Antiviral 1,3-dioxoindene compounds

Abstract

To provide an antiviral 1,3-dioxoindene compound. [Solution] The compounds of formula (I) described herein are provided together with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions to treat viral infections. The present invention provides novel compounds having potent antiviral activity in vitro. The present invention also provides pharmaceutical compositions containing the novel compounds, and methods of using the compounds and compositions to inhibit viral replication or reactivation and to treat disease conditions associated with or caused by viruses. JPEG2026090536000067.jpg24128

Description

[Technical Field]

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

[0002] Picornaviruses are non-enveloped, positive-stranded single-stranded RNA viruses with RNA genomes 7.2–8.5 kb long. These viruses are very small and spherical, about 22–30 nm in size, and were first identified a long time ago. Viruses belonging to the Picornaviridae family include rhinoviruses, polioviruses, coxsackievirus A, coxsackievirus B, enteroviruses including echoviruses, and hepatitis A virus.

[0003] Diseases caused by picornaviruses are diverse, ranging from respiratory to digestive, circulatory, and skin diseases. Examples include polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpangina, and foot-and-mouth disease. However, there are no cures for these diseases. Most drugs under development are descathing inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory diseases, which pose sanitary, social, and economic problems. Picornaviruses are the main causative agents of waterborne diseases. Because they are very stable and difficult to disinfect, RNA viruses continuously cause related diseases.

[0004] Human rhinovirus (hRV) has recently been associated with a large proportion of asthma exacerbations and is known to be present even in the bronchial tissue of many stable asthma patients. Comparison of bronchial mucosal biopsy samples from asthma and non-asthma patients has shown that human rhinovirus is detected at a significantly higher frequency in the lower respiratory tract of asthma patients compared to non-asthma patients. A correlation between the presence of human rhinovirus and the clinical severity of asthma has also been reported. Furthermore, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, and asthma.

[0005] Rhinovirus is the main cause of the common cold, but enterovirus-induced diseases include meningitis and respiratory infections. Extensive efforts to provide poliovirus vaccination have significantly reduced polio incidence worldwide, although cases are still reported in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is now controllable to some extent thanks to vaccines for the hepatitis A virus. However, vaccines for coxsackievirus, echovirus, or rhinovirus have not yet been developed.

[0006] In particular, coxsackievirus B is a major cause of myocarditis, which can develop into idiopathic dilated cardiomyopathy, requiring a heart transplant in severe cases.

[0007] Enviroxime derivatives are considered the most promising candidates with broad anti-enteroviral and anti-rhinoviral activity. Enviroxime interferes with the synthesis of positive-strand RNA by binding to viral protein 3A, which is necessary for the formation of RNA intermediates in viral replication (Heinz BA and Vance LM: J Virol, 1995, 69(7), 4189-97). However, clinical trials have observed that the compounds have little to no therapeutic effect, accompanied by poor pharmacokinetics and undesirable side effects (Miller FD et al.: Antimicrob Agents Chemother, 1985, 27(1), 102-6).

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

[0009] The elucidation of the molecular structure of viral capsids provided the prerequisites for the intentional design of capsid blockers, known as "WIN substances" (Diana GD: Curr Med Chem 2003, 2, 1-12). These substances inhibit the adsorption and / or detachment of rhinoviruses and enteroviruses. Some WIN substances exhibit highly specific effects only against individual genera or viral types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. For example, allildone, disoxalil, and pirodavir belong to the WIN substance group. These compounds showed very good antiviral effects in cell cultures. However, their clinical application was impossible due to insufficient solubility (allildone), low bioavailability (allildone and disoxalil), rapid metabolism and excretion (disoxalil and WIN54954), and side effects such as skin rash (WIN54954).

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

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

[0012] However, no antiviral drugs have yet been developed that have received approval for use in the treatment of enteroviruses or rhinoviruses. New treatments and therapies for enteroviruses or rhinoviruses remain in need. As a result of intensive and thorough research on effective viral replication inhibitors against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, it was found that a novel 1,3-dioxoindene derivative exhibits high inhibitory activity against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, leading to the present invention. [Prior art documents] [Non-patent literature]

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

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

[0015] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, G 1 This is selected from linear or branched C1-C4 alkyl C3-C4 cycloalkyl or linear or branched C1-C4 alkoxy; the C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy may be substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl; L is a bond or CH2; E is a)-CH(CHOHCH3)(NMe2); or b) a monocyclic 4- to 6-membered heterocyclyl containing one or two nitrogen atoms or a 5- to 6-membered heteroaryl containing one nitrogen atom, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, and SO2R; each R is independently selected from linear or branched C1-C3 alkyl, a monocyclic 5- to 6-membered heterocyclyl containing one or two nitrogen atoms, and NR 1 R 2 selected from; the monocyclic 5- to 6-membered heterocyclyl is optionally substituted with C1-C3 alkyl or NR 3 R 4 ; each R 1 and R 2 are independently selected from H and C1-C3 alkyl, and the C1-C3 alkyl is optionally substituted with NR 3 R 4 ; each R 3 and R 4 are independently selected from H or methyl). In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers. In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the present invention and one or more therapeutic agents.

Mode for Carrying Out the Invention

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

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

[0018] As used herein, the term “subject” refers to an animal. In certain embodiments, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In certain embodiments, a subject is a human. As used herein, “patient” refers to a human subject. As used herein, a subject “needs” treatment if such a subject would benefit from such treatment in biological, medical, or quality of life.

[0019] As used herein, the terms “inhibit” or “suppress” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0020] As used herein, the term “to treat” or “to cure” any disease or disorder means, in one embodiment, to improve the disease or disorder (i.e., to delay, prevent, or reduce the progression of the disease or at least one of its clinical symptoms). In another embodiment, “to treat” or “to cure” means to alleviate or improve at least one physical parameter, including one that may not be recognizable by the patient. In yet another embodiment, “to treat” or “to cure” means to modulate the disease or disorder by any means, either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, “to treat” or “to cure” means to prevent or delay the onset, development, or progression of the disease or disorder.

[0021] Where used herein, “a,” “an,” “the,” and similar terms (in particular, in the context of the claims) should be construed to encompass both singular and plural forms unless otherwise specified herein or unless the context clearly contradicts this.

[0022] All methods described herein may be carried out in any preferred order, unless otherwise specified herein or unless the context clearly contradicts it. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to further illustrate the invention and not to limit the scope of the claimed invention.

[0023] "Optionally substituted" means that the group mentioned can be substituted at one or more positions by any one or any combination of the groups subsequently listed. The number, arrangement, and selection of substituents are understood to include only those substitutions that the professional chemist expects to be reasonably stable, and therefore, "oxo" means, for example, a substituent on an aryl or heteroaryl ring, and a single carbon atom does not have three hydroxyl or amino substituents. Unless otherwise specified, optional substituents are typically halo, oxo, CN, amino, hydroxyl, and -C. 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * ,-COOR * , and -CONR * 2 (in the formula, each R * H or C 1-3 It consists of up to four groups selected from alkyl groups.

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

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

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

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

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

[0029] When used herein, "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, such as C3-C6, is specified, the definition should be modified accordingly.

[0030] "4-8 membered heterocyclil," "5-6 membered heterocyclil," "3-10 membered heterocyclil," "3-14 membered heterocyclil," "4-14 membered heterocyclil," and "5-14 membered heterocyclil" refer to heterorings of 4-8, 5-6, 3-10, 3-14, 4-14, and 5-14 members, respectively. Unless otherwise specified, such rings contain 1-7, 1-5, or 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the rings may be saturated or partially saturated but are not aromatic. Heterocyclic groups can be bonded to another group by nitrogen or carbon atoms. The term "heterocyclil" includes monocyclic groups, fused ring groups, and bridging groups. Examples of such heterocyclines include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidinenon, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxatian, 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, azetidine, ethylenedioxo, oxetane, or thiazole. In certain 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, optionally being halo, oxo, CN, amino, hydroxy, or C. 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * ,-COOR * , and -CONR * 2 (in the formula, each R * H or C 1-3 They are substituted with up to four groups selected from alkyl groups. In particular, heterocyclic groups containing a sulfur atom are optionally substituted with one or two oxo groups at the sulfur atom.

[0031] A "heteroaryl" is a completely unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, heteroaryls are 5- to 10-membered rings or ring systems (e.g., 5- to 7-membered monocyclic groups or 8- to 10-membered bicyclic groups), often 5- to 6-membered rings containing up to 4 heteroatoms selected from N, O, and S, but often heteroaryl rings contain one or fewer divalent O or S atoms in the ring. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazoli Examples include 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyridazinyl, 2-pyridinyl, and 2-, 4-, or 5-pyrimidinyl. The heteroaryl group can optionally be halo, CN, amino, hydroxy, or C. 1-3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * ,-COOR * , and -CONR * 2 (in the formula, each R * H or C 1-3 It is substituted with up to four groups selected from alkyl groups.

[0032] The terms "hydroxy" or "hydroxyl" refer to the group -OH.

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

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

[0035] Embodiment 2. The compound described in Embodiment 1, having formula (II), or a pharmaceutically acceptable salt thereof: [ka]

[0036] Embodiment 3. The compound described in Embodiment 1, having formula (III), or a pharmaceutically acceptable salt thereof: [ka]

[0037] Embodiment 4.G 1 The compound described in any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, is a linear or branched C1-C4 alkyl group.

[0038] Embodiment 5.G 1 However, the compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, is a C3-C4 cycloalkyl compound.

[0039] Embodiment 6.G 1 The compound described in any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, is a linear or branched C1-C4 alkoxy.

[0040] Embodiment 7. A compound according to any one of Embodiments 1 to 6, 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.

[0041] Embodiment 8. A compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the substituent is independently selected from cyclopropyl and linear or branched C1-C3 alkyl.

[0042] Embodiment 9. The compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is a bond. The compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is a C1-C4 linear or branched alkylene linker. The compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is CH2.

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

[0044] Embodiment 11.E is a compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Embodiment 11.E is a monocyclic 4-6 membered heterocycline.

[0045] Embodiment 12.E is a monocyclic 4-6 member heteroaryl, one of Embodiments 1-11 Any one of the compounds listed, or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 13. A compound according to any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 4- to 6-membered heterocyclil contains one or two nitrogen atoms.

[0047] Embodiment 14.5 A compound according to any one of Embodiments 1 to 13, wherein the 5-6 membered heteroaryl contains one nitrogen atom, or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 15.4 A compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein a 4-6 membered heterocyclyl and a 5-6 membered heteroaryl are optionally substituted with one, two, or three substituents.

[0049] Embodiment 16. A compound according to any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the substituent is independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, and -SO2R.

[0050] Embodiment 17.R independently comprises a linear or branched C1-C3 alkyl, a monocyclic 5-6 membered heterocycline, and NR 1 R 2 A compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the above.

[0051] Embodiment 18. A monocyclic 5-6 membered heterocycline is optionally C1-C3 alkyl or NR. 3 R 4 A compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, which is substituted with.

[0052] Embodiment 19.R 1 and R 2 However, independently selected from H and C1-C3 alkyl, the compound described in any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof. The C1-C3 alkyl is optionally NR 3 R 4 A compound according to any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, which is substituted with.

[0053] Embodiment 20. Each R 3 and R 4 However, independently, a compound according to any one of Embodiments 1 to 19, selected from H or methyl, or a pharmaceutically acceptable salt thereof.

[0054] Embodiment 21.G 1 The compound according to any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, is optionally a linear or branched C1-C4 alkyl group substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl groups.

[0055] Embodiment 22.G 1 The compound according to any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, is a C3-C4 cycloalkyl group that is optionally substituted with one, two, or three substituents independently selected from linear or branched C1-C3 alkyl groups.

[0056] Embodiment 23.G 1 The compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, is optionally a linear or branched C1-C4 alkoxy substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl groups.

[0057] Embodiment 24. The compound described in Embodiment 1 having formula (Ia), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, A 1 It is selected from the group consisting of H, a linear or branched C1-C3 alkyl group, and SO2R. A 2 (This is selected from the group consisting of H and SO2R).

[0058] Embodiment 25.A 1 The compound according to Embodiment 24, wherein the compound is methyl or SO2CH3.

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

[0060] Embodiment 27. The compound described in Embodiment 1, having formula (Ib), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, Y is either H or CH3).

[0061] Embodiment 28. The compound described in Embodiment 1, having formula (Ic), or a pharmaceutically acceptable salt thereof: [ka] (wherein X is selected from the group consisting of methyl, ethyl, and cyclopropyl).

[0062] Embodiment 29. A compound from any of the preceding embodiments of any of the examples, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-( (1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide; N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide; N-(1-amino-4b-hydroxy-7-isopropyl-10-ox So-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide;N-(1-amino-7-((1R, 2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-(2-methylcyclobutyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide;N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide; N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pi Rol-2-carboxamide; (2S,3S)-N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide; N-(1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(((S)-3-(dimeth (1-amino)pyrroridine-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-methylpiperazine-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-methylpiperazine-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-methylpiperazine-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-i; Indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide; N-(1-amino-4b-hydroxy-7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-Indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro -9bH-Indeno[1,2-b]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide; N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-Indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide; N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-di Hydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-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-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-((1 S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide;N-(1-amino-7-(sec-butyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide; N-(1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b [1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide;N-(1-amino-4b- Droxy-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-(methylsulfonyl)-1H-pyrrole-2-carboxamide and N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxamide. This embodiment includes each of the examples shown in the table of bioactivity data herein.

[0063] Embodiment 30. A compound comprising one or more of the examples shown in the table of bioactivity data in this specification.

[0064] Embodiment 31. Chemical formulas I-III or the present specification for preventing or treating viral diseases A compound described in any one of the embodiments in this book, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.

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

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

[0067] Embodiment 34. Use of a compound described in Chemical Formulas 1 to III or any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for the prevention or treatment of a viral disease.

[0068] Embodiment 35. The use described herein in which a viral disease is caused by a coxsackievirus.

[0069] Embodiment 36. The use described herein in which the viral disease is caused by the poliovirus.

[0070] Embodiment 37. The use described herein in which a viral disease is caused by an echovirus.

[0071] Embodiment 38. The use described herein in which a viral disease is caused by an enterovirus.

[0072] Embodiment 39. The use described herein in which a viral disease is caused by a rhinovirus.

[0073] Embodiment 40. The use described herein in an embodiment in which a viral disease is caused by a picornavirus.

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

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

[0076] Another embodiment of the present invention provides the above-mentioned compound, or a pharmaceutically acceptable salt thereof, as a pharmaceutical.

[0077] Furthermore, within the scope of the present invention,

[0078] There is also the use of the compound described in formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment or prevention of viral diseases and / or infectious diseases in humans.

[0079] The scope of the present invention includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0080] According to a further embodiment of this embodiment, the pharmaceutical composition according to the present invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0081] The present invention also provides the use of the above-described pharmaceutical compositions for treating viral infections or other viruses in humans who have or are at risk of having a viral infection.

[0082] The present invention also provides the use of the above-described pharmaceutical compositions for treating viral diseases or other viral infections in humans who have or are at risk of having a viral disease.

[0083] Another aspect of the present invention relates to a method for treating or preventing viral diseases and / or infections in humans by administering to humans an antivirally effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or the above composition, in combination with at least one other antiviral agent administered alone, together, or separately.

[0084] An additional aspect of the present invention is a product comprising a composition effective for treating herpesvirus diseases and / or infections, and packaging material including a label indicating that the composition can be used to treat viral diseases and / or infections, wherein the composition comprises a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof.

[0085] A further aspect of the present invention relates to a method for inhibiting viral replication, comprising exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions that inhibit viral replication. This method can be carried out in vitro or in vivo.

[0086] Furthermore, the use of a compound of formula (I) or a salt thereof to inhibit viral replication is also included within the scope of the present invention.

[0087] 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 include 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 a range of, including another viral inhibitor.

[0088] These additional agents may be combined with the compound of the present invention to create a single pharmaceutical dosage form. Alternatively, these additional agents may be administered separately to the patient as part of multiple dosage forms, for example, using a kit. Such additional agents may be administered to the patient before, concurrently with, or after administration of the compound of the present invention or a pharmaceutically acceptable salt thereof.

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

[0090] The actual pharmacokinetic or therapeutic dose naturally depends on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In all cases, the combination is administered in a dosage and manner that allows for the delivery of a pharmacokinetic dose based on the patient's specific condition.

[0091] If the composition of the present invention comprises a combination of the compound of the present invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents need to be present at drug dose levels of approximately 10-100%, and sometimes approximately 10-80%, of the drug dose typically administered in a monotherapy regimen.

[0092] Antiviral agents intended for use in such combination therapies include, but are not limited to, agents (compounds or biologics) that are effective in inhibiting the formation and / or replication of viruses in humans, by interfering with either the host or viral mechanism necessary for the formation and / or replication of viruses in humans.

[0093] Many of the compounds of the present invention contain one or more chiral centers. These compounds can be prepared and used as single isomers or as mixtures of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of preferred methods are described herein. In certain embodiments, the compounds of the present invention are used as a single, substantially pure isomer, meaning that at least 90% of a sample of the compound is a specific isomer and less than 10% of the sample is any other isomer or a mixture of isomers. In some embodiments, at least 95% of the sample is a single isomer. Typically, one isomer is more active in the herpesvirus DNA polymerase in vitro assay described herein and becomes the single isomer, so the selection of a preferred isomer is within the range of normal skill levels. If the difference in in vitro activity between isomers is relatively small, e.g., less than about 4 times, a single isomer, e.g., an isomer with a lower IC50 or EC50, may be selected based on the level of activity for viral replication in cell cultures, using methods such as those described herein.

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

[0095] The present invention also provides a method for producing compounds of formula I as described herein, and intermediates useful for the preparation of compounds of formula (I). Thus, the present invention also includes a method for producing compounds of formula (I). The present invention uses an intermediate product which can be obtained at any stage as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reactant is their salt or an optically pure material This further includes any variations of this process used in the form of [this].

[0096] The present invention also relates to a form of process in which a compound that can be obtained as an intermediate at any stage of the process is used as a starting material and the remaining process steps are carried out, or a form of process in which the starting material is formed under reaction conditions or used in the form of a derivative, such as a protected form or a salt form, or a form of process in which a compound that can be obtained by the process according to the present invention is produced under process conditions and further treated in situ.

[0097] The terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomer configurations that may exist for a given compound of the present invention, including geometric isomers. Substituents are understood to be bonded to the chiral center of a carbon atom. The term "chiral" refers to a molecule that possesses non-superimposability relative to its enantiomer partner. On the other hand, the term "achiral" refers to molecules that can be superimposed on their enantiomer partners. Therefore, the present invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used as appropriate to refer to a racemic mixture. A "diastereoisomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Absolute stereochemistry is specified according to the Kahn-Ingold-Prelogue RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. A split compound whose absolute configuration is unknown may be designated (+) or (-) depending on the direction in which it rotates plane polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0098] Depending on the selection of starting materials and procedures, compounds may exist in one form of one of the possible isomers, or a mixture thereof, depending on the number of chiral carbon atoms, for example, as a pure optical isomer or as an isomer mixture such as a racemic mixture and a mixture of diastereoisomers. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or can be divided using the prior art. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomer forms are also intended to be included.

[0099] Any resulting mixture of isomers can be separated into pure or substantially pure geometric isomers, optical isomers, or diastereomers based on the physicochemical differences of their components, for example, by chromatography and / or fractional crystallization.

[0100] Any resulting racemic product or intermediate can be separated into optical counterparts by known methods, for example, by separating its diastereomer salt obtained using an optically active acid or base and liberating the optically active acidic or basic compound. Therefore, the compounds of the present invention can be separated into their optical counterparts by, in particular, using a basic moiety to fractionally crystallize salts formed with optically active acids, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor 10-sulfonic acid. Racemic products can also be separated by chiral chromatography, for example, high-pressure liquid chromatography (high-pressure chromatography) using a chiral adsorbent. It can also be separated by pressure liquid chromatography (HPLC).

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

[0102] The compounds of the present invention (including their salts, hydrates, and solvates) may be polymorphic in nature or by design.

[0103] As used herein, the term “salt)” refers to an acid-addition salt or base-addition salt of the compound of the present invention. “Salt” includes, in particular, “pharmaceutically acceptable salt.” “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compound of the present invention and is not typically biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid and / or base salts in the presence of an amino group and / or a carboxyl group or similar group.

[0104] Pharmacologically acceptable acid addition salts include inorganic and organic acids, such as acetate, aspartate, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, and laurate. It can be formed from lyl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0105] Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0106] Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0107] Examples of inorganic bases that can be used to derive salts include ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts being ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0108] Examples of organic bases that can derive salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, and pipette. Examples include radin and tromethamine.

[0109] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), 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, an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred when feasible. A list of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th edition, Mack. Publishing Company (Easton, Pa. (1985); and can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

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

[0111] Furthermore, heavier isotopes, especially deuterium (i.e., 2 More broad substitutions with H or D may result in certain therapeutic benefits due to greater metabolic stability, such as extended half-life in vivo, reduced drug dose requirements, or improved therapeutic index. In this context, deuterium is considered a substituent of the compounds of the present invention, and typically, a sample of a compound having deuterium as a substituent is understood to have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, means the ratio of the isotopic abundance to the natural abundance of a particular isotope. When the substituent in a compound of the present invention is deuterium, such a compound has at least 3500 (each designated deuterium atom) It has an isotope enrichment factor of at least 52.5% deuterium in the elementary atom, at least 4000 (60% deuterium), at least 4500 (67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium), at least 6000 (90% deuterium), at least 6333.3 (95% deuterium), at least 6466.7 (97% deuterium), at least 6600 (99% deuterium), or at least 6633.3 (99.5% deuterium).

[0112] The pharmaceutically acceptable solvates according to the present invention are those in which the crystallization solvent is isotope-substituted, for example, D2O, d 6 -acetone, d 6 -Includes those that may be DMSO.

[0113] Compounds of the present invention containing groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming cocrystals with suitable cocrystal-forming agents. These cocrystals can be prepared from the compounds of the present invention by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contact in solution of the compounds of the present invention and the cocrystal-forming agent under crystallization conditions, and isolation of the cocrystals thereby formed. Suitable cocrystal-forming agents include those described in International Publication No. 2004 / 078163. Accordingly, the present invention further provides cocrystals comprising the compounds of the present invention.

[0114] All methods described herein may be carried out in any preferred order, unless otherwise specified herein or unless the context clearly contradicts it. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to further illustrate the invention and not to limit the scope of the claimed invention.

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

[0116] The compounds of the present invention may also be used in combination with other agents (combination partners), such as additional antiviral agents of formula I or not of formula I, for the treatment of viral infections in subjects.

[0117] The terms “combination / combination / combination” mean any combination fixed in a single unit dosage form, either as separate dosage forms suitable for use together, either simultaneously or sequentially, or as a kit of components for combination administration, in particular, within a time interval that allows the combination partner to exhibit cooperative, for example, synergistic, effective, or any combination thereof.

[0118] In certain embodiments of the present invention, the compounds of the present invention are used in combination with a second antiviral agent, such as those named herein.

[0119] A second antiviral agent may be administered in combination with the compounds of the present invention, and the second antiviral agent may be administered before, simultaneously with, or after one or more compounds of the present invention. If simultaneous administration of the compound of the present invention and a second drug is desired and the administration route is the same, the compound of the present invention may be formulated in the same dosage form as the second drug. Examples of dosage forms containing the compound of the present invention and the second drug are tablets or capsules.

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

[0121] The “effective amount” of a compound is the amount necessary or sufficient to treat or prevent a viral infection and / or disease or condition described herein. In one example, the effective amount of the viral inhibitor of formula I is sufficient to treat a viral infection in a subject. In another example, the effective amount of the inhibitor is sufficient to treat a viral infection in a subject requiring such treatment. The effective amount may vary depending on factors such as the size and weight of the subject, the type of disease, or the specific compound of the present invention. For example, the selection of the compound of the present invention may affect what constitutes the “effective amount.” Those skilled in the art can test the factors described herein and make a determination regarding the effective amount of the compound of the present invention without excessive experimentation.

[0122] The administration regimen may affect what constitutes the effective dose. The compounds of the present invention can be administered to subjects either before or after the onset of a viral infection. Furthermore, several divided and staggered dosages may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. Moreover, the dosage of the compounds of the present invention may be increased or decreased proportionally, as indicated by the urgency of the therapeutic or preventive situation.

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

[0124] The term "pharmaceutical composition" includes preparations suitable for administration to mammals, such as humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, such as humans, the compounds may be given as themselves, or as pharmaceutical compositions containing, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of at least one compound of formula (I) or any subgenus thereof as an active ingredient in combination with a pharmaceutically acceptable carrier or optionally two or more pharmaceutically acceptable carriers.

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

[0126] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition.

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

[0128] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, oral, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage forms and may 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 is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent, sometimes about 5 percent to about 70 percent, and sometimes about 10 percent to about 30 percent of the active ingredient.

[0129] 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 minor components. Generally, formulations are prepared by homogeneously and closely associating the compounds of the present invention with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0130] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as liquids or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, lick, or paste.

[0131] In the solid dosage forms of the present invention for oral administration (such as capsules, tablets, pills, sugar-coated tablets, powders, and granules), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginate, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; humectants such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; talc, stearate Lubricants such as calcium, 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 buffers. Similar types of solid compositions may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0132] Tablets may be prepared by compression or molding with one or more optional adjuncts. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0133] Tablets, as well as other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be prepared with coatings and shells, such as notches, enteric coatings, and other coatings well known in the field of pharmaceutical formulation. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water, or by some other sterile injection medium immediately before use. These compositions may also optionally contain an opaque agent, and may optionally release the active ingredient sustainably only in the gastrointestinal tract, or, for example, in a specific part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymer substances and waxes. The active ingredient may also be in microencapsulated form having one or more of the above excipients, as needed.

[0134] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsion formulations, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain, for example, water or other solvents, solubilizers, and emulsifiers such as inert diluents commonly used in the art, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0135] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances, and preservatives.

[0136] In addition to the active compound, the suspension may contain a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyoxide, bentonite, agar, and tragacanth, or mixtures thereof.

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

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

[0139] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, liquids, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

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

[0141] The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0142] 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 flow of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or by dispersing the active compounds in a polymer matrix or gel.

[0143] Ophthalmic preparations, eye ointments, powders, and liquids are also conceived as being within the scope of the present invention.

[0144] The pharmaceutical compositions of the present invention, suitable for parenteral administration, may contain one or more compounds of the present invention in combination with one or more pharmaceutically acceptable carriers, such as a sterile isotonic aqueous solution or nonaqueous solution, dispersion, suspension, emulsion, or sterile powder, which can be reconstituted into a sterile injectable solution or dispersion immediately before use, and which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the preparation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0145] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, maintaining the required particle size in the case of a dispersion, and using a surfactant.

[0146] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, long-term absorption of injectable pharmaceutical forms may be achieved with aluminum monostearate. This can also be achieved by including absorption-delaying agents such as gelatin.

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

[0148] Injectable depot formulations are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsion formulations compatible with body tissues.

[0149] The preparations of the present invention may be administered orally, parenterally, topically, or rectally. Naturally, they may be administered in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation in the form of tablets or capsules, by injection, inhalation, eye drops, ointment, or suppository; topically as a lotion or ointment; and rectally as a suppository.

[0150] As used herein, the terms “parenteral administration” and “administered parenterally” mean, but are not limited to, injections and infusions of a mode of administration other than enteral and topical administration, typically by injection, including intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and substernal injections and infusions. Sometimes, intravenous infusion is the method of delivery of the compounds of the present invention. Infusions may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion over intervals of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once daily, twice daily, or up to three times per day.

[0151] When used herein, the terms “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other material that enters the patient’s system and is therefore administered in a manner other than directly to the central nervous system, such as through metabolism and other similar processes, such as subcutaneous administration.

[0152] These compounds may be administered to humans and other animals for therapeutic purposes by any preferred route of administration, including orally and nasally, for example by spray, rectally, vaginally, parenterally, intracisionally, and topically, in the form of powder, ointment, or drops (including oral and sublingual).

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

[0154] The actual drug dose level of the active ingredient in the pharmaceutical composition of the present invention may be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0155] The selected drug dose level depends on the activity of the specific compound of the present invention used, or its ester, salt, or amide, the route of administration, the time of administration, and the elimination of the specific compound used. It depends on a variety of factors, including the speed, duration of treatment, other drugs, compounds, and / or materials used in combination with the specific compound used, the age, sex, weight, condition, overall health, and medical history of the patient being treated, as well as similar factors well known in the pharmaceutical field.

[0156] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound of the present invention used in the pharmaceutical composition at a lower level than necessary to achieve the desired therapeutic effect and to gradually increase the drug dose until the desired effect is achieved.

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

[0158] If necessary, the effective daily dose of the active compound may be administered in unit dosage form, either as a single daily dose or as two, three, four, five, or six or more secondary doses administered separately at appropriate intervals throughout the day. Compounds delivered orally or by inhalation are generally administered in doses of one to four times per day. Compounds delivered by injection are typically administered once daily or every other day. Compounds delivered by infusion are typically administered in doses of one to three times per day. If multiple doses are administered within a day, the doses may be administered at intervals of approximately four hours, six hours, eight hours, or twelve hours.

[0159] While the compounds of the present invention may be administered alone, they may also sometimes be administered as part of a pharmaceutical composition, such as those described herein. Therefore, a method of using the compounds of the present invention includes administering the compounds as part of a pharmaceutical composition, wherein at least one of the compounds of the present invention is mixed with a pharmaceutically acceptable carrier before administration. General synthesis procedure

[0160] The compounds described herein may be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

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

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

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

[0164] Salts of the compounds of the present invention having at least one salt-forming group can be prepared in known ways. For example, salts of the compounds of the present invention having an acid group can be formed by treating the compound with a metal compound such as an alkali metal salt of a suitable organic carboxylic acid, e.g., the sodium salt of 2-ethylhexanoic acid, an organic alkali metal or alkaline earth metal compound such as a corresponding hydroxide, carbonate or bicarbonate, e.g., sodium or potassium hydroxide, carbonate or bicarbonate, a corresponding calcium compound, or ammonia or a suitable organic amine, sometimes using a stoichiometric amount or a slight excess of the salt-forming agent. Acid addition salts of the compounds of the present invention can be obtained in a conventional way, for example, by treating the compound with an acid or a suitable anion exchange reagent. Intramolecular salts of the compounds of the present invention containing acid and basic salt-forming groups, e.g., free carboxyl groups and free amino groups, can be formed, for example, by treatment with a weak base or an ion exchanger, or by neutralization to the isoelectric point of the salt, such as an acid addition salt.

[0165] Salts can be converted to free compounds in the usual manner. Metal salts and ammonium salts can be converted, for example, by treatment with suitable acids and acid addition salts, or by treatment with suitable basic agents.

[0166] A mixture of isomers that can be obtained according to the present invention can be separated into individual isomers in ways known to themselves. Diastereoisomers can be separated, for example, by liquid-liquid separation, recrystallization, and / or by chromatographic separation, for example, on silica gel, or by medium-pressure liquid chromatography, for example, on a reversed-phase column, and racemates can be separated, for example, by salt formation with an optically pure salt-forming reagent and separation of the mixture of diastereoisomers thus obtained, for example, by fractional crystallization, or by chromatography on an optically active column material.

[0167] Intermediates and final products can be post-processed and / or purified according to standard methods, such as chromatography, partitioning, and (re)crystallization. High-resolution mass spectrometry using LC-MS

[0168] ESI-MS data was recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The resolution of the MS system was approximately 30,000. Drug candidates were injected into the mass spectrometer from the sample probe using a UPLC (Acquity, Waters). The Acquity UPLC BE was injected at a flow rate of 0.15 mL / min with a 5% to 95% gradient over 3 minutes. Separation was performed using a 1×50 mm H₂C₁₄ column. Solvent A was water containing 0.1% trifluoroacetic acid, and solvent B was 75% methanol and 25% isopropyl alcohol containing 0.1% trifluoroacetic acid. The mass accuracy of the system was found to be less than 5 ppm. [Examples]

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

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

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

[0172] To a suspension of anhydrous 2 (50 g, 0.26 mol) in dry DCM (260 mL), ethyl acetoethyl (42 mL, 0.31 mol) and Ac2O (48.5 mL, 0.52 mol) were added at ambient temperature. To this suspension, Et3N (108 mL, 0.78 mol) was added dropwise over 30 minutes at room temperature (exothermic). A few mL of TEA was added. This was stirred at the same temperature for a further 15 minutes, and then the DCM was evaporated. The resulting crude product was then dissolved in 2 liters of water and cooled to 0°C. This was fixed in an overhead stirrer, and 300 mL of 2N HCl was added dropwise under vigorous stirring conditions, maintaining the temperature below 0°C. A precipitate slowly began to form. This was stirred at 0°C for a further 15 minutes, then filtered through a Buchner funnel and washed with ice-cold water (500 mL). Next, this was air-dried for three days to obtain a solid product. 4-Nitro-1H-Inden-1,3(2H)-Zeon(4):

[0173] Ethyl 4-nitro-1,3-dioxo-2,3-dihydro-1H-indene-2-carboxylate 3 (272.5 g, 1.04 mol) was placed in 1 liter of MeCN:water (20:1, 1.0 M). To this suspension, TFA (60 mL, 1.14 mol) was slowly charged at room temperature, and the mixture was then heated at 50°C. After 4 hours, the reaction mixture was concentrated in 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. The product was obtained, and the filtrate was concentrated again to obtain a second crop (cro More product was obtained at p). 2,2-dihydroxy-4-nitro-1H-idden-1,3(2H)-dione(5):

[0174] 4-nitro-1H-indene-1,3(2H)-dione 4 (10.0 g, 52.3 mmol) was placed in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added to this, and the mixture was refluxed at 105-110°C for 5 hours. The reaction mixture was then filtered through Celite under thermal conditions, and then concentrated to remove volatile substances to obtain crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione. 7-Bromo-4b,9b-dihydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(7):

[0175] Next, crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 was placed in ice AcOH (210 mL, 0.25 mmol), to which 3-bromophenol 6 (9.96 g, 57.5 mmol) was charged, and the mixture was maintained under reflux for another 12 hours. The reaction mixture was concentrated and placed in EA (500-600 mL). This was filtered through Celite, and the residue was washed with EA. The filtrate was washed with water (200 mL x 2) and brine (100 mL). This 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) to obtain the pure product. 7-Bromo-9b-chloro-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(8):

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

[0177] 9b-Chloro-4b-hydroxy-4-nitro-8-(trifluoromethyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 8 (21.2, 53.4 mmol) was placed in THF (530 mL, 0.1 M) and cooled to -40°C. 2.0 M NH3 in IPA (54 mL, 0.11 mmol) was added at the same temperature, and the mixture was stirred for the next 3 hours. The reaction mixture was diluted with water (approx. 150 mL) and brine (150 mL). The aqueous layer was extracted with EA (approx. 300 mL x 2). The combined organic layers were washed with brine (approx. 100 mL). This 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 containing 20% ​​DCM as cosolvent) to obtain the pure product. tert-butyl(7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(10):

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

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

[0180] A racemic mixture of tert-butyl(7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) carbamate 10 (10.3 g, 21.5 mmol) was placed in EtOH:water (10:1, 110.0 mL, 0.20 M), to which Fe powder (3.57 g, 63.9 mmol) was added, followed by concentrated HCl (0.8 mL, cat.). This mixture was refluxed at 90°C for the next 3 hours. The reaction mixture was filtered through Celite under warm conditions using hot EA (50-100 mL). The filtrate was concentrated and placed in EA (approximately 1000-1200 mL), and washed with water (approximately 300-500 mL) and brine (approximately 300 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (10 → 30% EA in hx) to obtain a pure product. tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (12) and tert-butyl((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (13): 7000 mg of tert-butyl(1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (11) was purified by chiral chromatography using an AD column, HPLC = 20 mL / min, heptane / EtOH = 70 / 30, 724 psi to obtain 3100 mg of tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (12) (peak 2, tR 15.59 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.48 (br t,J=7.7Hz,1H),7.37(br s,1H),7.11(br s,1H),7.02(br d,J=7.1Hz,1H),6.95(s,1H),6.72(br s,1H),1.42(br s,5H),1.13(br s,4H)LCMS:447.2 / 449.2[M+H] + As such, 3060 mg of tert-butyl((4bS,9bS)-1-amino-7-bromo-4b-hydroxy-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl) carbamate (13) (peak 1, tR 8.97 min); 1H NMR (500 MHz, METHANOL-d4) δ: 7.48 (br t, J=7.6 Hz, 1H), 7.37 (br s, 1H), 7.11 (br s, 1H), 7.02 (br d, J=6.9 Hz, 1H), 6.95 (s, 1H), 6.72 (br s, 1H), 1.42 (br s, 5H), 1.13 (br s, 4H) LCMS: 447.2 / 449.2 [M+H] + It was obtained as such. [ka] Intermediates (14 and 18) were prepared according to J.Am.Chem.Soc.2013,135,82-85. ((1S,2S)-2-methylcyclopropyl)boronic acid (15):

[0181] A solution of (4S,5S)-N4,N4,N5,N5-tetramethyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane-4,5-dicarboxamide 14 (4.21 g, 14.4 mmol) in water (145 mL) was stirred at room temperature for 12 hours. The aqueous layer was extracted with ether (100 mL x 3), the combined etheric layers were washed with water, dried over NA2SO4, and the solvent was evaporated at low temperature to obtain the product. The crude product was not purified before proceeding to the next step. 6-Methyl-2-((1S,2S)-2-methylcyclopropyl)-1,3,6,2-dioxazabolocan-4,8-dione(17):

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

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

[0184] A solution of ((1R,2R)-2-methylcyclopropyl)boronic acid 19 (6.03 g, 60.3 mmol) in toluene / DMSO (10 / 1, 300 mL / 30 mL) was added to 2,2 ’-(methylazanediyl)diacetic acid 16 (13.3 g, 90.5 mmol), and then 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, and then the desired product was formed. 1 H NMR (300 MHz, CDCl3) δ 3.92 (d, J = 16.6 Hz, 2H), 3.72 (dd, J = 16.6, 4.8 Hz, 2H), 3.04 (s, 3H), 1.10 (d, J = 5.8 Hz, 3H), 0.70 (dt, J = 11.3, 5.7 Hz, 1H), 0.47 - 0.35 (m, 1H), 0.34 - 0.22 (m, 1H), -0.61 (dt, J = 9.2, 6.1 Hz, 1H).

Chemical formula

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

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

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

[0188] Methyl 3-methyl-1-tosyl-4,5-dihydro-1H-pyrrole-2-carboxylate 26 (30 g, 102 mmol) was dissolved in THF (204 mL), and DBU (46 mL, 306 mmol) was slowly added. The resulting reaction mixture was stirred at 50°C for 20 hours. The reaction mixture was cooled to room temperature and diluted with 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 plug, and the solvent was evaporated to obtain the product. Methyl 3-methyl-4-(methylthio)-1H-pyrrole-2-carboxylate (28):

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

[0190] Methyl 3-methyl-5-(methylthio)-1H-pyrrole-2-carboxylate 28 (185 mg, 1.0 mmol) was placed 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 the next 3 hours. The volatile substances were then removed under reduced pressure, and the suspension of solids in water was extracted with EA (70 mL × 2) using only a small amount of water to dissolve the inorganic substances. The combined organic layers were washed with water (30 mL) and brine (30 mL). This 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) to obtain the pure product. 3-Methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid (30):

[0191] A solution of ethyl 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylate 29 (390 mg, 1.68 mmol) in H2O:THF (17 mL) was mixed with LiOH.H2O (353 mg, 8.4 mmol). 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 x 2). The combined organic layers were washed with water and brine. The organic layers were dried over anhydrous Na2SO4, and the solvent was evaporated to obtain the product, which was used directly in the next step without purification. [ka] tert-butyl((4bR,9bR)-1-amino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(31):

[0192] tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (112 mg, 0.25 mmol) was placed in nitrogen-purged toluene:water (5 mL). To this, 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-dioxazabolocan-4,8-dione 20 (79 mg, 0.38 mmol) were added. The reaction mixture was refluxed at 100°C for 2 hours, and the reaction product was filtered through a Celite 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. (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-(1R,2R)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-onhydrochloride(32):

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

[0194] 3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid 30 (48 mg, 0.23 mmol) was taken in DMF (4 mL, 0.05 M). To this, HAT was added. U (111 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) were added and the mixture was stirred for 20 minutes. Then, (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1R,2R)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-onehydrochloride 32 (70 mg, 0.2 mmol) was added and the mixture was stirred at 30°C for 36 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography and again by ADH chiral column chromatography to obtain the product. 1 H-NMR(300MHz,MeOD)δ 0.66-0.72(m,1H),0.78-0.84(m,1H),0.95-1.03(m,1H),1.13(d,J=6.0Hz,3H),1.49-1.55(m,1H),2.48(s,3H),3.05(s,3H),6.45(s,1H) ,6.63-6.67(m,1H),6.76(d,J=8.1Hz,1H),7.02(d,J=7.2Hz,1H),2.27(d,J=8.1Hz,1H),7.38(s,1H),7.43-7.49(m,1H).LCMS:508.4[M+H] + . Example 2: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2R)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide [ka]

[0195] This compound was prepared in the same manner as the above compound. LCMS: 420.2[M+H] + . Example 3: N-((4bR,9bR)-1-Amino-7-((S)-1-cyclopropylethyl-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide

Chem.

[0196] This compound was prepared in the same manner as in Example 1 above. LCMS: 458.2 [M+H] + . Example 4: N-(1-Amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-inden[1,2-b]benzofuran-9b-yl)-5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxamide (51):

Chem.

[0197] 4-nitro-1H-indene-1,3(2H)-dione(4) (250 g, 1.31 mol) was placed in 1,4-dioxane (2 liters) and AcOH (200 mL). SeO2 (291 g, 2.62 mol) was added at room temperature and maintained under reflux at 110°C for the next 4 hours. This was stirred at room temperature for the next 12 hours. Next, 500 g to 600 g of Celite was charged to this. This was stirred and filtered through a Celite pad. The residue was washed with ethyl acetate (300 to 500 mL). The resulting filtrate was concentrated to obtain crude product 5, which was then used as is. Crude 2,2-dihydroxy-4-nitro-1H-indene-1,3(2H)-dione 5 (1.31 mol) was placed in 2 liters of ice AcOH, and 3-isopropylphenol 34 (196 g, 1.44 mol) was added. The mixture was maintained under reflux for the next 10 hours. The mixture was then concentrated and purified by silica gel column chromatography (30% EA in hexane) to obtain the pure product. 9b-Chloro-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(36):

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

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

[0200] 3-Nitrobutan-2-ol 38 (7.5 g, 63 mmol) was placed 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 the next 24 hours, the reaction mixture was quenched with MeOH (8 mL) and stirred for the next hour. This was then placed in DCM (250 mL) and washed with saturated NaHCO3 (100 mL x 2), water (100 mL), and brine (approximately 100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the pure product as an oily substance. Ethyl formyl glycinate (41):

[0201] To a solution of glycine ester hydrochloride 40 (20.0 g, 0.143 mol) in ethyl formate (90 mL, 1.6 M), pTSA (1.36 g, 7.2 mmol) was added. This was refluxed, and TEA (22.0 mL, 0.157 mol) was added dropwise at this temperature. The reaction mixture was refluxed for the next 24 hours, or monitored by TLC. This was then cooled to room temperature (20°C) and concentrated. The crude product was then filtered through a silica short pad using 50% EA in hexane (3000 mL). This was then concentrated to obtain the product, which was used directly in the next step. According to NMR, the bio The resulting product contained TEA. Since the next step would involve using an excess of TEA, it was retained for that step. Ethyl 2-isocyanoacetate (42):

[0202] To a solution of ethylformylglycinate 41 (9.40 g, 80 mmol) and TEA (28 mL, 0.2 mol) in 0°C DCM (80 mL, 1.0 M), POCl3 (7.5 mL, 80 mmol) was slowly added dropwise. The solution turned red, and was then allowed to reach room temperature after the addition was complete, and stirred for the next 4 hours. The reaction mixture was then slowly quenched with Na2CO3 solution and solid Na2CO3, and stirred at room temperature for the next 30 minutes. 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). This was dried over anhydrous Na2SO4 and concentrated to obtain the pure product in liquid form.

[0203] Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate (43): 3-Nitrobutane-2-yl acetate 39 (8.9 g, 55.0 mmol) and ethyl 2-isocyanoacetate 42 (8.1 g, 71.5 mmol) were placed in THE:water (1:1, 110 mL, 0.5 M), and anhydrous K2CO3 (12.2 g, 88.0 mmol) was slowly added little by little while vigorously stirring. The reaction mixture was then stirred at room temperature for the next 3 days. The reaction mixture was then concentrated until it became a thick slurry. This was then diluted with ice-cold water (100 mL) and then slowly neutralized with 5% HCl (2N, pH=5) at 0°C. This was then extracted with EA (150 mL x 3). The combined organic layers were washed with 5% brine (100 mL x 2). This 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) to obtain a pure product. Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate (44):

[0204] Ethyl 3,4-dimethyl-1H-pyrrole-2-carboxylate 43 (1.67 g, 10.0 mmol) was placed 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 the next 3 hours. The reaction mixture was quenched with crushed ice (120 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was passed through a silica gel short pad together with DCM, and the filtrate was concentrated to obtain the pure product. Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate(46):

[0205] Ethyl 5-(chlorosulfonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 44 (530 mg, 2.0 mmol) was placed in DCM (20 mL, 0.1 M), to which tert-butyl(2-aminoethyl)carbamate 45 (385 mg, 2.4 mmol), followed by DIPEA (0.52 mL, 3.0 mmol) was added at room temperature. The reaction mixture was then stirred at room temperature (25°C) for the next 2 hours. The reaction mixture was quenched with water (50 mL) and then extracted with DCM (70 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). This 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) to obtain the pure product. 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (47):

[0206] Ethyl 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulf (682 mg, 1.75 mmol) of (amoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylate 46 was placed 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 volatile substances. This was then acidified with 1N HCl (pH < 2 ~ 3). The precipitated solid was then filtered, washed with cold water, and dried to obtain the pure product. [ka] tert-butyl(2-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole)-2-sulfonamide)ethyl)carbamate(48):

[0207] 5-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid 47 (452 ​​mg, 1.25 mmol) was placed in DMF (5 mL, 0.25 M) and cooled to 0°C. EDCI (360 mg, 1.88 mmol) was then added, followed by HOBt (254 mg, 1.88 mmol). After 10 minutes, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (425 mg, 1.25 mmol), followed by DIPEA (0.55 mL, 3.13 mmol), and the mixture was allowed to reach room temperature (35°C) over the next 18 hours. Next, the reaction mixture was quenched with water (60 mL) and extracted with EA (100 mL x 2). The combined organic layer was washed with water (50 mL) and brine (30 mL). This 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) to obtain the product. 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide(49):

[0208] tert-butyl(2-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole)-2-sulfonamide)ethyl)carbamate 48 (275 mg, 0.4 mmol) was taken in DCM (8 mL, 0.05 M), and to this, 4 M HCl (1.0 mL, 4.0 mmol) in dioxane was added. l) was added. This 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. Since sufficient free amine was not liberated, 0.5 mL of TEA was added. This 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). This was dried over anhydrous Na2SO4 and concentrated to obtain a solid. 5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide(50):

[0209] 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 49 (88 mg, 0.15 mmol) was placed 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 the addition of NaBH3CN (33 mg, 0.53 mmol). This mixture was stirred at 0°C for the next 0.5 hours. The reaction mixture was quenched with water (40 mL) and extracted with EA (40 mL x 2). The combined organic layers were washed with water (30 mL) and brine (10 mL). This was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0% in DCM → 0.05% TEA in 10% MeOH) to obtain the pure product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(N-(2-(dimethylamino)ethyl)sulfamoyl)-3,4-dimethyl-1H-pyrrole-2-carboxamide(51):

[0210] 5-(N-(2-aminoethyl)sulfamoyl)-N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-1H-pyrrole-2-carboxamide 50 (46 mg, 0.075 mmol) was placed in EtOH:water (10:1, 5.0 mL, 0.015 M), to which iron powder (13 mg, 0.23 mmol) was added, followed by 1 M HCl (3 drops). This was refluxed at 90°C for the next 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 Celite under thermal conditions using EA (20 mL). The filtrate was concentrated and placed in EA (100 mL), then washed with water (20 mL) and brine (20 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. The crude product was purified by thin-layer preparative chromatography (10% MeOH in DCM) 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(sept,J=6.9Hz,1H),3.06(t,J=6.6Hz,2H),6.6 9(s,1H),6.77(d,J=7.8Hz,1H),6.85(d,J=7.8Hz,1H),7.03(d,J=7.2Hz,1H),7.36(d,J=7.8Hz,1H),7.45-7.50(m,1H).LCMS:582.3[M+H] + . Example 5: N-((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide(62) [ka] 2-(1-cyclopropyl vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(54):

[0211] In a reaction flask, anhydrous lithium chloride (7.06 g, 166.5 mmol), CuCl (16.5 g, 166.5 mmol), and dried N,N-dimethylformamide (500 mL) were added under nitrogen, and the mixture was stirred at room temperature for 1 hour. 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 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (100 mL), ethyl acetate (100 mL) was added, and the mixture was filtered through a Celite bed. The filtrate was extracted with hexane (200 mL x 3), the combined organic layer was collected, washed with water (100 mL x 3) and 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 the product as an oily substance. [ka] tert-butyl 2-(azetidine-1-yl)acetate (57):

[0212] Azetidine hydrochloride 56 (73 g, 78 mmol) was placed in THF:water (4:1, 170 mL, 0.3 M) and cooled to 0°C. A 2N NaOH (78 mL, 157 mmol) aqueous solution was added, and the mixture was stirred for 10 minutes. Next, tert-butyl 2-bromoacetate 55 (7.2 mL, 49 mmol) was added dropwise at 0°C, and the mixture was stirred at 30°C for the next hour. The reaction mixture was then extracted with EA (150 mL x 2), and the combined organic layer was washed with saturated brine (approximately 50 mL). This was dried over anhydrous Na2SO4 and concentrated to obtain the crude product as a liquid. 2-(azetidine-1-yl) acetate hydrochloride (58):

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

[0214] tert-butyl(1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (3.36 g, 7.50 mmol), Pd(dppf)Cl2 (613 mg, 0.75 mmol), and K2CO3 (3.11 g, 22.5 mmol) were placed in a sealed tube and charged with toluene:water (5:1, 75 mL, 0.10 M) that had been pre-purged with nitrogen. The reaction mixture was purged again with N2 (10 mins), and then 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 54 (2.15 g, 11.3 mmol) was charged, and the mixture was maintained at 90°C for the next 3 hours. The reaction mixture was passed through a Celite bed and concentrated. This was then separated into 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) to obtain the pure product. tert-butyl((4bR,9bR)-1-amino-7-((S)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(60):

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

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

[0217] 2-(azetidine-1-yl)acetic acid hydrochloride 58 (1.02 g, 6.75 mmol) was charged in 45 mL of anhydrous DMF (0.1 M) with HATU (2.57 g, 6.75 mmol) and DIPEA (2.35 mL, 13.5 mmol) at 0°C. 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) and stirred at room temperature (20°C) for 15 hours. The reaction mixture was quenched with water (approx. 100 mL) and saturated NaHCO3 (approx. 100 mL). This was extracted with EA (100 mL x 3). The combined organic layers were washed with water (100 mL x 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) 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[MH] - LCMS:434.2[M+H] + .

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

[0219] This compound was prepared in the same manner as in Example 5 above. LCMS: 522.2[M+H] + . Example 7: N-(1-amino-4b-hydroxy-7-(2-methylcyclobutyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboc Samido. [ka]

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

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

[0222] To a solution of 3-hydroxybenzaldehyde (30 g, 0.25 mol) and imidazole (21.7 g, 0.32 mol) in dry dichloromethane (250 mL), tert-butylchlorodimethylsilane (44.4 g, 0.30 mol) was slowly added at 0°C. 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 by silica gel column chromatography and eluted with EA / hexane (0 / 100 → 1 / 10) to obtain the desired product. 1 H NMR(300MHz,CDCl3)δ 9.95(s,1H),7.40(tdd,J=21.4,12.8,9.5Hz,3H),7.11(ddd,J=7.9,2.5,1.2Hz,1H),1.00(s,9H),0.23(d,J=3.0Hz,6H). (E)-tert-butyldimethyl(3-(prop-1-en-1-yl)phenoxy)silane(66):

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

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

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

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

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

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

[0229] To a solution of methyl 3-methyl-1H-pyrrole-2-carboxylate 27 (3.5 g, 25.2 mmol) in dry DMF (63 mL), NaH (1.51 g, 37.8 mmol) was added at 0°C, 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 hours. The reaction mixture 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 resulting product was recrystallized using DCM and HX. 5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-sulfinic acid (74):

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

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

[0232] Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 75 (491.2 mg, 1.3 mmol) was dissolved in DCM (13 mL). To this, tert-butylpiperazine-1-carboxylate 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 hours. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL x 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 product. tert-butyl 4-((5-(methoxycarbonyl)-4-methyl-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate (78):

[0233] tert-butyl 4-((5-(methoxycarbonyl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate 77 (660 mg, 1.25 mmol) 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 hours. Methanol was evaporated, and the resulting residue was dissolved in water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were washed with water and 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. 5-((4-(tert-butoxycarbonyl)piperazine-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid (79):

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

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

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

[0237] A solution of racemic N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazine-1-ylsulfonyl)-1H-pyrrole-2-carboxamide 81 (100 mg, 0.16 mmol) was added to a 35% aqueous solution of formaldehyde (0.15 mL, 1.6 mmol), followed by NaBH3CN (36 mg, 0.6 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction product was quenched with water, 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 obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a solid product. N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide(83):

[0238] To a solution of racemic N-(4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide 82 (36 mg, 0.06 mmol) in EtOH:H2O (10:1) (6 mL), Fe powder (10 mg, 0.2 mmol) and concentrated HCl (1 drop) were added, and the reaction mixture was stirred at 90°C for 3 hours. The thermal reaction mixture was filtered through a Celite 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 brine. The organic layers were dried over Na2SO4, and the solvent was evaporated. 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),0.81-0.89(m,1H),0.98-1.02(m,1H),1.16(d,J=5.7H z,1H),1.53-1.59(m,1H),2.29(s,3H),2.30(s,3H),2.50-2.53(m,4H),2 .99-3.12(m,4H),6.48(s,1H),6.54(s,1H),6.69-6.78(m,2H),7.04(d,J =7.2Hz,1H),7.33(d,J=6.3Hz,1H),7.46-7.51(m,1H).LCMS:592.2(M+H] + . Example 10: (2S,3S)-N-(1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(dimethylamino)-3-hydroxybutanamide [ka]

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

[0240] Methyl 5-(chlorosulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 75 (985 mg, 2.6 mmol) was dissolved in DCM (26 mL). To this, tert-butyl(S)-pyrrolidine-3-ylcarbamate (583 mg, 3.1 mmol) was added, followed by DIPEA (0.7 mL, 3.9 mmol). ) was added. The reaction mixture was stirred at 30°C for 15 hours. The reaction mixture was diluted with DCM, 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. (S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid (85):

[0241] To a solution of methyl(S)-5-((3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)sulfonyl)-3-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 84 (1.10 g, 2.1 mmol) in MeOH:THF:H2O (1:1:10) (42 mL), LiOH.H2O (855 mg, 20.8 mmol) was added, and the reaction mixture was stirred at 80°C for 15 hours. 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 obtain the solid product. tert-butyl((3S)-1-((5-((4b-hydroxy-7-((trans)-2-methylcyclopropyl)-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrole-2-yl)sulfonyl)pyrroridine-3-yl)carbamate(86):

[0242] 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) at 0°C, EDCI (212 mg, 1.1 mmol), followed by HOBt (149 mg, 1.1 mmol), was added. The mixture was stirred for 30 minutes, 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), followed by DIPEA (0.4 mL, 2.2 mmol), was added. The reaction mixture was stirred at room temperature (30°C) for 20 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and the organic layer was dried over Na2SO4. The solvent was evaporated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product. 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):

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

[0244] A racemic mixture 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 (120 mg, 0.2 mmol) was stirred in 0°C ice AcOH:MeCN=1:1 (7 mL, 0.03 M). Formaldehyde (35% aqueous solution) (0.34 mL, 3.9 mmol), followed by NaBH3CN (62 mg, 1.0 mmol), was added. The reaction mixture was stirred at 0°C for 2 hours. The reaction product was quenched with water, the aqueous layer was extracted with ethyl acetate, and washed with water and brine. The organic layer was dried with 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 the final product. N-(1-amino-4b-hydroxy-7-((trans)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(((S)-3-(dimethylamino)pyrrolidin-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxamide(89):

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

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

[0247] 580 mg, 1.4 mmol of tert-butyl 4-((5-(ethoxycarbonyl)-3,4-dimethyl-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate was placed in THF:MeOH:H2O (1:1:10, 28.0 mL, 0.05 M), and 294 mg, 7.0 mmol of LiOH.H2O was added. The reaction mixture was refluxed at 80°C for 5 hours. The reaction mixture was concentrated to remove volatile substances. This was then acidified with 1N HCl (pH) (pH < 2-3). The precipitated solid was then filtered, washed with cold water, and dried to obtain the product. tert-butyl4-(5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran- 9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate(125):

[0248] 5-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3,4-dimethyl-1H-pyrrole-2-carboxylic acid (264 mg, 0.75 mmol) was placed 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 the addition of DIPEA (0.33 mL, 1.875 mmol), and the mixture was allowed to reach room temperature (35°C) on its own. This mixture was then stirred for the next 18 hours. Next, the reaction mixture was quenched with water (30 mL) and extracted with EA (50 mL x 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) to obtain an impure product, which was then purified again using a MeOH / DCM system to obtain a pure product. N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(piperazine-1-carbonyl)-1H-pyrrole-2-carboxamide(126):

[0249] 135 mg, 0.2 mmol of tert-butyl 4-(5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-3,4-dimethyl-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (135 mg, 0.2 mmol) was placed in DCM (2.0 mL, 0.1 M), and 4 M HCl in dioxane (0.50 mL, 2.0 mmol) was added. This mixture was stirred at room temperature (25°C) for 15 hours. The reaction mixture was concentrated, and the residue was placed in EA (20-30 mL) and stirred with saturated NaHCO3 (approximately 20 mL) for 5-10 minutes. This was extracted with EA (50 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL). This was dried over anhydrous sodium 2SO4 and concentrated to obtain the crude product. The crude product was used in the next step without further purification. N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide(127):

[0250] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(piperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (90 mg, 0.15 mmol) was placed 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 the addition of NaBH3CN (33 mg, 0.525 mmol). The mixture was stirred at 0°C for the next 2 hours. The reaction mixture was quenched with water (20 mL) and saturated NaHCO3 (20 mL), and extracted with EA (40 mL x 2). The combined organic layers were washed with water (30 mL) and brine (10 mL). This was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by thin-layer silica gel column chromatography (0 → 5% MeOH in DCM) to obtain the pure product. N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-di Methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide(128):

[0251] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,4-dimethyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide (60 mg, 0.1 mmol) was placed in EtOH:water (10:1, 5.0 mL, 0.02 M), to which Fe powder (17 mg, 0.3 mmol) was added, followed by 6.0 M One drop of HCl was added. This was refluxed at 90°C for the next 2.0 hours. The reaction mixture was filtered through Celite using EA (30 mL) under warm conditions. The filtrate was concentrated and placed in EA (100 mL), and washed with saturated NaHCO3 (20 mL x 2), water (20 mL x 2), and brine (20 mL). This was 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) to obtain the pure product. 1H NMR(500MHz,METHANOL-d4)δ:7.48(br s,2H),7.05(br s,1H),6.89(br s,1H),6.70(br s,2H),3.10(br s,4H),2.87(dt,J=13.4,6.6Hz,1H),2.51(br t,J=4.4Hz,4H),2.29(s,3H),2.22(s,3H),2.21(s,3H),1.21(d,J=6.9Hz,6H);LCMS:594.2(M+H] + Example 13: N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b])benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0252] The above compounds were prepared according to the following scheme. [ka] tert-butyl 4-((5-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate (122): 5-((4-(tert-butoxycarbonyl)piperazine-1-yl)sulfonyl)-3-methyl-1H-pyrrole-2-carboxylic acid 79 (384 mg, 1.0 mmol) was placed in DMF (10 mL, 0.1 M) and cooled to 0°C. EDCI (288 mg, 1.5 mmol) was then added, followed by HOBt (203 mg, 1.5 mmol). After 10 minutes, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 37 (340 mg, 1.0 mmol), followed by DIPEA (0.43 mL, 2.5 mmol), and the mixture was allowed to reach room temperature (35°C) over the next 12 hours. Next, the reaction mixture was quenched with water (30 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with water (30 mL) and brine (30 mL). This was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (25 → 30% EA in hexane) to obtain the product. N-(4-((11-azanail)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazine-1-ylsulfonyl)-1H-pyrrole-2-carboxamide(122-1)

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

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

[0255] Fe powder (14 mg, 0.25 mmol) was added to a stirred solution of N-(4-((1-azanail)peroxy)-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-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 hours. The thermal reaction mixture was filtered through a Celite 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 x 2) and brine solution. 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 desired product. 1H NMR(300MHz,MeOD)δ 7.42-7.33(m,1H),7.03(d,J=7.4Hz,1H),6.87(d,J=7.9Hz,1H),6.81-6.72(m,1H),6.69(s,1H),6.52(s,1 H),3.11-2.98(m,4H),2.89-2.80(m,1H),2.59-2.46(m,4H),2.28(s,3H),1.19(d,J=6.9Hz,6H).Mass:[M+H] + :580.1 Example 14: N-((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide [ka] [ka]

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

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

[0258] This compound was prepared in the same manner as in Example 12. LCMS: 508.3[M+H] + . Example 17: N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b)]benzofuran-9b-yl)-2-(azetidine-1-yl)acetamide(92) [ka] tert-butyl((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(90):

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

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

[0261] 2-(azetidine-1-yl)acetate hydrochloride 58 (34 mg, 0.23 mmol) was charged in 1.5 mL of anhydrous DMF (0.1 M) with HATU (87.5 mg, 0.23 mmol) and DIPEA (79 μL, 0.23 mmol) at 0°C. After 10 minutes, (4bR,9bR)-1,9b-diamino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 91 (51 mg, 0.15 mmol) and stirred at room temperature (20°C) for 15 hours. The reaction mixture was quenched with water (approx. 20 mL) and saturated NaHCO3 (approx. 30 mL). This was extracted with EA (50 mL x 3). The combined organic layers were washed with water (30 mL x 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) to obtain the solid product. 1 H-NMR (300 MHz, MeOD) δ 7.51-7.39(m,1H),7.28(d,J=7.9Hz,1H),6.99(d,J=7.0Hz,1H),6.85(dd,J=7.9 ,1.3Hz,1H),6.78-6.65(m,2H),3.38(t,J=7.2Hz,4H),3.19(s,2H),2.14-2.03( m,2H),1.91-1.84(m,1H),1.25(d,J=7.0Hz,3H),0.96-0.80(m,1H),0.54-0.49( m,1H),0.37-0.32(m,1H),0.23-0.12(m,1H),0.10-0.02(m,1H).LCMS:432.2[MH] - .LCMS:434.3[M+H] + .

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

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

[0264] 4-nitro-1H-indene-1,3(2H)-dione 4 (10.0 g, 52.3 mmol) was placed in AcOH:dioxane (1:10, 105 mL, 0.5 M). SeO2 (12.77 g, 115.1 mmol) was added to this mixture, and the mixture was incubated at 105-110°C for 5 hours. The reaction mixture was then passed through a Celite filter under thermal conditions. The volatile substances were then concentrated and removed 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 3-isopropoxyphenol 93 (8.1 g, 53 mmol) 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 Celite bed and washed with ethyl acetate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain the solid product. 9b-Chloro-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(95):

[0265] 4b,9b-dihydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one 94 (5.4 g, 15 mmol) was dissolved in DCM (75 mL). Oxalyl 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 hours. The reaction mixture was diluted with DCM (300 mL), the organic layer was washed with water (200 mL x 2) and brine solution, and then dried over Na2SO4. 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 solid product. 9b-amino-4b-hydroxy-7-isopropoxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one(96):

[0266] This compound was prepared in the same manner as compound 37 described above. tert-butyl 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate (97):

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

[0268] tert-butyl 4-((5-((4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamoyl)-4-methyl-1H-pyrrole-2-yl)sulfonyl)piperazine-1-carboxylate 97 (145 mg, 0.2 mmol) was dissolved in DCM (4 mL). 4M HCl (0.5 mL) in dioxane was added to this solution. The clear solution was stirred at room temperature for 15 hours. The DCM was evaporated under vacuum. The residue was rinsed with water (1 The solution was dissolved in 00 mL of water, and the aqueous solution was neutralized with a saturated solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (100 mL x 2), and the combined organic layers were washed with water and brine. The organic layers were dried over Na2SO4, and the solvent was evaporated to obtain the crude solid product. The crude product was used directly in the next step without purification. N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide(99):

[0269] N-(4b-hydroxy-7-isopropoxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(piperazine-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 hours. Acetonitrile was evaporated, the residue was quenched with water, and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water, and then with brine. 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 (methanol: DCM) to obtain the solid product. N-(1-amino-4b-hydroxy-7-isopropoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-((4-methylpiperazine-1-yl)sulfonyl)-1H-pyrrole-2-carboxamide(100):

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

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

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

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

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

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

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

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

[0278] To a solution of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,5-dimethyl-4-sulfamoyl-1H-pyrrole-2-carboxamide 110 (110 mg, 0.2 mmol) in an EtOH-water mixture (1:1, 7 mL), Fe powder (33.5 mg, 0.6 mmol) and concentrated HCl (1 drop) were added. The resulting solution was refluxed at 90°C for 3 hours. The reaction mass was filtered through a Celite pad and washed with ethyl acetate. The organic layer was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL x 2), and then with brine solution. The combined organic layers were 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 (methanol: DCM) to obtain the product. (300MHz, CD30D)δ1.2(dd,J=6.2Hz,J=0.9Hz,6H),2.44(s,3H),2.49(s,3H),2.84-2.87(m,1H),6.70(m,2H), 6.89(m 1H),7.04(m 1H),7.48(m,2H).LCMS:510.78[M+1] + .LCMS:511.5[M+H] + . Example 26: N-(1-amino-4b-hydroxy7-((1R,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

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

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

[0281] (tert-butoxycarbonyl)-L-phenylalanine 112 (4.80 g, 16.4 mmol) was placed 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 the next 20 minutes, followed by the addition of 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), and then DIPEA (8.6 mL, 49.3 mmol). The mixture was stirred at 30°C for the next 24 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the product along with other isomers. (S)-2-amino-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenylpropanamide(114):

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

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

[0284] (S)-N-((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-phenyl-2-(3-phenylthioureido)propanamide 116 (1.70 g, 2.58 mmol) was dissolved in DCM (260 mL). To this solution, TFA (8.8 mL, 77.4 mmol) was added at room temperature. The reaction mixture was then heated to 50°C over 12 hours. The DCM was evaporated, and the resulting residue was dissolved in water. The aqueous layer was basicized with a saturated solution of NaHCO3, and then extracted with ethyl acetate. The combined 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 product. tert-butyl((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate (118):

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

[0286] tert-butyl((4bS,9bS)-7-bromo-4b-hydroxy-4-nitro -10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 118 (460 mg, 0.96 mmol) was dissolved in 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 hours. The reaction mass was filtered through a Celite pad and washed with ethyl acetate. The organic layer was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (250 mL) and washed with water (100 mL x 2), and then with brine solution. The combined organic layers were 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 (ethyl acetate:hexane) to obtain the product. tert-butyl((4bR,9bR)-1-amino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate(119):

[0287] To a degassed solution of tert-butyl((4bR,9bR)-1-amino-7-bromo-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)carbamate 12 (326 mg, 0.73 mmol) in toluene (12.5 mL), 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-dioxazabolocan-4,8-dione 17 (231 mg, 1.095 mmol) was added. The reaction mixture was purged with N2 for 10 minutes, and then stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL x 2), dried over 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 product. (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-onhydrochloride(120):

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

[0289] 3-Methyl-4-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid 30 (97.6 mg, 0.48 mmol) was dissolved in DMF (8 mL). The resulting solution was cooled to 0°C. HATU (28.2 mg, 0.60 mmol) and DIPEA (0.210 mL, 1.2 mmol) were added at 0°C, and the reaction mixture was stirred for 30 minutes. Then, (4bR,9bR)-1,9b-diamino-4b-hydroxy-7-((1S,2S)-2-methylcyclopropyl)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-onehydrochloride 120 (144 mg, 0.4 mmol) was added, and the reaction mixture was stirred at 30°C for 15 hours. 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 brine solution, and Na The product was dried with 2SO4 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] + . The biological activity of the compounds of the present invention was determined using the following method: Determination of drug efficacy against picornavirus using a cytopathic effect (CPE) inhibition assay.

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

[0291] The pharmacokinetic efficacy was determined using a virus-induced cytopathic effect (CPE) inhibition assay. For this assay, virus-compatible cells were grown in a 96-well plate. A dilution of the virus in DME (DME / 2%FBS) or MEM (MEM / 2%FBS) supplemented with 2%FBS was inoculated into each well of the plate at a concentration corresponding to 100 CCID50 (50% cell culture infectious dose) at 100 L. The cells were incubated at 33°C or 37°C for 30 minutes to 1 hour to allow the virus to adsorb onto the cells. After removing the culture medium, aliquots of various drug dilutions were added to each well at 100 μL. Human rhinovirus (HRV) was grown at 33°C, while other viruses were incubated in a CO2 incubator at 37°C for 2-3 days. Alternatively, 50 μL of each drug dilution at twice the concentration was added, followed by 50 μL of the virus dilution, after which the cells were cultured for 2-3 days without removing the medium. The virus was incubated in host HeLa cells at 37°C for 2-3 days in DME / 2% or MEM / 2% FBS.

[0292] In HeLa cells, the MTT assay is used to determine the drug concentration that induces an intermediate response between baseline and maximum, which is called the EC (Energy Control). 50 The drug was measured at the 50% maximum effective concentration. In RD and MRC-5 cells, CPE was determined using FDA (fluorescein diacetate) or MTT. To determine the effect of drug toxicity on efficacy results, simulated infection was included at the time of viral inoculation. Virus-free medium was added to the cell culture and then subjected to the same treatment as the virus-inoculated simulated infected cells. That is, after 1 hour of incubation, the medium was removed and a diluted drug solution in the medium was added again. After incubation for 2-3 days, cells were observed under a microscope, and the number of surviving cells in the drug-containing simulated infected wells was compared to the number of surviving cells in the drug-free control wells using the MTT assay to kill 50% of the cells. 50Cells were measured at a 50% cytotoxic concentration. In the FDA hydrolysis assay, after removing the culture medium, FDA was added to each well and incubated for 20-30 minutes. The fluorescence intensity was then measured using a spectrofluorometer to determine CPE, similar to the MTT assay.

[0293] Specifically, the survival rate (% survival rate) of simulated infected cells for cytotoxicity measurement was calculated using the following formula 1:

[0294] Cellular drug = Survival × [A (drug) - A (background solution) / A (cell control) - (background × 100% solution)]

[0295] 100% cell viability means that the drug has no cytotoxicity, while the highest level of cytotoxicity is reflected by 0% cell viability. The 50% cytotoxic concentration is defined as the concentration required to reduce cell numbers by 50%. This drug concentration is expressed as CC50. A higher value indicates lower cytotoxicity.

[0296] Furthermore, the antiviral effect can be calculated using the following formula 2: Antiviral effect = [A(drug / virus) - A(virus control) / A(cell control) - A(virus control)]

[0297] If the survival rate is 100%, the antiviral effect is 100%, but if the survival rate is 0%, there is no antiviral effect. The concentration of the drug that allows cells in a virus-infected well to show a 50% survival rate is EC. 50 It is calculated as follows, and the lower this value, the better the antiviral effect.

[0298] Table 1 below shows LCs that exhibit cytotoxicity to compounds in several examples. 50 The concentration of EC, and the activity against numerous rhinoviruses belonging to the Picornavirus family. 50 List the concentrations. Determination of drug efficacy against picornaviruses using a multicycle cytopathic effect (CPE) reduction assay.

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

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

[0301] The %CPE value, used to evaluate antiviral activity, was calculated using the following formula 3: %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(VC)]

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

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

[0304] In equations 3 and 4 above, OD(CC) represents the OD of background cell cultures that are neither induced by virus nor treated with chemicals, and OD(VC) represents the OD of control cell cultures that are induced by virus but not treated with chemicals. The OD (Oxygen Demand) values ​​represent the OD of the nutrient. OD(Virus + Compound) represents the OD of virus-infected cell cultures treated with concentrated compounds, OD(Compound) represents the OD of cell cultures treated with concentrated compounds only, and OD(Blank) represents the OD of wells to which only cell cultures were added.

[0305] Effective concentration (EC 50 ) represents the concentration of a drug at which 50% of cells can survive due to CPE of the induced virus, and the cytotoxic concentration (CC) 50 The values ​​represent the concentration of the drug that killed 50% of the cells, and these were calculated using logarithmic interpolation.

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

[0307] As shown in Table 1 above, most of the compounds according to the present invention have high CC 50 The concentration indicates low cytotoxicity. Furthermore, it was found that the compounds according to the present invention have high antiviral activity against a large number of rhinoviruses (HRV) in most cases.

[0308] Therefore, the compounds in the examples of the present invention exhibit low cytotoxicity and high antiviral activity against various rhinoviruses, thus providing a pharmacological composition for preventing or treating diseases caused by picomaviruses, to which rhinoviruses belong. It can be used to make a useful contribution to things.

[0309] Therefore, the compounds in the examples of the present invention have low cytotoxicity and exhibit antiviral activity against picomaviruses, including coxsackievirus, poliovirus, and rhinovirus, thus providing protection against diseases caused by such viruses, such as polio and rhinovirus. It can be effectively used to prevent or treat respiratory, cardiovascular, and nervous system diseases, including hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, bullous diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media.

[0310] The compounds represented by the formula according to the present invention, which are in equilibrium with each other, not only have low cytotoxicity but also possess high antiviral activity against picornaviruses, including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus. Therefore, they can be effectively used as pharmaceutical compositions for preventing or treating viral diseases such as polio, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. In one embodiment, for example, the following items are provided. (Item 1) Compounds of formula (I) or pharmaceutically acceptable salts thereof: [ka] (In the formula, G 1 The C1-C4 alkyl, C3-C4 cycloalkyl, or C1-C4 alkoxy groups are selected from linear or branched C1-C4 alkyl groups, C3-C4 cycloalkyl groups, and C1-C4 alkoxy groups; the C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy groups may be substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl groups; L is a bond or CH2; E is a)-CH(CHOHCH3)(NMe2); or b) A monocyclic 4-6 membered heterocycline containing one or two nitrogen atoms or a 5-6 membered heteroaryl containing one nitrogen atom, wherein the 4-6 membered heterocycline and the 5-6 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, =O, and -SO2R; each R is independently a linear or branched C1-C3 alkyl, a monocyclic 5-6 membered heterocycline containing one or two nitrogen atoms, and NR 1 R 2 Selected from; the monocyclic 5-6 membered heterocycline is optionally C1-C3 alkyl or NR 3 R 4 Replaced by; Each R 1 and R 2 The C1-C3 alkyl group is independently selected from H and C1-C3 alkyl groups, and the C1-C3 alkyl group is optionally selected from NR 3 R 4 Replaced by; Each R 3 and R 4 (The element is independently selected from H or methyl). (Item 2) Compounds having formula (II) as described in item 1, or pharmaceutically acceptable salts thereof: [ka] (Item 3) Compounds having formula (III) as described in item 1, or pharmaceutically acceptable salts thereof: [ka] (Item 4) A compound listed in any one of items 1-3, or a pharmaceutically acceptable salt thereof, wherein L is a bond. (Item 5) A compound listed in any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein E is -CH(CHOHCH3)(NMe2). (Item 6) A compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein E is a monocyclic 5-6 member heteroaryl containing one nitrogen atom, and the 5-6 member heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of linear or branched C1-C3 alkyl, -OH, and -SO2R. (Item 7) G 1 The compounds described in any one of items 1 to 6, or pharmaceutically acceptable salts thereof, are linear or branched C1-C4 alkyl groups that are optionally substituted with cyclopropyl and one, two, or three substituents independently selected from linear or branched C1-C3 alkyl groups. (Item 8) G 1 The compounds described in any one of items 1 to 6, or pharmaceutically acceptable salts thereof, are C3-C4 cycloalkyls that are optionally substituted with one, two, or three substituents independently selected from linear or branched C1-C3 alkyl groups. (Item 9) G 1 The compounds described in any one of items 1 to 6, or pharmaceutically acceptable salts thereof, are linear or branched C1-C4 alkoxy compounds that are optionally substituted with one, two, or three substituents independently selected from cyclopropyl and linear or branched C1-C3 alkyl groups. (Item 10) A compound having formula (Ia) as described in any one of items 1 and 7-9, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, A 1 It is selected from the group consisting of H, a linear or branched C1-C3 alkyl group, and SO2R. A 2 (This is selected from the group consisting of H and SO2R). (Item 11) A 1 The compounds listed in item 10, which are methyl or SO2CH3. (Item 12) A 2However, SO2R is SO2R, where R is a monocyclic 5-6 membered heterocycline containing one or two nitrogen atoms, substituted with CH3 or N(CH3)2; and NR 1 R 2 A compound selected from the group consisting of items 10 or 11. (Item 13) A compound having formula (Ib), as described in any one of items 1, 4-6, and 10-12, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, Y is either H or CH3). (Item 14) A compound having formula (Ic) as described in any one of items 1, 4-6, and 10-12, or a pharmaceutically acceptable salt thereof: [ka] (wherein X is selected from the group consisting of methyl, ethyl, and cyclopropyl). (Item 15) Select from the following, the compound listed in item 1 or a pharmaceutically acceptable salt thereof: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] . (Item 16) A compound listed in item 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: [Table 4] . (Item 17) A compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, as described in any one of items 1 to 15, for the prevention or treatment of a viral disease. (Item 18) A pharmaceutical composition for the prevention or treatment of a viral disease comprising a compound described in any one of items 1 to 15, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient. (Item 19) A combination comprising a compound described in any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 9, and one or more therapeutic agents. (Item 20) A method for treating a viral disease, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 1 to 15, or a pharmaceutical composition described in item 18, or a combination described in item 19, to the target. (Item 21) Use of the compounds described in item 15, or pharmaceutically acceptable salts thereof, or optical isomers thereof, or the pharmaceutical compositions described in item 18, or the combinations described in item 19, for the prevention or treatment of viral diseases. (Item 22) The aforementioned viral disease is caused by a coxsackievirus, and the compound described in item 15, or the pharmaceutical composition described in item 18, or the method described in item 20, or the use described in item 21. (Item 23) The aforementioned viral disease is caused by the poliovirus, and the compounds described in item 15, or the pharmaceutical compositions described in item 18, or the methods described in item 20, or the uses described in item 21. (Item 24) The aforementioned viral disease is caused by an echovirus, and the compound described in item 15, or the pharmaceutical composition described in item 18, or the method described in item 20, or the use described in item 21. (Item 25) The aforementioned viral disease is caused by an enterovirus, as described in item 15. Compounds, or pharmaceutical compositions as described in item 18, or the methods described in item 20, or the uses as described in item 21. (Item 26) The aforementioned viral disease is caused by a rhinovirus, and the compound described in item 15, or the pharmaceutical composition described in item 18, or the method described in item 20, or the use described in item 21. (Item 27) The aforementioned viral disease is caused by a picornavirus, and the compound described in item 15, or the pharmaceutical composition described in item 18, or the method described in item 20, or the use described in item 21. (Item 28) The compound described in item 15, or the pharmaceutical composition described in item 18, or the method described in item 20, or the use described in item 21, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media. (Item 29) Compounds described in item 16, pharmaceutically acceptable salts thereof, or optical isomers thereof, for the prevention or treatment of viral diseases. (Item 30) A pharmaceutical composition for the prevention or treatment of a viral disease, comprising a compound described in item 16, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and a pharmaceutically acceptable diluent or excipient. (Item 31) A combination comprising a compound listed in item 16 or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents. (Item 32) A method for treating a viral disease, comprising administering a therapeutically effective dose of a compound or a pharmaceutically acceptable salt thereof as described in item 16 to the target. (Item 33) Use of the compounds described in item 16, or pharmaceutically acceptable salts thereof, or optical isomers thereof, for the prevention or treatment of viral diseases. (Item 34) The aforementioned viral disease is caused by a coxsackievirus, and the compound described in item 16, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33. (Item 35) The aforementioned viral disease is caused by the poliovirus, and the compounds described in item 16, or the pharmaceutical compositions described in item 30, or the methods described in item 32, or the uses described in item 33. (Item 36) The aforementioned viral disease is caused by an echovirus, and the compound described in item 16, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33. (Item 37) The aforementioned viral disease is caused by an enterovirus, and the compound described in item 16, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33. (Item 38) The aforementioned viral disease is caused by a rhinovirus, the compound described in item 16 The substance, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33. (Item 39) The aforementioned viral disease is caused by a picornavirus, and the compound described in item 16, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33. (Item 40) The compound described in item 16, or the pharmaceutical composition described in item 30, or the method described in item 32, or the use described in item 33, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

Claims

【Request Item 1】 Respirator-related illness.

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