.48 (s, 3H),3.05 (s, 3H), 6.45 (s, 1H), 6.63-6.67 (m, 1H), 6.76 (d, J = 8.1Hz, 1H), 7.02(d, J = 7.2Hz, 1H), 2.27 (d, J = 8.1Hz, 1H), 7.38 (s, 1H), 7.43-7.49 (m, 1H). LCMS: 508.1 [M+H] + .

[0315] The bioactivity of the compounds of this invention was determined using the following methods. (Cytopathic effect) CPE Suppression analysis Determination of the efficacy of drugs against picornaviruses In the assay, HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblasts), and RD cells (derived from human rhabdomyosarcoma) were used. For comparison, ribavirin (Riv), pleco, and BTA-798 (BTA) were used as controls. Reagents were dissolved in 100% dimethyl sulfoxide (DMSO) at concentrations ranging from 10 mg / ml to 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 concentrations 3 to 5 times higher, resulting in a DMSO concentration between 0.5% and 1% in each well.

[0316] Drug efficacy was determined using a virus-induced cytopathic effect (CPE) inhibition assay. For this purpose, after growing virus-suited cells in 96-well plates, the virus was seeded at a concentration corresponding to 100 CCID50 (50% cell culture infection dose) in a 100 μL volume of either DME (DME / 2% FBS) or MEM (MEM / 2% FBS) supplemented with 2% FBS, and incubated at 33°C or 37°C for 30 minutes to 1 hour to allow viral adsorption to the cells. The culture medium was removed, and then aliquots of various concentrations of drug diluent were added to each well at a volume of 100 µL. While HRV (human rhinovirus) was grown at 33°C, other viruses were incubated at 37°C in a CO2 incubator for 2-3 days. Alternatively, cells were cultured for 2-3 days without removing the culture medium after adding 50 µL of each drug diluent at twice the concentration, followed by 50 µL of the virus diluent. The virus was incubated in host HeLa cells at 37°C for 2-3 days in DME / 2% or MEM / 2% FBS.

[0317] For HeLa cells, the EC50 of the drug was measured using the MTT assay. 50 (50% maximum effective concentration) is the drug concentration that induces a response at half the baseline and maximum. For RD and MRC-5 cells, CPE was measured using FDA (fluorescein diacetate) or MTT assay. To determine the effect of drug toxicity on efficacy results, a mock infection was included at the time of viral inoculation. Virus-free medium was added to the cell culture and then treated in the same way as the mock infected cells. That is, the medium was removed after one hour of incubation, and the drug was re-added to the medium as a dilution. After 2–3 days of incubation, the cells were observed under a microscope, and the CPE of the drug was determined using an MTT assay. 50(50% cytotoxic concentration), at which 50% of cells are killed, where the viable cell count in simulated infection wells containing the drug is compared with the viable cell count in control wells without the drug. In the FDA hydrolysis assay, FDA is added to each well after removing the culture medium and incubated for 20-30 min, then the fluorescence intensity is measured using a spectrophotometer to determine CPE in the same manner as the MTT assay.

[0318] That is, the survival rate (survival %) of simulated infected cells used for cytotoxicity measurement is calculated using the following mathematical formula 1: Cellular drug = Survival × [A (drug) – A (background solution) / A (cell control) - A (background × 100% solution)] While 100% cell survival means the drug has no cytotoxicity, 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. Higher values ​​indicate lower cytotoxicity.

[0319] In addition, 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)] If the survival rate is 100%, its antiviral effect is 100%; if the survival rate is 0%, it has no antiviral effect. Although EC... 50 The drug concentrations that show a 50% survival rate in cells infected with the virus were calculated, but the lower the value, the better the antiviral effect.

[0320] Table 1 below lists the LCs that exhibited cytotoxicity against the compound in some examples. 50 Concentration and activity against various rhinoviruses belonging to the piconemavirus family (EC) 50 concentration.

[0321] Using multi-cycle cytopathic effects ( CPE Reduce the number of tests to determine the drug's effectiveness against small RNA viruses. Multi-cycle CPE reduction assays were used to determine the efficacy of drugs against microRNA viruses. The antiviral activity of the compounds was initially determined by a CPE reduction assay based on MIS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazonium].

[0322] Specifically, 100 50% cell cultures were infected with the dose (CCID). 50The virus infection was used to grow confluent cells in 96-well plates. After adsorption at 37°C for 2 hours, the virus was removed and serial dilutions of the compound were added. The cultures were further incubated at 37°C for 3 days until complete CPE was observed in both infected and untreated virus controls (VC). After removing the medium, 90 µl of medium and 10 µl of MTS-phenazine methyl sulfate (Promega, Leiden, The Netherlands) were added to each well. After incubation at 37°C for 2 hours, the optical density (OD) of each well was read at 498 nm using a microplate reader.

[0323] The CPE% value used to assess antiviral activity is calculated using the following mathematical formula 3: CPE% = 100 × [OD (CC) - OD (virus + compound) / OD (CC) - OD (VC)] The CPE% value used to measure the cytotoxicity of a drug is calculated using the following mathematical formula 4: CPE% = 100 × [OD (CC) - OD (virus + compound) / OD (CC) - OD (blank)] In the above mathematical formulas 3 and 4, OD (CC) represents the OD of background cell cultures that are neither virus-induced nor chemically treated. OD (VC) represents the OD of a virus-induced but untreated control cell culture. OD (virus + compound) refers to the OD of cell cultures infected with a virus that has been treated with a concentrated compound. OD (compound) refers to the OD of cell cultures treated only with concentrated compounds, and OD (blank) indicates the OD of wells containing only cell culture.

[0324] Effective concentration (EC) 50 This indicates the drug concentration at which 50% of cells are induced to survive CPE (cytotoxicity concentration) of the virus, and the cytotoxic concentration (CC) 50 () represents the drug concentration of a compound that kills 50% of cells, and these concentrations are calculated using logarithmic interpolation.

[0325] Table 1 below lists the toxicity concentrations (CC) of some compounds from the examples against various viruses. 50 ) and effective concentration (EC 50 ).

[0326] Table 1: Bioactivity data table

[0327] As shown in Table 1 above, most of the compounds according to the present invention exhibit high CC. 50 The concentration was low, thus revealing low cytotoxicity. Furthermore, most of the compounds according to the invention were found to possess high antiviral activity against a variety of rhinoviruses (HRVs).

[0328] Therefore, since the compounds in the embodiments of the present invention exhibit low cytotoxicity and high antiviral activity against various rhinoviruses, they can be effectively used in pharmaceutical compositions for the prevention or treatment of diseases caused by the microRNA viruses to which they belong.

[0329] Therefore, since the compounds according to the embodiments of the present invention exhibit low cytotoxicity and antiviral activity against microRNA viruses belonging to Coxsackievirus, poliovirus, and rhinovirus, they can be effectively used to prevent or treat diseases caused by such viruses, such as respiratory diseases, cardiovascular diseases, and neurological diseases, including poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media.

[0330] Because the compounds represented by the chemical formulas according to the invention, in balance with each other, not only have low cytotoxicity against piconemaviruses (including Coxsackievirus, Enterovirus, Echovirus, Poliovirus, and Rhinovirus) but also have high antiviral activity, they can be effectively used as pharmaceutical compositions for the prevention or treatment of viral diseases such as poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, 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: in, G 1 Selected from straight-chain or branched C1-C4 alkyl, C3-C4 cycloalkyl, or straight-chain or branched C1-C4 alkoxy; wherein the C1-C4 alkyl, C3-C4 cycloalkyl and C1-C4 alkoxy can be substituted by one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl; L represents a chemical bond or CH2; E is a) -CH(CHOHCH3)(NMe2); or b) A monocyclic 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 monocyclic 5-6-membered heterocyclic group containing one or two nitrogen atoms, and NR. 1 R 2 The monocyclic 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, wherein the compound has formula (II): 。 3. The compound according to any one of claims 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III): 。 4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L is a chemical bond.

5. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein E is -CH(CHOHCH3)(NMe2).

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein E is a monocyclic 5-6-membered heteroaryl containing a nitrogen atom, wherein the 5-6-membered heteroaryl is optionally substituted by one to three substituents independently selected from the group consisting of: straight-chain or branched C1-C3 alkyl, -OH, -SO2R.

7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G 1 A straight-chain or branched C1-C4 alkyl group, optionally substituted with one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl groups.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt 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 according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a straight-chain or branched C1-C4 alkoxy group that is optionally substituted with one, two or three independent substituents selected from cyclopropyl and straight-chain or branched C1-C3 alkyl groups.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt 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 according to claim 10, wherein A 1 It is either methyl or SO2CH3.

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

13. The compound according to any one of claims 1, 4 to 6 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Ib): Where Y is H or CH3.

14. The compound according to any one of claims 1, 4 to 6 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Ic): X is selected from the group consisting of the following: methyl, ethyl, and cyclopropyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... 。 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 。 17. The compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, according to any one of claims 1 to 15, for the prevention or treatment of viral diseases.

18. 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 15, a pharmaceutically acceptable salt thereof or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

19. A combination comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, and one or more therapeutically active agents.

20. A method for treating a viral disease, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, or a combination according to claim 19.

21. Use of the compound of claim 15 or a pharmaceutically acceptable salt thereof or an optical isomer thereof, or a pharmaceutical composition of claim 18 or a combination of claims 19, for the prevention or treatment of viral diseases.

22. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by Coxsackievirus.

23. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by poliovirus.

24. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by echovirus.

25. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by an enterovirus.

26. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by a rhinovirus.

27. The compound of claim 15, the pharmaceutical composition of claim 18, the method of claim 20, or the use of claim 21, wherein the viral disease is caused by a microRNA virus.

28. The compound of claim 15 or the pharmaceutical composition of claim 18, or the method of claim 20, or the use of claim 21, wherein the viral disease is poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

29. The compound of claim 16, its pharmaceutically acceptable salt or its optical isomer, for the prevention or treatment of viral diseases.

30. A pharmaceutical composition for the prevention or treatment of viral diseases, said pharmaceutical composition comprising the compound of claim 16, a pharmaceutically acceptable salt thereof or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient.

31. A combination comprising the compound of claim 16 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

32. A method for treating a viral disease, the method comprising administering to a subject a therapeutically effective amount of the compound of claim 16 or a pharmaceutically acceptable salt thereof.

33. Use of the compound of claim 16 or a pharmaceutically acceptable salt thereof or an optical isomer thereof for the prevention or treatment of viral diseases.

34. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by Coxsackievirus.

35. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by poliovirus.

36. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by echovirus.

37. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by an enterovirus.

38. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by a rhinovirus.

39. The compound of claim 16, the pharmaceutical composition of claim 30, the method of claim 32, or the use of claim 33, wherein the viral disease is caused by a microRNA virus.

40. The compound of claim 16 or the pharmaceutical composition of claim 30, or the method of claim 32, or the use of claim 33, wherein the viral disease is poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpetic pharyngitis, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

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