Oxalamide-substituted tricyclic inhibitors of hepatitis B virus

Abstract

The present invention relates to compounds that are inhibitors of hepatitis B virus (HBV). The compounds of the present invention are useful alone or in combination with other agents for treating, ameliorating, preventing, or curing HBV infection and related conditions. The present invention also relates to pharmaceutical compositions containing said compounds.

Description

Technical Field

[0001] The present invention relates to compounds that are inhibitors of hepatitis B virus (HBV). The compounds of the present invention are useful alone or in combination with other agents for treating, alleviating, preventing or curing HBV infection and related conditions. The present invention also relates to pharmaceutical compositions containing said compounds.

Background Art

[0002] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnaviridae family that spreads by contact with infected blood and body fluids and causes acute and chronic necroinflammatory liver diseases of variable severity (Guidotti LG, Chisari FV. Annu Rev Pathol. 2006; 1:23-61). The HBV lipid envelope contains three in-frame viral envelope proteins (large, middle, and small), each of which has hepatitis B virus surface antigen (HBsAg) determinants (Seeger C, Mason WS. Virology. May 2015; 479-480:672-86). This envelope encloses a protein shell or capsid composed of 240 monomers of the core protein, each monomer having a hepatitis B virus core antigen (HBcAg or Cp) determinant. The capsid, in turn, encloses the partially double-stranded, relaxed circular DNA (rcDNA) form of the viral genome as well as molecules of the viral polymerase. Upon entry into susceptible cells (i.e., hepatocytes) by interaction of the large envelope protein with specific receptors on the hepatocyte membrane, the capsid is released into the cytoplasm and transported across the nuclear membrane. The rcDNA is then released into the nucleus and repaired by cellular polymerases into an episomal "minichromosome" called covalently closed circular DNA (cccDNA) that represents the viral transcription template. The minus strand of the viral DNA encodes mRNA species of 3.5, 2.4, 2.1, and 0.7 kb that are translated into the viral structural (envelope and core) and nonstructural (polymerase, precore, and X) proteins. After transport to the cytoplasm, one of the 3.5 kb RNAs (called pregenomic RNA) is selectively packaged into nascent capsids by interacting with the core and polymerase proteins being translated from its corresponding mRNA. Within these capsids, the viral polymerase reverse transcribes the pregenomic RNA into a single minus (-) strand DNA molecule, which serves as a template for viral polymerase-mediated DNA plus (+) strand synthesis, and by attachment structures in the linear DNA intermediate, they are converted into relaxed circular double-stranded molecules.The fraction of these "mature" capsids containing HBV DNA is transported to and returned from the nucleus, where second-strand synthesis is completed, the ends of both strands are ligated, leading to the amplification of the cccDNA pool. Another fraction of capsids binds to viral envelope proteins that are independently translated and translocated to the membrane of the endoplasmic reticulum (ER)-like structure. After binding, the envelope-type capsids bud into the lumen of the ER, exit the cell as infectious virions, and initiate a new cycle of infection.

[0003] Therefore, HBV core protein and related capsids are essential components and regulators of the HBV life cycle. The full-length core protein Cp183 or its N-terminal domain Cp149 assemble mainly into T = 4 icosahedral capsids. It is not surprising that HBV core protein and related capsids are widely recognized as antiviral targets of high interest because of their crucial roles in capsid assembly, pregenomic RNA packaging, and cccDNA maintenance (Durantel D, Zoulim F; J Hepatol. April 2016;64(Suppl 1):S117 - S131).

[0004] According to World Health Organization (WHO) statistics, HBV infection is one of the major medical disasters of our time. As an infectious disease transmitted through intravenous drug use, sexual contact, and from mother to infant at birth, one-third of the world's population is infected with HBV at some point in their lives (Burns GS, Thompson AJ; Cold Spring Harb Perspect Med. October 30, 2014;4(12)). Most of these people have successfully cleared the virus, but more than 250 million people remain persistently infected, and approximately 900,000 of these individuals die each year due to complications of chronic infection (i.e., cirrhosis and / or hepatocellular carcinoma). HBV infection is highly endemic in sub-Saharan Africa, the Pacific, and particularly Asia. Regions with high chronic HBV infection rates also include the Middle East, the Indian subcontinent, Central and South America, and the southern and central regions of Eastern Europe. In recent years, mainly due to the influx of immigrants from endemic areas, the number of chronic carriers has been steadily increasing in Western European countries. Furthermore, HBV acts as a helper virus for hepatitis delta virus (HDV), and it should be noted that more than 15 million people co-infected with HBV and HDV are at an increased risk of rapid progression to cirrhosis and hepatic decompensation (Hughes, S.A. et al. Lancet 2011, 378, 73 - 85).

[0005] Vaccines that induce neutralizing antibodies against HBsAg and exhibit good tolerability can efficiently prevent new HBV infections, but are not therapeutically viable for the millions of individuals who are already persistently infected (Zoulim, Durantel D; Cold Spring Harb Perspect Med. April 1, 2015;5(4)). Treatment of these individuals relies primarily on direct-acting antiviral (DAA) drugs (e.g., tenofovir, lamivudine, adefovir, entecavir, or telbivudine) that suppress viral production but do not eradicate HBV from the liver and require lifelong treatment. Patient cohorts still receive treatment based on pegylated interferon-α (PEG-IFN-α), which has the advantages of a limited treatment period and a higher HBsAg seroconversion rate but has the significant drawback of greater side effects. As a result, the number of patients receiving PEG-IFN-α is gradually decreasing.

[0006] Inhibitors of various chemical classes (also called capsid assembly modulators or CAMs) that target the HBV capsid formation process are under development and include heteroaryldihydropyrimidines (HAP) and sulfamoylbenzamides (SBA). For example, Novira Therapeutics recently showed, using a humanized mouse model of HBV infection, that a combination of CAM and PEG-IFN-α has higher antiviral activity than has been observed previously using DAAs. NVR3-778, the first member of this class of CAMs, showed a significant reduction in both HBV DNA and serum HBV RNA in a Phase 1b proof-of-concept clinical study. This compound was recently discontinued. The compound JNJ-56136,379 (or JNJ-6379) developed by Janssen has recently demonstrated potent antiviral activity and is currently in Phase 2 clinical trials.

[0007] WO2013 / 006394, published on January 10, 2013, relates to general formula A useful for the treatment of hepatitis B virus (HBV) infection:

[0008] [Chemical formula]

[0009] relates to a subclass of sulfamoyl-aryl amides having

[0010] WO2013 / 096744, published on June 26, 2013, relates to formula B which is active against HBV:

[0011] [Chemical formula]

[0012] relates to a sulfamoyl-aryl amide of

[0013] WO2014 / 106019, published on July 3, 2014, relates to compounds of formula C which include, but are not limited to, HBV pregenomic RNA capsid formation inhibitors for the treatment of hepatitis B virus (HBV) infection and related conditions, and are particularly useful as nucleocapsid assembly inhibitors for the treatment of the virus:

[0014] [Chemical formula]

[0015] relates to

[0016] WO2014 / 165128, published on October 9, 2014, WO2015 / 109130, published on July 23, 2015, and US2015274652, published on October 1, 2015, all relate to sulfamoyl-aryl amide compounds that are active against HBV.

[0017] WO2015 / 120178, published on August 13, 2015, relates to sulfamoyl-aryl amide compounds used in combination therapies using peginterferon alpha-2a or another interferon analog for the treatment of HBV infection.

[0018] WO2016 / 089990, published on June 9, 2016, relates to sulfidoalkyl and pyridyl reverse sulfonamide compounds for the treatment of HBV.

[0019] US2016185748, published on June 30, 2016, relates to pyridyl reverse sulfonamides for the treatment of HBV.

[0020] US2016151375, published on June 2, 2016, relates to sulfidoalkyl compounds for the treatment of HBV.

[0021] WO2017 / 001655A1, published on January 5, 2017, relates to cyclic sulfamoyl arylamide derivatives having the structure:

[0022]

Chemical formula

[0023] and relates to cyclic sulfamoyl arylamide derivatives having the structure:

[0024] Among the problems that HBV direct-acting antiviral agents may encounter are toxicity, mutagenicity, lack of selectivity, insufficient efficacy, insufficient bioavailability, low solubility and / or off-target activity, and to date, no compound in any of the structural classes identified above has been approved as a drug for the treatment of HBV patients.

Prior art documents

Patent documents

[0025]

Patent document 1

Patent document 2

Patent document 3

Patent document 4

[0026] [Non-Patent Document 1] Guidotti LG, Chisari FV. Annu Rev Pathol. 2006; 1:23 - 61 pages [Non-Patent Document 2] Seeger C, Mason WS. Virology. May 2015; 479 - 480:672 - 86 pages [Non-Patent Document 3] Durantel D, Zoulim F; J Hepatol. April 2016;64(Supplement 1):S117 - S131 [Non-Patent Document 4] Burns GS, Thompson AJ; Cold Spring Harb Perspect Med. October 30, 2014;4(12) [Non-Patent Document 5] Hughes, S.A. et al. Lancet 2011, 378, 73 - 85 pages [Non-Patent Document 6] Zoulim, Durantel D; Cold Spring Harb Perspect Med. April 1, 2015; 5(4)

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

[0027] There is a need for further HBV inhibitors that can overcome at least one of these drawbacks or have additional advantages such as increased efficacy, increased bioavailability, or increased safety window. MEANS FOR SOLVING THE PROBLEMS

[0028] The present invention provides small molecule drugs obtained by chemical modification of known sulfamoylaryl amide derivatives. In particular, the compounds of the present invention contain a pyrrole ring and are characterized by a fused tricyclic core structure having an oxalamide substituent at a specific position of the fused tricyclic core. The chemical species discovered in the present invention result in extremely potent HBV inhibitors with improved pharmacokinetic properties, good kinetic solubility, stability in mouse and human hepatocytes, low in vivo clearance, and positive liver-to-plasma concentrations. Considering the important role of the liver in metabolic regulation and the fact that it is the major tissue affected by hepatitis B disease, designing HBV inhibitors with a liver-selective distribution profile is an important strategy in the development of safe drug candidates (Tu M. et al., Current Topics in Medicinal Chemistry, 2013, 13, pages 857 - 866). The compounds of the present invention are further provided with pan-genotypic activity and thus show minimal variation in anti-HBV activity across genotypes A - E and are active against wild-type HBV and several variants that may be resistant to other CAMs. MODE FOR CARRYING OUT THE INVENTION

[0029] The compounds of the present invention are inhibitors of hepatitis B virus (HBV). Therefore, the object of the present invention is to provide a compound of general formula (I):

[0030] [ka]

[0031] [In the formula, Cy is aryl or heteroaryl; A is C-R3 or N; X is O, S, NH, SO, SO2 or a single bond; Y, Y', Y'' and Y''' are each independently optionally substituted with one or more R4; C 1~6 Alkanediyl or C 2~7 alkenediyl, or a single bond; R1 is H or C 1~6 is alkyl, R2 is H, OH, halogen and C 1~6 alkyl, R3 is H, C 1~6 Alkyl, C 3~8 Cycloalkyl, HaloC 1~6 selected from alkyl and halogen; R4 is H, OH, C 1~6 Alkyl, C 3~8 cycloalkyl and halogen, or two geminal R4 together with the atoms to which they are attached form a spiro-C 3~8 Cycloalkyl or spiro-C 3~8 forming a heterocycloalkyl, R5 is H or C 1~6 is alkyl, or R2 and R5 together form C 1~6 Forms an alkanediyl bridge, R6 is H, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, C 1~6 Alkylaryl, C 1~6 Alkylheteroaryl and C 1~6 Alkyl-C 3~8Selected from cycloalkyl, said C 1~6 alkyl, C 3~8 cycloalkyl, C 3~8 heterocycloalkyl, C 1~6 alkylaryl, C 1~6 alkylheteroaryl or C 1~6 alkyl-C 3~8 Each of the cycloalkyls may be substituted with one or more substituents independently selected from OH, halogen, haloC 1~6 alkyl, cyano and NH2, Each of R7 and R8 is, - hydrogen, - OH, halogen, CN, NH2, NH(R9), N(R9)2, haloC 1~6 alkyl, aryl, heteroaryl, a 3- to 7-membered saturated ring and a 5- to 7-membered partially saturated ring, each of which may be substituted with one or more substituents independently selected from the group consisting of C 1~12 alkyl, wherein each of said saturated or partially saturated rings may contain one or more heteroatoms selected from the group consisting of O, N and S, and each of said aryl, heteroaryl, 3- to 7-membered saturated ring or 5- to 7-membered partially saturated ring is OH, halogen, C 1~6 alkyl, haloC 1~6 alkyl, CN, haloC 1~6 alkoxy and C 1~6 alkoxy, each of which may be substituted with one or more substituents independently selected from the group consisting of C 1~12 alkyl, - aryl or heteroaryl, wherein each of said aryl or heteroaryl is OH, halogen, haloC 1~6 alkyl, CN, haloC 1~6 alkoxy and C 1~6 alkoxy, each of which may be substituted with one or more substituents independently selected from the group consisting of aryl or heteroaryl, and - a 3- to 8-membered saturated or partially saturated cyclic or bicyclic ring which may contain one or more heteroatoms independently selected from the group consisting of O, S and N, and is OH, halogen, CN, C 1~6Alkyl, hydroxy C 1~6 Alkyl, C(O)OR9, C(O)R9, halo C 1~6 Alkyl, halo C 1~6 Alkoxy and C 1~6 A 3- to 8-membered saturated or partially saturated cyclic or bicyclic ring which may be substituted with one, two or more substituents each independently selected from the group consisting of alkoxy and C Independently selected from Or R7 and R8, together with the nitrogen atom to which they are attached, form a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine and piperazine, each of said cyclic amines being OH, halogen, CN, C 1~6 Alkyl, hydroxy C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy and C 1~6 May be substituted with one or more substituents each independently selected from the group consisting of alkoxy and C Ra, Rb, Rc and Rd are hydrogen, halogen, CN, C 1~6 Alkyl, C 1~6 Alkoxy, halo C 1~6 Alkyl, halo C 1~6 Independently selected from the group consisting of alkoxy, C(O)OR9, C(O)R9, NH2, NH(R9), N(R9)2, C(O)N(R9)2, SO2N(R9)2, NHCON(R9)2 Each R9 is H, C 1~6 Alkyl, halo C 1~6 Alkyl, C 1~6 Alkylaryl, C 1~6 Alkylheteroaryl and C 1~6 Alkyl-C 3~8 Independently selected from cycloalkyl] A compound represented by or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0032] In certain embodiments, R2 is H, OH and C 1~6Selected from alkyl, Ra, Rb, Rc and Rd are each independently hydrogen, halogen, CN, C 1~6 alkyl, C 1~6 alkoxy, haloC 1~6 alkyl, haloC 1~6 alkoxy, C(O)OR9, C(O)R9, NH2, NH(R9) and N(R9)2, each R9 being C 1~6 alkyl, haloC 1~6 alkyl, C 1~6 alkylaryl, C 1~6 alkylheteroaryl and C 1~6 alkyl-C 3~8 independently selected from cycloalkyl.

[0033] Preferably, Cy is aryl. Preferably, X is O or S. Preferably, Y is methanediyl, Y' and Y'' are methanediyl or ethanediyl, and Y''' is a single bond.

[0034] Preferably, R2 is H, C 1~6 alkyl or OH, and R3 is H or C 1~6 alkyl or halogen.

[0035] In one embodiment, the present invention relates to a compound of formula (I-A):

[0036]

Chemical formula

[0037] or formula (I-B):

[0038]

Chemical formula

[0039] and pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof. In particular, in formula I-A, R2 is H or C 1~6 alkyl, and R3 is H, C 1~6is alkyl or halogen, and the remaining substituents are as defined above.

[0040] In a preferred embodiment, the compound of the present invention has the formula (II-A), (III-A) or (III-B):

[0041] [Chemical formula]

[0042] [wherein, X is O, S, NH, SO, SO2, R2 is H, C 1~6 alkyl or OH, R3 is H, C 1~6 alkyl or halogen, each R4 is independently selected from H, OH, C 1~6 alkyl, C 3~8 cycloalkyl and halogen, or two R4s together with the atom to which they are attached form spiro-C 3~8 cycloalkyl or spiro-C 3~8 heterocycloalkyl, [and the remaining substituents are as defined above] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0043] A further embodiment of the present invention is the formula (II-B):

[0044] [Chemical formula]

[0045] [wherein,

[0046] [Chemical formula]

[0047] represents a single bond or a double bond, R2 is H or C 1~6 is alkyl, R3 is H, C 1~6 alkyl or halogen] relates to a compound represented by or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0048] In a more preferred embodiment of the compound of formula (I), formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III-A), formula (III-B), or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, Cy is phenyl, R1 is CH3, R3 is H, methyl, chlorine or bromine, R5 is hydrogen or methyl, and R6 is hydrogen.

[0049] Another embodiment of the present invention is that R7 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl,

[0050]

Chemical formula

[0051] selected from the group consisting of, and / or R8 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl,

[0052]

Chemical formula

[0053] selected from the group consisting of, relates to the compound of formula (I), formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III-A), formula (III-B), or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0054] Preferably, in any of the compounds of formula (I), (I-A), (I-B), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Cy is aryl (in particular, phenyl).

[0055] Preferably, in any of the compounds of formula (I) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, A is C-R3.

[0056] Preferably, in any of the compounds of formula (I), (I-A), (I-B), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, X is O or S.

[0057] Preferably, in any of the compounds of formula (I), (I-A) or (I-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Y is C 1~6 alkanediyl (in particular, methanediyl).

[0058] Preferably, in any of the compounds of formula (I) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Y' and / or Y'' are C 1~6 alkanediyl (in particular, methanediyl).

[0059] Preferably, in any of the compounds of formula (I) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Y''' is a single bond.

[0060] Preferably, in any of the compounds of formula (I) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Y, Y', Y'' are C 1~6It is alkanediyl (especially, methanediyl), and Y''' is a single bond.

[0061] Preferably, in any of the compounds of formula (I), (I-A), (I-B), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R1 is C 1~6 alkyl (especially, methyl).

[0062] Preferably, in any of the compounds of formula (I), (I-A), (I-B), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R2 is H or C 1~6 alkyl (especially, methyl).

[0063] Preferably, in any of the compounds of formula (I), (I-A), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R3 is H, methyl, bromine, fluorine or chlorine, and more preferably, R3 is H, methyl or chlorine.

[0064] Preferably, in any of the compounds of formula (I), (I-A), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R5 is H or C 1~6 alkyl (especially, methyl),

[0065] Preferably, in any of the compounds of formula (I), (I-A), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R6 is H.

[0066] Preferably, in any of the compounds of formula (I), (I-A), (II-A), (II-B), (III-A) or (III-B) as defined above, or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, R7 and R8 are - hydrogen, - halogen (especially fluorine), haloC 1~6 alkyl (especially trifluoromethyl) and a 3- to 7-membered saturated ring (especially oxetanyl, cyclopropyl or cyclobutyl) which may contain an oxygen atom, each independently selected from one or more substituents which may be substituted by 1~12 alkyl (especially C 1~4 alkyl, preferably methyl, ethyl, i-propyl, t-butyl or i-butyl), and - C 1~6 alkyl (especially methyl), halogen (especially fluorine) and haloC 1~6 alkyl (especially trifluoromethyl), each independently selected from one or more substituents which may be substituted by an optionally oxygen-containing 3- to 8-membered saturated or partially saturated cyclic or bicyclic ring (especially oxetanyl, cyclopropyl or cyclobutyl) independently selected from or R7 and R8 together with the nitrogen atom to which they are attached form an azetidine which may be substituted by one or more halogens (especially fluorine).

[0067] Preferably, in any of the compounds as defined above or in its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers, Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, halogen (especially fluorine or chlorine), C 1~6 alkyl (especially methyl) and CN.

[0068] In a preferred embodiment, the present invention provides Cy is aryl (especially phenyl), A is C-R3, X is O or S, Y, Y', Y'' are C1~6 alkanediyl (especially, methanediyl), Y''' is a single bond, R1 is C 1~6 alkyl (especially, methyl), R2 is H or C 1~6 alkyl (especially, methyl), R3 is H, methyl or chlorine, R5 is H or C 1~6 alkyl (especially, methyl), R6 is H, R7 and R8 are - hydrogen, - halogen (especially, fluorine), haloC 1~6 alkyl (especially, trifluoromethyl) and a 3- to 7-membered saturated ring (especially, oxetanyl, cyclopropyl or cyclobutyl) which may contain an oxygen atom, each independently selected from one or more substituents which may be substituted, C 1~12 alkyl (especially, C 1~4 alkyl, preferably, methyl, ethyl, i-propyl, t-butyl or i-butyl) and - C 1~6 alkyl (especially, methyl), halogen (especially, fluorine) and haloC 1~6 alkyl (especially, trifluoromethyl), each independently selected from one or more substituents which may be substituted, a 3- to 8-membered saturated or partially saturated cyclic or bicyclic ring (especially, oxetanyl, cyclopropyl or cyclobutyl) which may contain an oxygen atom independently selected from, or R7 and R8, together with the nitrogen atom to which they are attached, form an azetidine which may be substituted with one or more halogens (especially, fluorine), Ra, Rb, Rc and Rd are each independently hydrogen, halogen (especially, fluorine or chlorine), C 1~6 alkyl (especially, methyl), haloC 1~6 alkyl (especially, CF3 or CHF2) and CN, selected from the group consisting of, To provide a compound of general formula (I) as defined above.

[0069] More preferably, the compound of the present invention is - cis-2-(2-(dimethylamino)-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - cis-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-Cyano-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(tert-Butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - cis N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - cis-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - cis-7-Methyl-2-(2-(methylamino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - cis-2-(2-Amino-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((3,3-Difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isobutylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((Cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isopropylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(Cyclobutylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - Trans-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - Trans-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclobutyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl- 2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((3,3-Difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-Chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3,4-Difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - trans-8-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocine-1-carboxamide 4,4-dioxide; - trans-8-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide; - trans-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide; - trans-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; and -(3aS,10aS)-N-(4-Fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; or is selected from the group consisting of its pharmaceutically acceptable salts, tautomers, solvates or stereoisomers.

[0070] Preferably, the compound or its pharmaceutically acceptable salt, tautomer, solvate or stereoisomer as defined above is for medical use. More preferably, the compound or its pharmaceutically acceptable salt, tautomer, solvate or stereoisomer as defined above is for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection. Preferably, the conditions associated with HBV infection are selected from the group consisting of chronic hepatitis B, HBV / HDV coinfection, HBV / HCV coinfection, HBV / HIV coinfection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and liver injury resulting from HBV infection.

[0071] Even more preferably, the compound or its pharmaceutically acceptable salt, tautomer, solvate or stereoisomer as defined above is for use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury resulting from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from potential HBV infection.

[0072] Preferably, the HBV infection and / or the condition associated with HBV infection is caused by HBV of any genotype including genotype A, B, C, D or E, and / or the HBV infection or condition is caused by a drug-resistant HBV mutant or variant.

[0073] Preferred compounds inhibit HBV by more than 50% at test concentrations (in the range of 1.0 micromolar to 0.1 micromolar) and / or have an EC as defined below in this specification of less than 0.5 micromolar. 50 HBV inhibition indicates inhibition of HBV expression and replication. The inhibitory activity of the compounds of the present invention can be measured as described below in this specification. Preferably, the compounds of the present invention target the HBV core protein, misdirect capsid assembly, and thus act as a capsid assembly modulator / inhibitor (CAM), causing suppression of HBV replication and virion production.

[0074] Preferably, the compounds or pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof as defined above are for use in combination with at least one further therapeutic agent. Preferably, use in said combination involves administration of at least one further therapeutic agent.

[0075] The object of the present invention is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, alone or in combination with at least one further therapeutic agent and at least one pharmaceutically acceptable excipient.

[0076] Preferably, at least one additional therapeutic agent is selected from the group consisting of a therapeutic vaccine, an RNA interference therapeutic agent / antisense oligonucleotide, an immunomodulatory substance, a STING agonist, a RIG-I modulator, an NKT modulator, an IL agonist, an interleukin or another immunomodulatory protein, a therapeutic and prophylactic vaccine, an immune checkpoint modulator / inhibitor, an HBV entry inhibitor, a cccDNA modulator, an inhibitor of HBV protein expression, an agent targeting HBV RNA, a capsid assembly inhibitor / modulator, a core or X protein targeting agent, a nucleotide analogue, a nucleoside analogue, interferon or a modified interferon, an HBV antiviral agent of an unknown or distinct mechanism, a cyclophilin inhibitor, an sAg release inhibitor, an HBV polymerase inhibitor, a dinucleotide, an SMAC inhibitor, an HDV targeting agent, a viral maturation inhibitor, a reverse transcriptase inhibitor, an HBV RNA destabilizing agent or another small molecule inhibitor of HBV protein expression, or a combination thereof.

[0077] Preferably, the therapeutic vaccine is selected from HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (HB-110E), CVI-HBV-002, RG7944 (INO-1800), TG-1050, FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204, NU-500, INX-102-00557, HBV MVA and PepTcell.

[0078] Preferably, the RNA interference therapeutic agent is siRNA, ddRNA or shRNA. Preferably, the RNA interference therapeutic agent is selected from TKM-HBV (ARB-1467), ARB-1740, ARC-520, ARC-521, BB-HB-331, REP-2139, ALN-HBV, ALN-PDL, LUNAR-HBV, GS3228836 and GS3389404.

[0079] Preferably, the immunomodulatory substance is a TLR agonist. Preferably, the TLR agonist is a TLR7, TLR8 or TLR9 agonist. Preferably, the TLR7, TLR8 or TLR9 agonist is selected from RG7795 (RO-6864018), GS-9620, SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate) and ARB-1598.

[0080] Preferably, the RIG-I modulator is SB-9200. Preferably, the IL agonist or other immunomodulatory protein is INO-9112 or recombinant IL12. Preferably, the immune checkpoint modulator / inhibitor is BMS-936558 (Opdivo (nivolumab)) or pembrolizumab. Preferably, the HBV entry inhibitor is Myrcludex B, IVIG-Tonrol or GC-1102.

[0081] Preferably, the cccDNA modulator is selected from direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, and inhibitors of cccDNA transcription.

[0082] Preferably, the capsid assembly inhibitor / modulator (CAM), core or X protein targeting agent, direct cccDNA inhibitor, inhibitor of cccDNA formation or maintenance, or cccDNA epigenetic modifier is selected from BAY 41-4109, NVR 3-778, GLS-4, NZ-4 (W28F), Y101, ARB-423, ARB-199, ARB-596, AB-506, JNJ-56136379, ASMB-101 (AB-V102), ASMB-103, CHR-101, CC-31326, AT-130, EP-027367, and RO7049389.

[0083] Preferably, the interferon or modified interferon is selected from interferon alpha (IFN-α), pegylated interferon alpha (PEG-IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, peginterferon alpha-2a (Pegasys), interferon alpha-2b (Intron A), recombinant interferon alpha-2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, peginterferon beta-1a, interferon delta, interferon lambda (IFN-λ), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon alphacon-1, interferon alpha-n1, interferon alpha-n3, albumin interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-infergen, Belerofon, INTEFEN-IFN, albumin / interferon alpha2a fusion protein, rHSA-IFN alpha2a, rHSA-IFN alpha2b, PEG-IFN-SA and interferon alpha biobetter. Peginterferon alpha-2a, peginterferon alpha-2b, glycosylated interferon alpha-2b, peginterferon beta-1a and peginterferon lambda-1 are particularly preferred. More specifically, peginterferon alpha-2a is preferred.

[0084] Preferably, the HBV antiviral agent of a distinct or unknown mechanism is selected from AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), its analogs, REP-9AC (REP-2055), REP-9AC' (REP-2139), REP-2165, and HBV-0259.

[0085] Preferably, the cyclophilin inhibitor is selected from OCB-030 (NVP-018), SCY-635, SCY-575, and CPI-431-32.

[0086] Preferably, the HBV polymerase inhibitor is selected from entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevudine, besifovir, adefovir (hepsera), and tenofovir. Preferably, tenofovir is in a salt form. Preferably, tenofovir is tenofovir disoproxil fumarate (Viread), tenofovir alafenamide fumarate (TAF), tenofovir disoproxil orotate (DA-2802), tenofovir disoproxil aspartate (CKD-390), AGX-1009, and CMX157 in a salt form selected therefrom.

[0087] Preferably, the dinucleotide is SB9200. Preferably, the SMAC inhibitor is birinapant. Preferably, the HDV targeting agent is lonafarnib.

[0088] Preferably, the HBV RNA destabilizer or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452.

[0089] Preferably, at least one further therapeutic agent is a drug useful in the treatment and prevention of hepatitis B. Preferably, at least one further therapeutic agent is an anti-HDV agent, an anti-HCV agent and / or an anti-HIV agent.

[0090] Preferably, at least one further therapeutic agent is selected from the group consisting of HBV polymerase inhibitors, interferons, virus entry inhibitors, BAY 41-4109, reverse transcriptase inhibitors, TLR-agonists, AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide) and combinations thereof, the HBV polymerase inhibitor is preferably at least one of lamivudine, entecavir, tenofovir, adefovir, telbivudine, clevudine, and the TLR agonist is preferably selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate) and combinations thereof.

[0091] Any combination of the above further therapeutic agents is contemplated for use in the present invention.

[0092] Preferably, the compound of the present invention is for use in combination with one, two or more further therapeutic agents as defined above.

[0093] Preferably, the pharmaceutical composition of the present invention comprises one, two or more further therapeutic agents as defined above.

[0094] Preferably, the pharmaceutical composition is for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection, and the conditions associated with HBV infection are preferably selected from the group consisting of chronic hepatitis B, HBV / HDV coinfection, HBV / HCV coinfection, HBV / HIV coinfection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver injury resulting from HBV infection. Even more preferably, the pharmaceutical composition is for use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of the viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of the recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury resulting from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from latent HBV infection.

[0095] Preferably, in a pharmaceutical composition for use as defined above, the HBV infection and / or condition associated with HBV infection is caused by HBV of any genotype including genotype A, B, C, D or E, and / or the HBV infection or condition is caused by a drug-resistant HBV mutant or variant.

[0096] In one embodiment, the present invention provides a kit comprising at least one pharmaceutically acceptable vial or container containing one or more doses of a compound of the present invention or a pharmaceutical composition of the present invention, and optionally a) instructions for use thereof in mammals and / or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

[0097] A further object of the present invention is a method for synthesizing a compound of general formula (I), (I-A), (I-B), (II-A), (II-B), (III-A) or (III-B) according to the synthetic scheme included in the description of the present invention. In particular, the present invention provides a method for synthesizing a compound of formula I or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, wherein A is C-R3, Y' and Y'' are both methanediyl, Y''' is a single bond, R1 is methyl, R6 is H, and Cy, X, Y, R2, R5, R7, R8, Ra, Rb, Rc and Rd are as defined above, said method comprising the following steps:

[0098]

Chemical formula

[0099] - reacting a compound of formula (5a) wherein m and n are each independently 1 or 2 with a compound of formula (8a) or a compound of formula (8b);

[0100]

Chemical formula

[0101] - reacting a compound of formula (6) wherein m and n are each independently 1 or 2 with an amine of formula NHR7R8;

[0102]

Chemical formula

[0103] - reacting a compound of formula (7) wherein m and n are each independently 1 or 2 with an amine of formula NHR7R8 and comprising at least one of: the following steps: - reacting a compound of formula (5a) with methyl 2-chloro-2-oxoacetate to obtain a compound of formula (6); - A step of hydrolyzing the compound of formula (6) in the presence of a base to obtain the compound of formula (7).

[0104]

Chemical formula

[0105] - In a solvent such as dichloromethane, reacting a compound of formula (9) where m and n are each independently 1 or 2 and R3 = H with sulfuryl dichloride to obtain a compound of formula (9) where R3 = Cl. - In a solvent such as chloroform, reacting a compound of formula (9) where m and n are each independently 1 or 2 and R3 = H with N-bromosuccinimide to obtain a compound of formula (9) where R3 = Br. It may further include at least one of the above steps.

[0106] Next, the present invention also provides a compound of formula (9), formula (9') or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, where all substituents are as defined above:

[0107]

Chemical formula

[0108] In a preferred embodiment, the method for synthesizing the compound of the present invention comprises the following steps: - In the presence of an amine such as 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, in a solvent such as ethanol, reacting a compound of formula (5b) where Ra is selected from the group consisting of Cl, F, CHF2, CF3 and CH3 with methyl (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate to obtain a compound of formula (9a):

[0109]

Chemical formula

[0110] The step of obtaining - In a solvent such as dichloromethane, a compound of formula (9a) wherein R3 is H and Ra is selected from the group consisting of Cl, F, CHF2, CF3 and CH3 is reacted with sulfuryl dichloride to give a compound of formula (9b):

[0111]

Chemical formula

[0112] The step of obtaining includes at least one of.

[0113] A further object of the present invention is a pharmaceutical composition comprising an effective amount of a compound as defined above or a pharmaceutically acceptable prodrug thereof, alone or in combination with other active compounds and at least one pharmaceutically acceptable excipient.

[0114] In a preferred embodiment, the present invention relates to a compound of formula (I) wherein Cy is phenyl. More preferably, the present invention relates to a compound of formula (I) wherein X is O or S.

[0115] The present invention includes within its scope prodrugs of the compounds of formula (I), formula (I-A), formula (I-B), formula (II-A) or formula (II-B) as described above. Generally, such prodrugs are functional derivatives of the compounds of formula (I), formula (I-A), formula (I-B), formula (II-A) or formula (II-B) and are readily convertible in vivo to the required compounds of formula (I), (I-A), (I-B), (II-A) or (II-B). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", H. Bundgaard, edited by Elsevier, 1985.

[0116] A prodrug can be a pharmacologically inactive derivative of a bioactive substance (the "parent drug" or "parent molecule") that requires transformation in the body to release the active drug and has improved delivery characteristics over the parent drug molecule. In vivo transformation can be the result of several metabolic processes such as chemical or enzymatic hydrolysis of carboxylic acid, phosphate or sulfate esters or reduction or oxidation of labile functional groups, for example.

[0117] The present invention also includes all suitable isotope variations of the compounds of the present disclosure. Examples of isotopes that can be incorporated into the compounds of the present disclosure include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl and the like. Certain isotope variations of the present disclosure, for example, 3 H or 14 C and the like incorporating radioisotopes are useful in drug and / or substrate tissue distribution studies. Further, substitution with isotopes such as deuterium 2 H can provide certain therapeutic advantages due to greater metabolic stability. Isotope variations of the compounds of the present disclosure can generally be prepared by conventional procedures such as by exemplary methods or by the preparations described in the examples below herein using appropriate isotope variations of suitable reagents.

[0118] The present invention includes within its scope solvates, such as hydrates, alcoholates, etc., of the compounds of formula (I), formula (I-A), formula (I-B), formula (II-A) or formula (II-B), or related salts.

[0119] Furthermore, the compounds disclosed herein may exist as tautomers, and even if only one tautomeric structure is shown, all tautomeric forms are intended to be embraced by the scope of the present invention.

[0120] Compounds may exist in different isomeric forms, and all of them are embraced by the present invention. For example, certain compounds of the present invention may exist as cis and trans geometric isomers, and all are embraced by the present invention.

[0121] The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (as described on pages 1119 - 1190 of E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994), and occur as racemic compounds, racemic mixtures, and as individual diastereomers, having all possible isomers including optical isomers and mixtures thereof, and all such stereoisomers are included in the present invention.

[0122] The pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by application of procedures known in the art and are intended to be embraced by the scope of the present invention. In particular, the terms "pure stereoisomeric form" or "stereoisomerically pure" indicate at least 80%, preferably at least 85% stereoisomerically enriched compound. For example, enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts or by chromatographic techniques using a chiral stationary phase. Pure stereoisomeric isomeric forms can also be derived from the corresponding pure stereoisomeric isomeric forms of the appropriate starting materials under conditions such that stereoisomers are formed stereospecifically. The term "enantiomerically pure" should be interpreted similarly taking into account the enantiomeric ratio.

[0123] In any component, if any variable (e.g., R1 and R2, etc.) occurs more than once, its definition at each occurrence is independent of all other occurrences. Also, substitutions and combinations of variables are only acceptable if such combinations result in stable compounds. A line drawn from a substituent into the ring structure indicates that the indicated bond may be attached to any of the ring atoms that can be substituted. When the ring structure is polycyclic, it is intended that the bond be attached only to any suitable carbon atom of the proximal ring.

[0124] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art in order to provide compounds that are chemically stable from readily available starting materials and can be easily synthesized by techniques known in the art and by the methods shown below. When a substituent is itself substituted with two or more groups, it is understood that these groups may be on the same carbon or on different carbons as long as a stable structure results. The phrase "optionally substituted" should be taken as equivalent to the phrase "unsubstituted or substituted with one or more substituents", and in such cases, preferred embodiments have from 0 to 3 substituents. More specifically, there are from 0 to 2 substituents.

[0125] The expressions "one or more substituents" and "one, two or more substituents" refer in particular to 1, 2, 3, 4 or more substituents, in particular 1, 2, 3 or 4 substituents, more particularly 1, 2 or 3 substituents.

[0126] As used herein, "Y is a single bond" means that in general formula (I), formula (I-A) and formula (I-B), X is directly linked by a single bond to the carbon atom having R2, "Y' is a single bond" means that in general formula (I), the carbon atom having R5 is directly linked by a single bond to N, "Y'' is a single bond" means that in general formula (I), N is directly linked by a single bond to the carbon atom having R2, and "Y'' 'is a single bond" means that in general formula (I), the carbon atom having R5 is directly linked by a single bond to the carbon atom having R2. "X is a single bond" means that in general formula (I), Y is directly linked by a single bond to pyrrole or pyrazole.

[0127] As used herein, "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1~12 alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons in a straight-chain or branched arrangement, and specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl and the like. As another example, "C 1~6 alkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a straight-chain or branched arrangement, and specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl and the like. Preferably, "C 1~12 alkyl" and "C 1~6 alkyl" refer to "C 1~4 alkyl" or "C 1~3 alkyl". "C 1~4 alkyl" is defined to include groups having 1, 2, 3 or 4 carbons in a straight-chain or branched arrangement. For example, "C 1~4 alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl and the like. "C 1~3 alkyl" is defined to include groups having 1, 2 or 3 carbons in a straight-chain or branched arrangement. For example, "C1~3 "Alkyl", specifically, includes methyl, ethyl, n-propyl, i-propyl, etc. Preferred alkyl groups are methyl, ethyl, i-propyl, t-butyl or i-butyl.

[0128] As used herein, "alkoxy" represents an alkyl group of the indicated number of carbon atoms bonded by an oxygen bridge. "Alkoxy" thus encompasses the above definition of alkyl. C 1~6 The alkoxy group is preferably a straight-chain or branched C 1~4 alkoxy group, more preferably a C 1~3 alkoxy group, even more preferably a C 1~2 alkoxy group. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy or t-butoxy. Preferred alkoxy groups include methoxy, ethoxy and t-butoxy.

[0129] As used herein, "halo C 1~6 alkyl" and "halo C 1~6 alkoxy" mean a C 1~6 alkyl or C 1~6 alkoxy group in which one or more (especially 1-3) hydrogen atoms are replaced by halogen atoms, especially fluorine or chlorine atoms. The halo C 1~6 alkoxy group is preferably a straight-chain or branched halo C 1~4 alkoxy group, more preferably a halo C 1~3 alkoxy group, even more preferably a halo C 1~2 alkoxy group, for example, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most particularly OCF3 or OCHF2. The halo C 1~6 alkyl group is preferably a straight-chain or branched halo C 1~3 alkyl group, more preferably a halo C 1~2An alkyl group, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 or CH(CH3)CF3, and most particularly CF3, CHF2 or CH(CH3)CF3.

[0130] As used herein, the term "hydroxy C" 1~6 alkyl" means a C 1~6 alkyl group in which one or more (particularly 1 to 3) hydrogen atoms are replaced by hydroxy groups. Similarly, the term "hydroxy C" 1~4 alkyl" means a C 1~4 alkyl group in which one or more (particularly 1 to 2) hydrogen atoms are replaced by hydroxy groups. Exemplary examples include, but are not limited to, CH2OH, CH2CH2OH, CH(CH3)OH and CHOHCH2OH.

[0131] As used herein, the term "aryl" means a monocyclic or polycyclic aromatic ring containing carbon and hydrogen atoms. When shown, such aromatic rings may contain one or more heteroatoms and thus are also referred to as "heteroaryl", preferably 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, preferably including nitrogen. As will be well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts. Thus, for the purposes of the present invention, heteroaryl groups need to have only a certain degree of aromatic character. Exemplary examples of aryl groups include optionally substituted phenyl. Exemplary examples of heteroaryl groups according to the present invention include optionally substituted thiophene, oxazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine and pyridine. Thus, examples of monocyclic aryl that may contain one or more heteroatoms, such as 1 or 2 heteroatoms, include 5- or 6-membered aryl or heteroaryl groups, such as, but not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxadiazolyl and oxazolyl. Examples of polycyclic aromatic rings that may contain one or more heteroatoms, such as 1 or 2 heteroatoms, include 8- to 10-membered aryl or heteroaryl groups, such as, but not limited to, benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, indolyl, indolizinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, quinazolinyl, quinolyl, quinoxalinyl, quinolizinyl, naphthyl, naphthyridinyl and phthalazinyl. Preferred aryl according to the present invention is phenyl. Preferred heteroaryl according to the present invention is pyridyl.

[0132] A complex ring, a complex ring compound, or a ring structure or heterocycloalkyl is a cyclic compound having at least two different elemental atoms as members of the ring.

[0133] Substituents on a saturated, partially saturated or unsaturated heterocyclic ring can be attached at any substitutable position.

[0134] As used herein, "C 1~6 alkanediyl" as a group or part of a group defines a divalent straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. C 1~6 alkanediyl groups are preferably C 1~4 alkanediyl groups, C 1~3 alkanediyl or more preferably C 1~2 alkanediyl. Examples include, but are not limited to, methanediyl, ethanediyl, propanediyl, butanenediyl, pentanediyl and hexanediyl. Methanediyl, ethanediyl and propanediyl are preferred.

[0135] As used herein, "C 2~7 alkenediyl" as a group or part of a group defines a divalent straight-chain or branched-chain (where carbon number limitations are tolerated) unsaturated hydrocarbon group having 2 to 7 carbon atoms. C 2~7 Non-limiting examples of alkenediyl include -C=CH-, -CH=C(CH3)CH2-, -CH=CH-CH2-.

[0136] As used herein, "C 3~8The term "cycloalkyl" or the term "3- to 8-membered saturated ring" means a saturated cyclic hydrocarbon (cycloalkyl) having 3, 4, 5, 6, 7, or 8 carbon atoms, and is a general term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Depending on the ring size, it can be of a bicyclic structure such as bicycle[3.1.0]hexane, bicycle[4.1.0]heptane, octahydropentalene, etc. In a specific embodiment of the present invention, the "3- to 8-membered saturated ring" is limited to a "3- to 7-membered saturated ring". The saturated ring may contain one or more heteroatoms (also called heterocyclyl or heterocyclic ring or heterocycloalkyl) such that at least one carbon atom is replaced by a heteroatom selected from N, O, and S, particularly from N and O. In a specific embodiment, "C 3~8 The term "heterocycloalkyl" means a 3- to 8-membered saturated or partially saturated non-aromatic monocyclic or bicyclic ring structure containing one or more heteroatoms selected from N, O, or S. Examples include, but are not limited to, oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperazinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, thiazolidinyl, thiolane 1,1-dioxide, pyrrolidinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, azocanyl, oxazocanyl, and hexahydrofuro[2,3-b]furan systems. Saturated cyclic hydrocarbons having 3 or 4 or 5 carbon atoms and one oxygen or one nitrogen atom are preferred. Examples include oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, piperidinyl, or pyrrolidinyl. Preferred 3- to 7-membered saturated rings include oxetanyl, cyclopropyl, and cyclobutyl.

[0137] As used herein, the expression "3- to 8-membered partially saturated ring" refers to a ring containing 3 to 8 carbon atoms and at least one double bond. Depending on the size of the ring, it can be of a cyclic or bicyclic structure. In certain embodiments of the present invention, the "3- to 8-membered partially saturated ring" is restricted to a "5- to 7-membered partially saturated ring". Each of the above rings may contain one or more heteroatoms such that at least one carbon is replaced by a heteroatom selected from N, O, and S, particularly from N and O. By way of example, and not limited thereto, cyclopentenyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclohexa-1,4-dienyl, cycloheptenyl, cyclohepta-1,4-dienyl, dihydrofuranyl, dihydropyrrole, dihydropitanyl, hexahydro-1H-cyclopenta[c]furanyl, etc. may be mentioned.

[0138] It should be noted that various different isomers of heterocycles may exist within the definitions as used throughout this specification. For example, pyrrolyl can be 1H-pyrrolyl or 2H-pyrrolyl.

[0139] It should also be noted that the position of the radical on any molecular moiety used in the definition may be at any location on such a moiety as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, 4-pyridyl.

[0140] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine, among which fluorine, chlorine, and bromine are preferred.

[0141] The term "heteroatom" refers to an atom other than carbon or hydrogen in a ring structure or saturated backbone as defined herein. Common heteroatoms include N(H), O, S.

[0142] "C 1~6 alkylaryl", when used herein, indicates one or more aryl groups attached to a C 1~6 alkyl radical. As used herein, "C1~6 The term "alkylheteroaryl" refers to one or more heteroaryl groups attached to a C 1~6 alkyl radical. As used herein, "C 1~6 alkyl-C 3~8 cycloalkyl" refers to one or more C 1~6 cycloalkyl groups attached to an alkyl radical. 3~8

[0143] The terms "spiro-C 3~8 cycloalkyl" and "spiro-C 3~8 heterocycloalkyl" each refer to a bicyclic organic compound having rings connected by only one atom, the C 3~8 cycloalkyl or C 3~8 heterocycloalkyl. The rings may be different or the same, naturally. The connecting atom is also called a spiro atom and is most often a quaternary carbon ("spiro carbon").

[0144] The free bases of the compounds of formula (I), (I-A), (I-B), (II-A) or (II-B), as well as their pharmaceutically acceptable salts and stereoisomers, are included in the present invention. Some of the specific compounds exemplified herein are protonated salts of amine compounds. Compounds of formula (I), (I-A), (I-B), (II-A) or (II-B) containing one or more N atoms can be protonated at any one, some or all of the N atoms. The term "free base" refers to an amine compound in its non-salt form. The pharmaceutically acceptable salts included are not only the salts exemplified for the specific compounds described herein, but also the usual pharmaceutically acceptable salts of the free forms of the compounds of formula (I), (I-A), (I-B), (II-A) or (II-B). The free forms of the described specific salt compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treatment with a dilute aqueous base solution, such as dilute NaOH, potassium carbonate, ammonia and sodium bicarbonate aqueous solutions. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the present invention.

[0145] The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of the present invention containing a basic or generating moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography in a suitable solvent or various combinations of solvents, or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base. In a preferred embodiment, the compounds of the present invention have at least one acidic proton and, for example, the corresponding sodium or potassium salts can be formed by reaction with a suitable base.

[0146] Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting the basic compounds with inorganic or organic acids or acidic compounds with inorganic or organic bases. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Further included as conventional non-toxic salts are those prepared from inorganic bases such as potassium, sodium hydroxide, magnesium hydroxide or calcium, and organic bases such as ethylenediamine, lysine, tromethamine, meglumine, etc. Preferably, the pharmaceutically acceptable salts of the present invention contain 1 equivalent of a compound of formula (I), (I-A), (I-B), (II-A) or (II-B) and 1, 2 or 3 equivalents of an inorganic or organic acid or base. More specifically, pharmaceutically acceptable salts of the present invention include tartrate, trifluoroacetate or chloride salts.

[0147] When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include those containing aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, e.g., arginine, betaine caffeine, choline, N,N 1- Dibenzylethylenediamine, diethylamine, 2 - diethylaminoethanol, 2 - dimethylaminoethanol, ethanolamine, ethylenediamine, N - ethylmorpholine, N - ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like can be mentioned.

[0148] The preparation of the above - mentioned pharmaceutically acceptable salts and other ordinary pharmaceutically acceptable salts is fully described by Berg et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977:66:1 - 19.

[0149] Under physiological conditions, the deprotonated acidic moiety in the compound, for example, a carboxyl group may be anionic, and then this electronic charge may be internally balanced against the cationic charge of a protonated or alkylated basic moiety, for example, a quaternary nitrogen atom. Therefore, it should also be noted that the compounds of the present invention are potentially internal salts or zwitterions.

[0150] The compounds of the present invention find use in various applications for the health of humans and animals. The compounds of the present invention are inhibitors of hepatitis B virus (HBV).

[0151] In the context of the present invention, HBV can be any known isolate, genotype, strain, etc. of HBV.

[0152] In particular, hepatitis B virus is classified into eight major genotypes (named A - H), and two additional genotypes (I and J) have been tentatively proposed. HBV genotypes are further divided into several sub - genotypes that differ by 4.0 - 7.5% in the overall nucleotide sequence. HBV genotypes are substantially different in a number of virological and perhaps some clinical parameters, but the exact role of HBV genotypes in the evolution of infection remains a matter of debate. Due to geographical distribution, in most regions of the world, only two or three HBV genotypes co - circulate, thereby limiting genotype comparisons.

[0153] The compounds of the present invention are inhibitors of hepatitis B virus (HBV) that are useful for the treatment and / or prevention of HBV infection. In particular, the compounds of the present invention are inhibitors of hepatitis B virus (HBV) core (HBc) protein that are useful for the treatment and / or prevention of HBV infection.

[0154] The compounds, compositions and methods provided herein are particularly useful for the treatment, remission or prevention of HBV infection and related conditions, including chronic hepatitis B, HBV / HDV co - infection, HBV / HCV co - infection, HBV / HIV co - infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and liver injury resulting from HBV infection.

[0155] In the present invention, the expression "HBV infection" includes, but is not limited to, any and all conditions resulting from HBV infection, including hepatitis B, preferably chronic hepatitis B, HBV / HDV co - infection, HBV / HCV co - infection, HBV / HIV co - infection.

[0156] HBV infection leads to a wide range of liver complications, all of which are intended as conditions related to HBV infection. As used herein, "conditions related to HBV infection" are preferably selected from the group consisting of chronic hepatitis B, HBV / HDV co - infection, HBV / HCV co - infection, HBV / HIV co - infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and liver injury resulting from HBV infection.

[0157] Expressions such as "treating, eradicating, reducing, decelerating or inhibiting HBV infection" are used to indicate the application or administration of a therapeutic agent, i.e., a compound of the present invention (alone or in combination with another pharmaceutical), to a patient having HBV infection, symptoms of HBV infection or a likelihood of developing HBV infection, for the purpose of treating, curing, alleviating, mitigating, modifying, remedying, improving, ameliorating or affecting HBV infection, symptoms of HBV infection or a likelihood of developing HBV infection, or the application or administration of a therapeutic agent to excised tissue or cell lines obtained from a patient (e.g., for diagnostic or ex vivo applications). Such treatments can be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0158] The effectiveness of the treatment can be determined by quantification of the viral load or other evidence of infection, such as measurement of HBeAg, HBsAg, HBV DNA levels, ALT activity levels, serum HBV levels, etc., thereby allowing adjustment of the treatment dose, treatment frequency and length of treatment.

[0159] HBeAg represents hepatitis B e-antigen. This antigen is a protein derived from the hepatitis B virus that circulates in the blood of an infected person when the virus is actively replicating.

[0160] ALT represents alanine transaminase, an enzyme involved in the transfer of an amino group from the amino acid alanine to alpha-ketoglutaric acid to produce glutamic acid and pyruvic acid. ALT is mainly localized in the liver and kidneys and is present in lesser amounts in the heart and skeletal muscle. ALT is generally clinically measured as part of liver function tests.

[0161] The compounds of the present invention can reduce the viral load in an individual suffering from HBV infection. In non-limiting embodiments, the compounds of the present invention effect a reduction in viral load during treatment in an individual in need thereof, from a minimum of 1 or 2 log reductions to a maximum of about 8 log reductions.

[0162] As used herein, the expression "alleviation of liver injury from HBV infection" means that chronic necroinflammatory liver disease has ceased due to the fact that viral antigens have disappeared from the organ (and the immune system no longer attacks liver cells).

[0163] As used herein, the term "treating prophylactically" means that in the absence of anything occurring, there is no occurrence of a disorder or disease, or in the case where there is already an occurrence of a disorder or disease, there is no further occurrence of a disorder or disease. Also considered is the ability to prevent some or all of the symptoms associated with the disorder or disease. An example of prophylactic treatment may also indicate the need to reduce the risk of infection of a liver graft (in the case of liver transplantation in a chronically infected patient) or of a neonate (in the case of a chronically infected mother infecting the virus at the time of delivery).

[0164] As used herein, "reducing recurrence of HBV infection" indicates that a patient may have reactivation of HBV replication and conditions associated with HBV infection, such as exacerbation of hepatitis, after several years of quiescence. These patients may still be at risk of developing conditions associated with HBV infection, such as hepatocellular carcinoma. Antiviral therapy is also recommended as prophylaxis for patients who are HBsAg positive and for patients who are HBsAg negative and hepatitis B core antibody positive and who require treatment with immunosuppressive therapy and are predicted to have a moderate to high risk of HBV reactivation.

[0165] The compounds of the present invention can be administered to mammals, preferably humans, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including by intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0166] The present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid, binding agents such as starch, gelatin, polyvinyl-pyrrolidone or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated and may be coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period. For example, water-soluble flavor masking materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose or time delay materials such as ethylcellulose, cellulose acetate butyrate can be used.

[0167] Formulations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0168] The aqueous suspension contains the active material in a mixture with excipients suitable for the manufacture of the aqueous suspension. Such excipients include antisettling agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic, and the dispersing or wetting agents may be naturally occurring phospholipids such as lecithin or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate or condensation products of alkylene oxides with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol or condensation products of alkylene oxides with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate or condensation products of alkylene oxides with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or aspartame.

[0169] The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. To provide a palatable oral preparation, sweetening agents such as those indicated above and flavoring agents can be added. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0170] Dispersants and granulating agents suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already described above. Further excipients, such as sweetening agents, flavoring agents and coloring agents, may also be present. These compositions can be preserved by the addition of antioxidants, such as ascorbic acid.

[0171] The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents can be naturally occurring phosphatides, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0172] Syrups and elixirs can be formulated using sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain demulcents, preservatives, flavoring agents and coloring agents and antioxidants.

[0173] The pharmaceutical composition can be in the form of a sterile aqueous solution for injection. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.

[0174] The sterile injectable preparation can also be a sterile water-in-oil microemulsion for injection in which the active ingredient is dissolved in the oily phase. For example, the active ingredient can first be dissolved in a mixture of soybean oil and lecithin. Then, the oil solution is placed in a mixture of water and glycerol and treated to form a microemulsion.

[0175] By local bolus injection, an injectable solution or microemulsion can be placed into the patient's bloodstream. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the compound. To maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is the Deltec CADD-PLUS (trademark) Model 5400 intravenous pump.

[0176] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension can be formulated according to known techniques using the suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Further, sterile hardened oils are conventionally used as the solvent or suspension medium. For this purpose, any sterile hardened oil containing synthetic mono- or diglycerides can be used. Further, fatty acids, such as oleic acid, are useful in the preparation of injectable substances.

[0177] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hardened vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0178] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. (For the purposes of this application, topical application must include mouse washes and gargles.)

[0179] The compounds of the present invention can be administered intranasally by topical use of a suitable nasal vehicle and delivery device, or by the transdermal route using a transdermal skin patch well known to those skilled in the art in the form of an intranasal form. For administration in the form of a transdermal delivery system, of course, the dosage administered will be more continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention can also be delivered as suppositories using bases such as cocoa butter, glycerinated gelatin, hardened vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0180] The compounds of the present invention can be presented in liposomes or other microparticles or other nanoparticles designed to target the compound. Acceptable liposomes may be neutral, negatively charged, or positively charged, and the charge is a function of the charge of the liposome components and the pH of the liposome solution. Liposomes can generally be prepared using a mixture of phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol. Polyethylene glycol can be added to improve the blood circulation time of liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

[0181] When the compounds of the present invention are administered in a human subject, the daily dosage will generally be determined by the prescribing physician and will generally vary according to age, weight, sex and the individual patient's response and the severity of the patient's symptoms.

[0182] In one exemplary application, a suitable amount of the compound is administered to a mammal undergoing anti-HBV treatment. The administration generally occurs at an amount between about 0.01 mg / kg body weight to about 100 mg / kg body weight per day, preferably between about 0.01 mg / kg body weight to about 60 mg / kg body weight per day, preferably between about 0.1 mg / kg body weight to about 50 mg / kg body weight per day, preferably between about 0.5 mg / kg body weight to about 40 mg / kg body weight per day.

[0183] The compound is also useful in combination with known therapeutic agents for simultaneous, separate or sequential administration.

[0184] In one embodiment, the compounds of the invention can be used in combination with at least one or more additional therapeutic agents, particularly anti-HBV agents.

[0185] Showing that the compounds of the invention are for use in the treatment and / or prevention of HBV infection indicates that the compounds are effective for the treatment, eradication, reduction, deceleration or inhibition of HBV infection.

[0186] The therapeutic agent is any agent commonly used in the treatment and / or prevention and / or remission of HBV infection or conditions associated with HBV infection. Therapeutic agents are known in the art.

[0187] The term "anti-HBV agent" or more simply "HBV antiviral agent" also includes compounds that are therapeutic nucleic acids, antibodies or proteins, either in their native form or chemically modified and / or stabilized. A hepatitis B virus (HBV) strain that is resistant to at least one anti-HBV agent is defined as drug resistant. The term therapeutic nucleic acid includes, but is not limited to, nucleotides and nucleosides, oligonucleotides, polynucleotides, non-limiting examples of which include antisense oligonucleotides, miRNAs, siRNAs, shRNAs, therapeutic vectors and DNA / RNA editing components.

[0188] The term "anti-HBV agent" also includes compounds that can treat HBV infection by immunomodulation, i.e., immunomodulatory substances or immunomodulatory compounds. Examples of immunomodulatory substances include interferon-α (IFN-α), pegylated interferon-α, or stimulants of the innate immune system, such as Toll-like receptor 7 and / or 8 agonists, as well as therapeutic or prophylactic vaccines. One embodiment of the present invention relates to immunomodulatory compounds of compounds of formula (I), (I-A), (I-B), (II-A) or (II-B) as detailed herein, or any subgroup thereof, more particularly in combination with Toll-like receptor 7 and / or 8 agonists.

[0189] Further anti-HBV agents can be selected, for example, from therapeutic vaccines, RNA interference therapeutics / antisense oligonucleotides (e.g., siRNA, ddRNA, shRNA), immunomodulatory substances (e.g., TLR agonists (e.g., TLR7, TLR8 or TLR9 agonists), STING agonists, RIG-I modulators, NKT modulators, IL agonists, interleukins or other immunologically active proteins, therapeutic and prophylactic vaccines and immune checkpoint modulators, HBV entry inhibitors, cccDNA modulators (e.g., direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, inhibitors of cccDNA transcription, etc.), inhibitors of HBV protein expression, agents that target HBV RNA, capsid assembly inhibitors / modulators, core or X protein targeting agents, nucleotide analogs, nucleoside analogs, interferon or modified interferon, HBV antiviral agents of distinct or unknown mechanisms, cyclophilin inhibitors, sAg release inhibitors, HBV polymerase inhibitors, dinucleotides, SMAC inhibitors, HDV targeting agents, viral maturation inhibitors, reverse transcriptase inhibitors, HBV RNA destabilizing agents and other small molecule inhibitors of HBV protein expression.

[0190] In particular, known anti-HBV agents from before, such as interferon-α (IFN-α), pegylated interferon-α, 3TC, tenofovir, lamivudine, entecavir, telbivudine, and adefovir, or combinations thereof, can be used as a medicine in combination therapy with a compound of formula (I), (I-A), (I-B), (II-A), or (II-B), or any subgroup thereof. Further examples of additional therapeutic agents that can be combined with the compounds of the present invention include zidovudine, didanosine, zalcitabine, stavudine, abacavir, ddA emtricitabine, apricitabine, atelavirine, ribavirin, acyclovir, valacyclovir, famciclovir, ganciclovir, valganciclovir, cidofovir, efavirenz, nevirapine, delavirdine, and etravirine.

[0191] Specific examples of such HBV antiviral agents include, but are not limited to: - RNA interference (RNAi) therapeutic agents: TKM-HBV (also known as ARB-1467), ARB-1740, ARC-520, ARC-521, BB-HB-331, REP-2139, ALN-HBV, ALN-PDL, LUNAR-HBV, GS3228836, and GS3389404, - HBV entry inhibitors: Myrcludex B, IVIG-Tonrol, GC-1102, - HBV capsid inhibitors / modulators, core or X protein targeting agents, direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, or cccDNA epigenetic modifiers, BAY 41-4109, NVR 3-778, GLS-4, NZ-4 (also known as W28F), Y101, ARB-423, ARB-199, ARB-596, AB-506, JNJ-56136379, ASMB-101 (also known as AB-V102), ASMB-103, CHR-101, CC-31326, AT-130, RO7049389, - HBV polymerase inhibitors: entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevudine, besifovir, adefovir (hepsera), tenofovir (especially tenofovir disoproxil fumarate (Viread), tenofovir alafenamide fumarate (TAF)), tenofovir disoproxil orotate (also known as DA-2802), tenofovir disoproxil aspartate (also known as CKD-390), AGX-1009 and CMX157), - HBV RNA destabilizers and other small molecule inhibitors of HBV protein expression: RG7834, AB-452, - Cyclophilin inhibitors: OCB-030 (also known as NVP-018), SCY-635, SCY-575 and CPI-431-32, - Dinucleotides: SB9200, - Compounds of distinct or unknown mechanism, for example, but not limited to only, AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide) and similar analogs; REP-9AC (also known as REP-2055), REP-9AC' (also known as REP-2139), REP-2165 and HBV-0259, - TLR agonists (TLR7, 8 and / or 9): RG7795 (also known as RO-6864018), GS-9620, SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate), ARB-1598, - RIG-I modulators: SB-9200, - SMAC inhibitor: birinapant, - Immune checkpoint inhibitor: BMS-936558 (Opdivo (nivolumab)), KEYTRUDA (registered trademark) (pembrolizumab), - Therapeutic vaccine: HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (also known as HB-110E), CVI-HBV-002, RG7944 (also known as INO-1800), TG-1050, FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204, NU-500, INX-102-00557 HBV MVA, PepTcell, - IL agonist and immunomodulatory protein: INO-9112, recombinant IL12, - Interferons: interferon alpha (IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, peginterferon alpha-2a (Pegasys), interferon alpha-2b (Intron A), recombinant interferon alpha-2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, peginterferon beta-1a, interferon delta, interferon lambda (IFN-λ), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon alphacon-1, interferon alpha-n1, interferon alpha-n3, albumin-interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-infergen, Belerofon, INTEFEN-IFN, albumin / interferon alpha2a fusion protein, rHSA-IFN alpha2a, rHSA-IFN alpha2b, PEG-IFN-SA, interferon alpha biobetter, in particular, peginterferon alpha-2a, peginterferon alpha-2b, glycosylated interferon alpha-2b, peginterferon beta-la and peginterferon lambda-1, more particularly, peginterferon alpha-2a, - HDV targeting agents: lonafarnib include.

[0192] As used herein in connection with the compounds of the present invention, the term "administer" and variations thereof (e.g., "administering" a compound) mean introducing a compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the present invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administer" and variations thereof are each understood to include the simultaneous and sequential introduction of the compound or its prodrug and the other agent(s).

[0193] In some embodiments, pulsed dosing is more effective than continuous treatment because the total pulse dose is often lower than that predicted from continuous dosing of the same composition. Each pulse dose can be reduced and the total amount of drug administered over the course of treatment is minimized. The individual pulses can be delivered continuously to the patient over a period of hours, e.g., about 2, 4, 6, 8, 10, 12, 14 or 16 hours, or over several days, e.g., 2, 3, 4, 5, 6 or 7 days.

[0194] As used herein, the term "composition" is intended to encompass a product containing the specified amounts of the specified ingredients and any product directly or indirectly resulting, in whole or in part, from the combination of the specified amounts of the specified ingredients.

[0195] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other clinician.

[0196] The present invention is illustrated by the following non-limiting examples and biological data are presented.

[0197] Materials and Methods Chemistry General Unless otherwise specified, commercially available reagents and solvents (HPLC grade) were used without further purification.

[0198] Specifically, the following abbreviations may be used in the description of the experimental methods: NMR: Nuclear Magnetic Resonance, 1 H: Proton, MHz: Megahertz, Hz: Hertz, CDCl3: Chloroform-d, HPLC: High Performance Liquid Chromatography, LC-MS: Liquid Chromatography-Mass Spectrometry, m / z: Mass-to-charge ratio, s: Second, min: Minute, h: Hour, mg: Milligram, g: Gram, mL: Milliliter, mmol: Millimole, nm: Nanomole, μM: Micromole, M: Molarity or Molar Concentration, Rt: Retention Time in Minutes, sat.aq.: Saturated Aqueous Solution, MW: Microwave, Boc: tert-Butyloxycarbonyl Protecting Group, DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene, DCM: Dichloromethane, DMF: Dimethylformamide, DIPEA: N,N-Diisopropylethylamine, DMSO: Dimethyl Sulfoxide, EtOAc: Ethyl Acetate, LiHMDS: Lithium Bis(trimethylsilyl)amide, NaHMDS: Sodium Bis(trimethylsilyl)amide, MeOH: Methanol, MeCN: Acetonitrile, PE: Petroleum Ether, PMB: p-Methoxybenzyl Protecting Group, PyBop: Benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium Hexafluorophosphate, TFA: Trifluoroacetic Acid, eq.: Equivalent, RT: Room Temperature, THF: Tetrahydrofuran, pTSA: p-Toluenesulfonic Acid, TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium Tetrafluoroborate.

[0199] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius) or K (Kelvin).

[0200] 1The 1H-NMR spectra were obtained using an Avance II 300 MHz Bruker spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are expressed in Hertz (Hz), and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).

[0201] LC-MS analysis was performed using a UPLC Acquity Waters System equipped with an SQD spectrometer, a single quadrupole mass detector, and a TUV detector, column 1: ACQUITY UPLC BEH SHIELD, RP 18 (2.1×50 mm, id = 1.7 μM), column 2: ACQUITY UPLC HSS T3, RP 18 (2.1×50 mm, id = 1.8 μM) and column 3: ACQUITY UPLC BEH SHIELD, RP 18 (2.1×100 mm, id = 1.7 μM). The column temperature was 40 °C. The sample temperature was 25 °C. Phase A was composed of water (HiPerSolv Chromanorm water VWR HPLC-MS grade) + 0.05% trifluoroacetic acid, and phase B was composed of CH3CN (HiPerSolv Chromanorm acetonitrile SuperGradient VWR, suitable for UPLC / UHPLC instruments) + 0.05% trifluoroacetic acid. The flow rate was 0.5 mL / min, UV detection (DIODE array) at 200 nm, ESI+ and ESI− detection in the range of 100 - 1000 m / z.

[0202] Method 1: Column 1, run time: 3 minutes, run gradient: 5% B - 100% B in 2.80 minutes + 100% B for 0.2 minutes, equilibration time: 0.8 minutes, ionization mode: ESI + 。 Method 2: Column 2, run time: 4 minutes, run gradient: 0% B - 45% B in 3.5 minutes + 45% B - 100% B in 0.05 minutes + 100% B for 0.45 minutes, equilibration time: 0.8 minutes, ionization mode: ESI + 。 Method 3: Column 3, Run time: 6 minutes, Run gradient: 5% B to 100% B in 1 minute + 100% B for 1 minute, Equilibration time: 2 minutes. Method 4: Column 3, Run time: 6 minutes, Run gradient: 5% B to 50% B in 5 minutes + 50% B to 100% B in 0.2 minutes + 100% B for 0.8 minutes, Equilibration time: 2 minutes, Ionization mode: ESI + 。 Method 5: Column 1, Run time: 3 minutes, Run gradient: 5% B to 100% B in 2.80 minutes + 100% B for 0.2 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 6: Column 2, Run time: 4 minutes, Run gradient: 0% B to 45% B in 3.5 minutes + 45% B to 100% B in 0.05 minutes + 100% B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 7: Column 3, Run time: 6 minutes, Run gradient: 5% B to 100% B in 5 minutes + 100% B for 1 minute, Equilibration time: 2 minutes, Ionization mode: ESI + 。 Method 8: Column 3, Run time: 6 minutes, Run gradient: 5% B to 50% B in 5 minutes + 50% B to 100% B in 0.2 minutes + 100% B for 0.8 minutes, Equilibration time: 2 minutes, Ionization mode: ESI + 。 Method 9: Column 1, Run time: 4 minutes, Run gradient: 5% B to 100% B in 3 minutes + 100% B for 1 minute, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 10: Column 1, Run time: 4 minutes, Run gradient: 5% B to 100% B in 3 minutes + 100% B for 1 minute, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 11: Column 1, Run time: 3 minutes, Run gradient: 40% B to 100% B in 2.80 minutes + 100% B for 0.2 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 12: Column 3, Run time: 6 minutes, Run gradient: 25% B to 70% B in 5 minutes + 100% B for 1 minute, Equilibration time: 2 minutes, Flow rate: 0.5 mL / min, Ionization mode: ESI + 。 Method 13: Column 2, Run time: 4 minutes, Run gradient: 0% B to 60% B in 3.5 minutes + 60% B to 100% B in 0.05 minutes + 100% B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 14: Column 2, Run time: 4 minutes, Run gradient: 0% B to 30% B in 3.5 minutes + 30% B to 100% B in 0.05 minutes + 100% B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 15: Column 3, Run time: 10 minutes, Run gradient: 5% B to 100% B in 9 minutes + 100% B for 1 minute, Equilibration time: 2 minutes, Ionization mode: ESI + 。

[0203] Synthesis According to a further aspect of the present invention, there is provided a method for preparing a compound of formula (I), formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III-A), formula (III-B) or a salt thereof. The following schemes are examples of synthetic schemes that can be used to synthesize the compounds of the present invention. In the following schemes, according to well-established techniques, reactive groups can be protected and deprotected using protecting groups. In the following schemes, unless otherwise specified, R1, R2, R3, R5, R7, R8, X, Y, Y', Y'', Y''', Cy, Ra, Rb, Rc, Rd are as defined hereinabove in each of formula (I), formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III-A), formula (III-B).

[0204] It will be understood by those skilled in the art that certain compounds of the present invention can be converted to other compounds of the present invention according to standard chemical methods. The compounds of the present invention are prepared according to the general routes shown in Scheme 1 below:

[0205]

Chemical formula

[0206] can be prepared according to the general routes shown.

[0207] Ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate, which is shown as compound (1) in Scheme 1 with R1 = CH3 and R3 = H, was prepared according to the procedure described in WO2017 / 001655. According to Scheme 1, a primary amine derivative (2) having a nucleophilic -XH substituent is reacted with compound (1) in the presence of a suitable base to obtain the corresponding sulfonamide product (3). The reaction of (3) with an arylamine or heteroarylamine in the presence of a strong non-nucleophilic base, such as LiHMDS, in a solvent such as tetrahydrofuran converts the ethyl carboxylate to an arylamide derivative (4). A subsequent cyclization step by an intramolecular nucleophilic attack of XH on fluorine gives the tricyclic core of compound (5). Depending on the specific protecting group (PG, as shown in Scheme 1) in compound (5), the product can be further refined by deprotection and / or further functionalization steps. In particular, when nitrogen is an N-Boc derivative, Boc can be removed by an acidic treatment, and the resulting NH can be further converted to, for example, a carbamate, urea, sulfonamide, sulfonylurea derivative, or alkylated, for example, via reductive amination chemistry. In a particular embodiment of the present invention, in the compound of general formula (5), the protected nitrogen is N-COOEt or N-PMB, and the protecting group can be cleaved via standard chemistry, for example, trimethylsilyl iodide for ethyl carbamate and hydrogenation for the p-methoxybenzyl group (PMB). In a further embodiment of the present invention, the nucleophilic group -XH in general compounds (2), (3) or (4) can be further refined via protection and replacement with different nucleophiles. Of further note is that the specific order of the steps shown in Scheme 1 can be changed to optimize the efficiency of the synthetic strategy.

[0208] Deprotection of the compound (5) shown in Scheme 1 gives a highly advanced intermediate of general structure (5a), which is further reacted as shown in Scheme 2 to obtain the compound of the present invention.

[0209] [Chemistry]

[0210] In preferred embodiments of compounds 5a, 6, 7 and 9, m and n are each independently 1 or 2. A compound of formula (9) in which R3 is H can be further reacted under halogenation conditions to obtain a compound of formula (9) in which R3 is halogen. For example, reaction of a compound of formula (9) in which R3 is H with sulfuryl dichloride in dichloromethane gives the corresponding chlorine addition derivative (i.e., R3 is Cl).

[0211] A certain amine derivative (2) of Scheme 1 was prepared according to the synthetic strategies outlined in Schemes 3, 4 and 5. The procedures in the schemes can be used for the synthesis of the compounds shown below and, by selecting starting materials with the appropriate stereochemical configuration, can similarly be used for the synthesis of compounds as single diastereoisomers and / or enantiomers.

[0212] [Chemistry]

[0213] [Chemistry]

[0214] [Chemistry]

[0215] Unless otherwise indicated, starting materials and / or intermediates were obtained from commercial sources or could be obtained via synthetic procedures known in the chemical literature. The indication of a commercial source for a particular compound in the description of the test procedure, when provided, is for ease of reference only for the skilled chemist and should not be construed as indicating use of only that particular commercial compound.

[0216] In the following paragraphs, Preparations 1 to 53 illustrate the preparation of intermediates used to make the compounds of the present invention and their salts. The Examples illustrate the preparation of the compounds of the present invention and their salts. It is understood that when a compound has more than one chiral center, it may exist as a mixture of diastereoisomers or as a single isomer. Both racemic and chiral compounds are within the scope of the present invention. The procedures shown are provided merely for the assistance of the skilled chemist. The starting materials may not necessarily be prepared from the batches of the Preparations or Examples referred to.

[0217] Preparation D1: Ethyl (3aR,6aR)-1-((R)-2-hydroxy-1-phenylethyl)tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5(3H)-carboxylate (D1)

[0218]

Chemical formula

[0219] Prepared starting from ethyl allyl(2-oxoethyl)carbamate (prepared as reported in US Patent Application Publication No. US2018 / 0222918) and (R)-2-(hydroxyamino)-2-phenylethan-1-ol (prepared as reported in WO Patent Application Publication No. WO2010 / 016005) according to the procedure reported in J. Org. Chem. 2003, 68, 8739 - 8741. 1 H NMR (300 MHz, CDCl3) δ ppm 1.15 (t, J = 7.11 Hz, 3 H) 2.87 (dd, J = 8.89, 4.40 Hz, 1 H) 3.06 - 3.56 (m, 5 H) 3.57 - 3.75 (m, 3 H) 3.75 - 3.83 (m, 1 H) 3.94 - 4.11 (m, 3 H) 4.27 (br t, J = 8.12 Hz, 1 H) 7.22 - 7.36 (m, 5 H). Method 3; Rt = 2.18 min. m / z = 307.32 (M + H) + .

[0220] Description D2: Ethyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate hydrochloride (D2)

[0221]

Chemical formula

[0222] Compound D1 (2.9 g, 9.47 mmol) was dissolved in methanol (150 mL, 3.703 mol), palladium(II) hydroxide (3.06 g, 4.35 mmol) was added, and the suspension was hydrogenated at 1 atm and room temperature for 16 h. Acetic acid (15.16 mL, 265.05 mmol) was added, the reaction mixture was stirred for 15 min, then filtered through paper and washed with methanol (approx. 70 mL). The solution was evaporated (30 °C), the residue was treated with 1 M HCl (20 mL), and then evaporated further. The residue was dissolved in water (10 mL), the pH was adjusted using 1 M HCl (3 mL), washed with DCM, the aqueous layer was evaporated further, and co-evaporated with toluene to remove traces of acetic acid, and the title compound D2 (1.6 g, 7.12 mmol) was obtained as an off-white powder (yield = 75%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.18 (t, J=7.06 Hz, 3 H), 2.54 - 2.66 (m, 1 H), 3.17 - 3.66 (m, 6 H), 3.72 - 3.88 (m, 1 H), 3.93 - 4.14 (m, 2 H), 8.10 (br s, 3 H). Method 13; Rt = 1.02 min; m / z = 189.15 (M+H) + .

[0223] Description D3: Ethyl (2,2-dimethoxyethyl)(2-methylallyl)carbamate (D3)

[0224]

Chemical formula

[0225] Step 1 Ethyl (2,2-dimethoxyethyl)carbamate (334125, Fluorochem, CAS: 71545-60-3) (1.73 g, 9.74 mmol) was charged into a 20 mL vial. The vial was sealed and evacuated. 1M NaHMDS in THF (13.45 mL, 13.45 mmol) was added all at once. The reaction mixture was stirred at room temperature for 40 minutes. 3-Chloro-2-methylprop-1-ene (0.47 mL, 4.64 mmol) (094695, Fluorochem, CAS: 563-47-3) was added all at once and the reaction mixture was stirred at room temperature for 30 - 40 minutes and then heated at 60 °C for 30 minutes and then at 70 °C for 4 hours by microwave irradiation in the presence of DMF (2 mL, 0.026 mol). The reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (10 mL × 3). The combined organic layers were evaporated and purified directly by flash chromatography (eluent petroleum ether / EtOAc) to give D3 (0.5 g, 2.16 mmol, 22% yield) as a colorless oil.

[0226] Step 2 A solution of ethyl (2,2-dimethoxyethyl)carbamate (0.64 g, 3.61 mmol) (334125, Fluorochem, CAS: 71545-60-3) in toluene (4 mL) was treated with potassium hydroxide (1.04 g, 18.53 mmol) and N-benzyl-N,N-diethylethanaminium chloride (14.92 mg, 0.08 mmol) (146562, Sigma Aldrich, CAS 56-37-1). The vial was sealed and the mixture was stirred for 15 minutes to obtain a pink suspension. 3-Bromo-2-methylprop-1-ene (0.461 mL, 4.44 mmol) (067665, Fluorochem, CAS: 1458-98-6) was dissolved in toluene (0.4 mL) and added dropwise over 1 minute. The reaction was stirred overnight at room temperature, then filtered through paper, diluted with EtOAc, washed with brine and concentrated. The residue (0.25 g) was purified directly by flash chromatography (eluent petroleum ether / EtOAc) to give D3 (0.64 g, 2.9 mmol, 80% yield) as a colorless oil. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.18 (br d, J=6.42 Hz, 3 H), 1.62 (s, 3 H), 3.15 - 3.23 (m, 2 H), 3.25 - 3.31 (m, 6 H), 3.74 - 3.91 (m, 2 H), 4.05 (br d, J=6.60 Hz, 2 H), 4.40 - 4.54 (m, 1 H), 4.63 - 4.78 (m, 1 H), 4.79 - 4.91 (m, 1 H). Method 9; Rt: 1.79-1.82 min. m / z: 254.22 (M+Na) + .

[0227] Description of D4: Synthesis of ethyl (2-methylallyl)(2-oxoethyl)carbamate (D4)

[0228]

Chem.

[0229] A solution of D3 (0.25 g, 1.08 mmol) in acetone (2 mL) and water (1.5 mL) was heated at 80 °C by microwave irradiation in the presence of 1 M pyridinium 4-methylbenzenesulfonate in water (25 μL, 0.025 mmol). After 1 hour, 1 M pyridinium 4-methylbenzenesulfonate in water (100 μL, 0.1 mmol) was further added and the reaction was heated at 100 °C for 15 min (×3 runs) by microwave irradiation. Acetone was removed in vacuo and the reaction mixture was extracted with DCM (4×3 mL) to give D4 (0.158 mg, 79% yield) as a colorless oil, which was used in the next step without any further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.02 - 1.28 (m, 3 H), 1.54 - 1.71 (m, 3 H), 3.81 (s, 2 H), 3.91 - 4.17 (m, 4 H), 4.63 - 4.80 (m, 1 H), 4.85 (s, 1 H), 9.48 (d, J=4.77 Hz, 1 H). Method 1; Rt: 1.04 - 1.54 min. m / z: 186.24 (M+H) + .

[0230] Synthesis of the title D5: cis-ethyl 1-benzyl-3a-methyltetrahydro-1H-pyrrolo[3,4-c]isoxazole-5(3H)-carboxylate (D5)

[0231]

Chemical Structure

[0232] D4 (0.5 g, 2.7 mmol) and N-benzylhydroxylamine (0.366 g, 2.97 mmol) in toluene (5 mL) were heated at 50 °C for 30 minutes under microwave irradiation and then further at 100 °C for 1 hour. The reaction mixture was poured into a separatory funnel and washed with an aqueous solution of 5% citric acid (3 mL) and brine (5 mL). The solvent was removed and the residue was purified directly by flash chromatography (eluent: petroleum ether / EtOAc). The pure fractions were combined to give D5 (0.2 g, 0.689 mmol, 25% yield) as a yellowish oil. Method 9; Rt: 1.78. m / z: 291.31 (M+H) + 。

[0233] Description of D6: Synthesis of cis-ethyl 4-amino-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (D6)

[0234]

Chem.

[0235] Procedure 1 A 40 mL tube was filled with a solution of D5 (0.4 g, 1.38 mmol) in methanol (24 mL), ammonium formate (0.434 g, 6.89 mmol) was added, and then 10% Pd / C (146.6 mg) was added. The tube was sealed and the black reaction suspension was heated at 70 °C for 1.5 hours. The reaction mixture was filtered through paper, washed with methanol, and evaporated to give D6 (230 mg, 1.137 mmol, 82% yield), which was used in the next step without any further purification.

[0236] Procedure 2 A solution of D5 (0.176 g, 0.61 mmol) in ethanol (11.4 mL) and water (1.2 mL) was hydrogenated by an H-CUBE apparatus (registered trademark of ThalesNano) equipped with a 10% Pd / C small cartridge (THS01111, ThalesNano) under the following conditions: pressure H2: 10 bar; flow: 1 mL / min at T = 80 °C. The solvent was removed to obtain D6 (0.11 g, 0.54 mmol, 88% yield) as a colorless oil. The product was used in the next step without any purification. Method 9; Rt: 0.68. m / z: 203.26 (M+H) + 。

[0237] Described D7: N-(4-methoxybenzyl)prop-2-en-1-amine (D7)

[0238]

Chem.

[0239] Potassium carbonate (3.2 g, 22.82 mmol) was charged into a round-bottom flask (50 mL), and prop-2-en-1-amine (12 mL, 159.75 mmol) was added (the reaction was carried out under neat conditions). p-Anisyl chloride (2.6 mL, 19.18 mmol) (270245, Sigma Aldrich, CAS: 824-94-2) was added over 50 minutes, and the reaction mixture was stirred at room temperature overnight. Allylamine was removed by evaporation, and the residue was dissolved in water (10 mL) and EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and finally evaporated to obtain D7 (3.45 g, 19.47 mmol) as a colorless oil (quantitative yield). Method 9; Rt: 0.90 min. m / z: 178.13 (M+H) + 。

[0240] Described D8: 1-(allyl(4-methoxybenzyl)amino)propan-2-one (D8)

[0241]

Chem.

[0242] A mixture of D7 (2.27 g, 16.21 mmol) was suspended in MeCN (1 mL) and treated at once with chloroacetone (0.87 mL, 10.81 mmol). The mixture was heated at 70 °C for 4 h by conventional heating in a sealed vial. The solvent was removed by evaporation. The residue was partitioned between water (15 mL) and EtOAc (15 mL), the organic layer was evaporated, and the residue was purified directly by flash chromatography (petroleum ether / EtOAc) to give D8 (1.5 g, 6.43 mmol, yield: 59%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3 H), 3.11 - 3.24 (m, 4 H), 3.61 (s, 2 H), 3.82 (s, 3 H), 5.16 - 5.27 (m, 2 H), 5.90 (ddt, J=17.02, 10.30, 6.42, 6.42 Hz, 1 H), 6.88 (d, J=8.53 Hz, 2 H), 7.21 - 7.32 (m, 3 H). Method 9; Rt: 0.96 min; m / z: 234.14 (M+H) + .

[0243] Described D9: 1-(allyl(4-methoxybenzyl)amino)propan-2-one oxime (D9)

[0244]

Chemical Structure

[0245] D8 (1.5 g, 6.43 mmol) was dissolved in ethanol (50 mL) and added to a mixture of hydroxylamine hydrochloride (0.89 g, 12.86 mmol) and sodium acetate (1.07 g, 12.86 mmol). The resulting white suspension was stirred at room temperature for 3 hours overnight. The solvent was removed, and the residue was dissolved in water (15 mL), extracted with EtOAc (10 mL × 2), dried over anhydrous Na2SO4, filtered, and evaporated. The organic layer was evaporated, and the residue was purified directly by flash chromatography (petroleum ether / EtOAc) to give D9 (1.6 g, 6.43 mmol, quantitative yield). 1 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68 - 1.98 (m, 2 H), 2.13 - 2.40 (m, 4 H), 4.05 (br d, J=7.52 Hz, 2 H), 4.46 (br dd, J=13.02, 2.57 Hz, 3 H), 4.82 (br d, J=14.12 Hz, 3 H), 6.95 (dd, J=11.88, 0.87 Hz, 1 H), 7.28 (s, 1 H), 7.50 (d, J=8.53 Hz, 1 H), 7.69 - 7.83 (m, 2 H), 10.95 (br s, 1 H), 11.91 (br s, 1 H). Method 9; Rt: 1.01 min. m / z: 249.21 (M+H) + .

[0246] Described D10: cis-5-(4-methoxybenzyl)-6a-methylhexahydro-1H-pyrrolo[3,4-c]isoxazole (D10)

[0247]

Chemical Structure

[0248] In a 150 mL sealed container, D9 (1.6 g, 6.44 mmol) was dissolved in o-xylene (70 mL, 0.574 mol) and heated at 130 °C for 32 hours. The solvent was removed under reduced pressure. The residue was purified directly by flash chromatography (eluent EtOAc / MeOH) to obtain the impure title product (700 mg), which was further purified by a second direct flash chromatography (eluent DCM / MeOH) to obtain D10 (0.55 mg, yield 34%). Method 9; Rt: 0.81 min. m / z: 249.27 (M+H) + 。

[0249] Described D11: cis-(4-Amino-1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl)methanol (D11)

[0250]

Chemical Structure

[0251] D10 (0.479 g, 1.91 mmol) was dissolved in acetic acid (10 mL), transferred to a 20 mL vial, and treated with a single portion of zinc (0.505 g, 7.72 mmol). The vial was sealed and the mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc, filtered, evaporated, and stripped with toluene (3 times). The residue (0.6 g) was dissolved in a solution of NaHCO3 (0.45 g) in water (6 mL). The organic layer was separated and collected. The aqueous layer was further basified with 1 M NaOH (10 mL) and extracted with DCM (5 mL × 3 times). The combined organic extracts were dried over Na2SO4 (anhydrous), filtered, and finally evaporated to obtain D11 (0.479 g, 1.913 mmol) as a yellowish oil. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (s, 3 H), 1.47 - 2.19 (m, 3 H), 2.26 - 2.38 (m, 2 H), 2.44 (d, J=8.80 Hz, 1 H), 2.66 (t, J=8.94 Hz, 1 H), 3.39 - 3.48 (m, 1 H), 3.48 - 3.63 (m, 3 H), 3.79 (s, 3 H), 3.94 - 5.32 (m, 1 H), 6.92 (d, J=8.62 Hz, 2 H), 7.26 (d, J=8.44 Hz, 2 H). Method 2; Rt: 1.40 min; m / z: 251.25 (M+H) + .

[0252] Description D12: cis-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-3-amine (D12)

[0253]

Chem.

[0254] A solution of D11 (0.170 g, 0.68 mmol) in DCM (0.2 mL) and DMF (1 mL) was treated with a solution of 1H-imidazole (0.108 mg, 1.58 mmol) in DMF (1 mL). The reaction was cooled in a dry ice / acetone bath, and then a solution of tert-butyldichlorodimethylsilane (0.114 mg, 0.76 mmol) in DMF (1 mL) was added dropwise over 2 minutes. The cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water (4 mL) and EtOAc (10 mL), stirred for 10 minutes, poured into a separatory funnel, and the aqueous layer was extracted with EtOAc (5 mL × 3). The combined organic extracts were washed with water (2 mL) and brine (2 mL), dried over anhydrous Na2SO4, filtered, and finally evaporated to give a residue (200 mg). Purification was carried out by direct flash chromatography (eluent EtOAc / MeOH) to give D12 (0.127 mg, 51% yield) as a yellowish oil.1 1H NMR (300 MHz, DMSO-d6) δ ppm 0.08 - 0.04 (m, 6 H), 0.76 - 0.88 (m, 9 H), 1.07 - 1.24 (m, 3 H), 1.52 (br s, 2 H), 1.78 - 1.91 (m, 1 H), 2.14 - 2.22 (m, 1 H), 2.23 - 2.30 (m, 1 H), 2.34 - 2.39 (m, 1 H), 2.56 - 2.65 (m, 1 H), 3.35 - 3.48 (m, 2 H), 3.49 - 3.58 (m, 1 H), 3.63 - 3.69 (m, 1 H), 3.69 - 3.73 (m, 3 H), 6.84 (d, J = 8.53 Hz, 2 H), 7.17 (d, J = 8.44 Hz, 2 H). Method 2; Rt: 1.56 min; m / z: 365.26 (M+H) + .

[0255] Description D13: Ethyl (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (D13) The compound was prepared according to the following scheme:

[0256]

Chemical Structure

[0257] Step 1: A solution of D2 (1351.61 mg, 7.18 mmol) in anhydrous MeCN (24 mL) was added with DIPEA (2.5 mL, 14.36 mmol), and then a solution of ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (1936.57 mg, 7.18 mmol) in anhydrous MeCN (12 mL) was added dropwise thereto over 10 minutes. The reaction mixture was stirred at room temperature for 90 minutes, then concentrated under reduced pressure, diluted with EtOAc (130 mL), washed with 5% citric acid solution (40 ml) and brine (20 ml), dried over Na2SO4 (anhydrous), filtered, and the solvent was removed under reduced pressure. The crude product was purified directly by flash chromatography (eluent DCM / AcOEt) to obtain ethyl 4-(N-((3R,4R)-1-(ethoxycarbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (2.9 g, yield = 91%) as a white solid. Method 1: Rt = 1.44 min; m / z = 422.41 (M+H) + 。

[0258] Step 2: To a solution of ethyl 4-(N-((3R,4R)-1-(ethoxycarbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (2.7 g, 6.43 mmol) and 4-fluoro-3-methylaniline (0.845 g, 6.75 mmol) (006273, Fluorochem, CAS: 452-69-7) in anhydrous THF (50 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF) (3.33 mL, 20 mmol) dropwise at room temperature. After 60 minutes, the reaction was quenched with water, diluted with DCM, and washed with 5% aqueous citric acid solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain D13 as a brown foamy substance, which was used without further purification. Method 1: Rt = 1.81 min; m / z = 501.16 (M+H) + 。

[0259] Description D14: Ethyl (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol)-3-sulfonamido)-4-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (D14)

[0260]

Chem.

[0261] To a solution of D13 (623 mg, 1.24 mmol) in anhydrous DCM (27 mL) were sequentially added triethylamine (0.35 mL, 2.49 mmol) and DMAP (15.2 mg, 0.12 mmol). The resulting solution was cooled to 0 °C and methanesulfonyl chloride (0.13 mL, 1.62 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 5 minutes and then at room temperature for 1 hour. The mixture was diluted with DCM and washed twice with 5% citric acid solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product D14 in almost quantitative yield (721 mg), which was used without further purification in the next step. Method 1; Rt = 1.98 min; m / z = 579.14 (M+H) + 。

[0262] Description D15: Ethyl (3R,4R)-3-((acetylthio)methyl)-4-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol)-3-sulfonamido)pyrrolidine-1-carboxylate (D15)

[0263]

Chem.

[0264] To a solution of D14 (257 mg, 0.44 mmol) in anhydrous DMF (7.6 ml) was added potassium thioacetate (634 mg, 5.55 mmol). The dark red reaction mixture was stirred at room temperature overnight and then diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography on silica (eluent petroleum ether / EtOAc) to give D15 (170 mg, y = 68.5%) as an off-white foamy substance. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.09 - 1.21 (m, 4 H), 2.23 (s, 3 H), 2.30 (s, 3 H), 2.33 - 2.43 (m, 1 H), 2.90 (m, J=7.50 Hz, 2 H), 3.03 - 3.16 (m, 1 H), 3.16 - 3.26 (m, 1 H), 3.35 - 3.48 (m, 2 H), 3.81 (s, 4 H), 3.93 - 4.05 (m, 2 H), 7.11 (t, J=9.35 Hz, 1 H), 7.41 - 7.53 (m, 2 H), 7.54 - 7.65 (m, 1 H), 8.04 - 8.30 (m, 1 H), 9.84 - 10.17 (m, 1 H). Method 1; Rt = 2.12 min; m / z = 559.18 (M+H) + .

[0265] Described D16: Ethyl (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(mercaptomethyl)pyrrolidine-1-carboxylate (D16)

[0266]

Chem.

[0267] A solution of D15 (443 mg, 0.79 mmol) in methanol (3.7 mL) was added to 1N NaOH solution (1.52 mL, 1.52 mmol), and the reaction mixture was stirred at room temperature for 40 minutes. The reaction was diluted with water, acidified to pH = 3 using 1N HCl (a white solid precipitated), and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give 396 mg of a pale yellow foamy substance (containing the target product and S-S dimer in a ratio of 1:1). The residue was dissolved in acetic acid (9 mL), zinc (1037 mg, 15.86 mmol) was added, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction was filtered through a pad of celite, washed with DCM, and concentrated under vacuum to give crude D16 (431 mg) as a white foamy substance, which was used without further purification in the next step. Method 1; Rt = 2.09 min; m / z = 517.17 (M+H) +

[0268] Synthesis of the title D17: cis-Ethyl 4-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrol)-3-sulfonamido)-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (D17) The compound was prepared according to the following scheme:

[0269]

Chemical formula

[0270] Step 1: D6 (110 mg, 0.54 mmol) was dissolved in MeCN (2 mL), cooled to 0 °C, treated with ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (146.7 mg, 0.54 mmol), and then treated with DIPEA (0.21 mL, 1.2 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer was evaporated, and the residue was purified directly by flash chromatography (direct phase, eluent petroleum ether / EtOAc) to give cis-ethyl 4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)-4-methylpyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.23 mmol) as a white solid. Method 1; Rt: 1.64; m / z: 436.19 (M+H) + .

[0271] Step 2: A solution of cis-ethyl 4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)-4-methylpyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.23 mmol) and 4-fluoro-3-methylaniline (30.2 mg, 0.24 mmol) in THF (1.45 mL) was treated with 1 M lithium bis(trimethylsilyl)amide in a single portion of THF (1.16 mL, 1.16 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with 5% citric acid, dried over Na2SO4 (anhydrous), filtered, and finally evaporated to give a residue, which was purified by Fraction-Lynx (H2O / CH3CN + 1‰ TFA). D17 (100 mg, 0.194 mmol) was obtained by Step 2. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.83 - 0.91 (m, 3 H), 1.05 - 1.12 (m, 3 H), 2.16 (d, J=1.28 Hz, 3 H), 2.49 - 2.70 (m, 1 H), 2.82 (br t, J=10.22 Hz, 1 H), 3.05 (br s, 1 H), 3.27 - 3.54 (m, 4 H), 3.67 - 3.80 (m, 3 H), 3.84 - 4.05 (m, 2 H), 4.55 - 4.78 (m, 1 H), 7.05 (t, J=9.22 Hz, 1 H), 7.42 (br d, J=4.40 Hz, 2 H), 7.53 (br d, J=6.69 Hz, 1 H), 7.77 (br d, J=8.62 Hz, 1 H), 9.96 (s, 1 H). Method 9; Rt: 1.91; m / z: 515.21 (M+H)+.

[0272] Description D18: cis-Ethyl 4-((4-fluoro-1-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-1H-pyrrol)-3-sulfonamido)-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (D18) The compound was prepared according to the following scheme:

[0273]

Chemical Structure

[0274] Step 1: D6 (110 mg, 0.54 mmol) was dissolved in MeCN (2 mL), cooled to 0 °C, treated with ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (146.7 mg, 0.54 mmol), and then treated with DIPEA (0.21 mL, 1.2 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between DCM and NaHCO3, the organic layer was evaporated, and the residue was purified directly by flash chromatography (direct phase, eluent petroleum ether / EtOAc) to give cis-ethyl 4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)-4-methylpyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.23 mmol) as a white solid. Method 1; Rt: 1.64; m / z: 436.19 (M+H) + 。

[0275] Step 2: A mixture of the intermediate compound obtained from Step 1 (55 mg, 0.13 mmol) and 3,4,5-trifluoroaniline (20.44 mg, 0.14 mmol) (002064, Fluorochem, CAS: 163733-96-8) in THF (1 mL) was treated with a single portion of 1 M lithium bis(trimethylsilyl)amide in THF (0.632 mL, 0.632 mmol) at room temperature. The resulting brown mixture was stirred at room temperature for 15 minutes. The solvent was removed in vacuo, the residue was partitioned between water and EtOAc, the organic layer was dried over Na2SO4 (anhydrous), filtered, and finally evaporated to give D18 (30 mg, 0.056 mmol), which was used in the next step without any further purification. Method 9: Rt. 2.04; m / z; 537.36 (M+H) + 。

[0276] Described D19: cis-3-fluoro-N-(4-fluoro-3-methylphenyl)-4-(N-(4-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-3-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carboxamide (D19) The compound was prepared according to the following scheme:

[0277] [Chemical formula]

[0278] Step 1: To a solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate (12.5 g, 79.6 mmol) (231254, Fluorochem, CAS: 168102-05-4) in anhydrous DMF (125 mL) cooled to 0 °C under a nitrogen atmosphere, sodium hydride (60 wt% in mineral oil, 3.7 g, 92.5 mmol) was added portionwise over 30 minutes. The reaction mixture was stirred for an additional 20 minutes, then iodomethane (5.8 mL, 93.2 mmol) was added dropwise over 30 minutes. The mixture was stirred at the same temperature for an additional 30 minutes and then quenched with 2N HCl (20 mL). The reaction mixture was poured into water (120 mL) and toluene (650 mL), and the mixture was stirred vigorously for 10 minutes. The two phases were separated, and the organic phase was washed with water (250 mL) and brine (250 mL), dried over Na2SO4 (anhydrous), and filtered. Ethyl 3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (13.6 g) was obtained as a pale yellow oil and used without further purification after evaporation of the solvent. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.11 Hz, 3 H), 3.78 (s, 3 H), 4.23 (q, J=7.06 Hz, 2 H), 5.99 (d, J=3.03 Hz, 1 H), 7.00 (dd, J=5.27, 3.07 Hz, 1 H).

[0279] Step 2: Ethyl 3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (13.6 g, 79.5 mmol) and 4-fluoro-3-methylaniline (10.3 g, 82.3 mmol) prepared in Step 1 were dissolved in anhydrous toluene (50 mL). LiHMDS (140 mL, 1 M in toluene, 140 mmol) was added dropwise over 30 minutes, and the reaction mixture was stirred at room temperature for an additional 30 minutes. The reaction mixture was cooled to 0 °C and quenched slowly with 2N HCl (200 mL), diluted with water (200 mL) and toluene (200 mL), and stirred at room temperature for 20 minutes. The two phases were separated, and the organic phase was washed with saturated NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4 (anhydrous), and filtered. After evaporation of the solvent, 3-fluoro-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide (19.8 g) was obtained as a light brown solid and used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H), 3.76 (s, 3 H), 6.01 (d, J=3.03 Hz, 1 H), 6.91 (dd, J=5.27, 3.07 Hz, 1 H), 7.08 (t, J=9.22 Hz, 1 H), 7.35 - 7.53 (m, 1 H), 7.59 (dd, J=7.06, 2.20 Hz, 1 H), 9.50 (br s, 1 H).

[0280] Step 3: A solution of 3-fluoro-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide (19.8 g, 79.5 mmol), prepared in Step 2, in anhydrous DCM (90 mL) cooled to 0 °C under a nitrogen atmosphere was added dropwise with chlorosulfonic acid (5.7 mL, 85.6 mmol) dissolved in anhydrous DCM (120 mL) over 90 minutes. The reaction mixture was stirred at the same temperature for an additional 30 minutes, then the precipitate formed was filtered and washed several times with Et2O. 4-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (23.1 g, 88% yield over 3 steps), obtained as a light gray solid, was dried under vacuum overnight and used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H), 3.70 (s, 3 H), 6.93 (d, J=5.04 Hz, 1 H), 7.07 (t, J=9.22 Hz, 1 H), 7.44 - 7.52 (m, 1 H), 7.60 (dd, J=7.06, 2.20 Hz, 1 H), 9.64 (s, 1 H).

[0281] Step 4: To a suspension of 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (14.9 g, 45.1 mmol), prepared in Step 3, in thionyl chloride (112 mL) was added anhydrous DMF (0.35 mL, 4.51 mmol). The reaction mixture was heated to 75 °C and stirred at the same temperature for 45 minutes. The brown solution was cooled to RT, diluted with toluene (200 mL), and slowly poured into a mixture of toluene (200 mL) and ice (500 mL) under vigorous stirring. The biphasic system was stirred for 20 minutes, the two phases were separated, the organic phase was washed with ice water (200 mL) and brine (200 mL), dried over Na2SO4 (anhydrous), filtered, concentrated, and concentrated under reduced pressure. The residue was purified by silica (eluent petroleum ether / AcOEt gradient) to give 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (13.9 g, 88% yield) as a beige powder. 1 H NMR (300 MHz, CDCl3) δ ppm 2.31 (s, 3 H), 4.06 (s, 3 H), 7.03 (t, J=8.89 Hz, 1 H), 7.26 - 7.36 (m, 2 H), 7.39 - 7.46 (m, 1 H), 7.72 (br d, J=8.16 Hz, 1 H).

[0282] Step 5: A solution of D12 (0.1 g, 0.27 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.16 mL, 0.92 mmol) in DCM (1.29 mL) was added all at once to 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (0.112 mg, 0.29 mmol) prepared in Step 4. The resulting solution was stirred overnight at room temperature. The reaction was diluted with DCM (2 mL), poured into a separatory funnel, and washed with water (2 mL). The organic layer was evaporated and treated with 6N HCl (5 mL), MeOH (3 mL) and MeCN (2 mL). The resulting mixture was stirred for 1 hour at room temperature to obtain a solution. The reaction was poured into a separatory funnel and extracted with DCM (5 mL×3). The organic layer was washed with NaHCO3 (saturated solution, 10 mL), dried over Na2SO4 (anhydrous), filtered, and finally evaporated to give a residue (0.2 g). Purification was carried out by direct flash chromatography (eluent 5% MeOH / EtOAc) to give D19 (0.075 g, 0.133 mmol, 49% yield). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (s, 3 H), 1.84 - 2.06 (m, 1 H), 2.23 (s, 3 H), 2.27 (br dd, J=4.22, 2.29 Hz, 1 H), 2.54 - 2.59 (m, 1 H), 2.62 - 2.69 (m, 1 H), 2.70 - 2.80 (m, 1 H), 3.35 - 3.54 (m, 3 H), 3.56 - 3.67 (m, 1 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 4.94 - 5.05 (m, 1 H), 6.76 - 6.91 (m, 2 H), 7.05 - 7.21 (m, 3 H), 7.28 - 7.38 (m, 1 H), 7.40 - 7.54 (m, 2 H), 7.54 - 7.66 (m, 1 H), 9.86 - 10.07 (m, 1 H). Method 9; Rt: 1.64 min; m / z: 563.30 (M+H) + .

[0283] Description D20: Ethyl (3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-2(3H)-carboxylate 5,5-dioxide (D20)

[0284] [Chemical formula]

[0285] To a solution of crude D16 (0.793 mmol) in DMF (14.5 mL) was added cesium carbonate (646 mg, 1.98 mmol), and the reaction mixture was stirred at 135 °C for 1 hour. The reaction was diluted with EtOAc and washed with water (×3). The organic layer was dried over Na2SO4 (anhydrous), filtered, and concentrated under vacuum. The resulting crude material was purified by flash chromatography on silica (eluent DCM / MeOH), and then by preparative HPLC-MS (H2O / CH3CN + 0.1% HCOOH), to give D20 (280 mg, yield = 71%) as a white solid after lyophilization. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (q, J=6.82 Hz, 3 H), 2.23 (s, 3 H), 2.31 - 2.44 (m, 1 H), 2.56 - 2.71 (m, 1 H), 2.87 - 3.09 (m, 1 H), 3.16 - 3.44 (m, 3 H), 3.54 - 3.83 (m, 4 H), 3.88 - 4.13 (m, 2 H), 4.59 - 4.85 (m, 1 H), 7.10 (t, J=9.35 Hz, 1 H), 7.42 - 7.60 (m, 2 H), 7.61 - 7.74 (m, 1 H), 8.01 - 8.25 (m, 1 H), 10.32 (s, 1 H). Method 3; Rt = 3.47 min; m / z = 497.24 (M+H) + .

[0286] Description D21: Ethyl (3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D21)

[0287] [Chemical formula]

[0288] In a pressure vessel, D13 (3.13 g, 6.25 mmol) was dissolved in anhydrous DMF (120 mL), cesium carbonate (5.3 g, 16.26 mmol) was added, the vial was sealed, and the mixture was heated at 140 °C for 4 hours. The solvent was removed under reduced pressure, the residue was taken up with EtOAc, and washed with water (×3). The organic layer was dried over Na2SO4 (anhydrous), filtered, and the solvent was removed under reduced pressure. Subsequently, the obtained light brown foamy substance was treated with Et2O to remove the residual solvent, and D21 (2.8 g, yield = 93%) was obtained as a light brown solid, which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.05 - 1.27 (m, 3 H), 2.24 (d, J=1.47 Hz, 3 H), 2.92 - 3.16 (m, 2 H), 3.41 (br d, J=10.91 Hz, 2 H), 3.64 - 4.10 (m, 7 H), 4.32 - 4.69 (m, 2 H), 7.11 (t, J=9.22 Hz, 1 H), 7.39 - 7.67 (m, 3 H), 7.96 (s, 1 H), 9.34 (s, 1 H). Method 1: Rt = 2.00 min; m / z = 481.24 (M+H) + .

[0289] Description D22: Ethyl (3aR,10aR)-8-((3-chloro-4-fluorophenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D22) The compound was prepared according to the following scheme:

[0290]

Chem.

[0291] Steps 1 and 2 were carried out according to the procedure described for the synthesis of compound D13, using 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) instead of 4-fluoro-3-methylaniline in step 2. Step 3 was carried out as described for compound D21. Method 1: Rt = 2.09 min; m / z = 501.30, 503.39 (M+H) + 。

[0292] Description D23: Ethyl (3aR,10aR)-7-methyl-8-((3,4,5-trifluorophenyl)carbamoyl)-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D23) The compound was prepared according to the following scheme:

[0293]

Chem.

[0294] Steps 1 and 2 were carried out according to the procedure described for the synthesis of compound D13, using 3,4,5-trifluoroaniline instead of 4-fluoro-3-methylaniline in Step 2. Step 3 was carried out as described for compound D21 to give D23. Method 1: Rt = 2.08 min; m / z = 503.19 (M+H) + 。

[0295] Description D24: Ethyl (3aR,10aR)-8-((3-cyano-4-fluorophenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D24) The compound was prepared according to the following scheme:

[0296]

Chemical Structure

[0297] Steps 1 and 2 were carried out according to the procedure described for the synthesis of compound D13, using 3-cyano-4-fluoroaniline (013105, Fluorochem, CAS: 53312-81-5) instead of 4-fluoro-3-methylaniline in Step 2. Step 3 was carried out as described for compound D21 to give D24. Method 1: Rt = 1.92 min. m / z = 492.45 (M+H) + 。

[0298] Description D25: cis-Ethyl 7,10a-dimethyl-8-((3,4,5-trifluorophenyl)carbamoyl)-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D25)

[0299]

Chemical Structure

[0300] A mixture of D18 (30 mg, 0.06 mmol) and cesium carbonate (45.55 mg, 0.14 mmol) in DMF (1.4 mL) was heated at 130 °C for 5 h by microwave irradiation. The reaction mixture was cooled to room temperature and evaporated. The residue was dissolved in water and EtOAc, and the resulting mixture was poured into a separatory funnel. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give a brown residue (30 mg). The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ TFA) to give D25 (10 mg, 0.019 mmol, 32% yield). 1 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.12 - 1.23 (m, 3 H), 1.27 (s, 3 H), 3.06 (d, J = 10.55 Hz, 1 H), 3.16 - 3.28 (m, 1 H), 3.28 - 3.44 (m, 1 H), 3.72 - 3.84 (m, 3 H), 3.84 - 4.14 (m, 5 H), 4.30 (br t, J = 10.82 Hz, 1 H), 7.49 (s, 1 H), 7.54 - 7.71 (m, 2 H), 8.38 - 8.54 (m, 1 H), 9.67 (br s, 1 H). Method 3: Rt = 3.71 min; m / z = 517.37 (M+H) + .

[0301] Described D26: cis-Ethyl 8-((4-fluoro-3-methylphenyl)carbamoyl)-7,10a-dimethyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (D26)

[0302]

Chemical formula

[0303] Starting from D17, D26 was obtained by following the same procedure described for the synthesis of D21. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15 - 1.25 (m, 3 H) 1.27 (s, 3 H) 2.24 (d, J = 1.47 Hz, 3 H) 3.07 (d, J = 10.73 Hz, 1 H) 3.16 - 3.28 (m, 1 H) 3.36 (s, 1 H) 3.72 - 3.84 (m, 3 H) 3.84 - 4.16 (m, 5 H) 4.31 (s, 1 H) 7.12 (t, J = 9.22 Hz, 1 H) 7.36 - 7.52 (m, 2 H) 7.52 - 7.67 (m, 1 H) 8.31 - 8.57 (m, 1 H) 9.24 - 9.45 (m, 1 H). Method 3: Rt = 3.56 min. m / z = 495.35 (M+H) + .

[0304] Described D27: cis-N-(4-Fluoro-3-methylphenyl)-2-(4-methoxybenzyl)-3a,7-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (D27)

[0305]

Chemical Structure

[0306] A solution of D19 (0.075 mg, 0.13 mmol) in DMF (2.68 mL) was treated with cesium carbonate (0.109 g, 0.33 mmol) and heated at 130 °C for 2 h by microwave irradiation. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc (5 mL × 3 times). The combined organic extracts were dried over Na2SO4 (anhydrous), filtered, and finally evaporated to give D27 (0.062 g, 0.114 mmol, 86% yield), which was used in the next step without any further purification. Method 1; Rt: 1.55 min; m / z: 543.37 (M+H)+ .

[0307] Description D28: (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide hydroiodide (D28)

[0308] [Chemical formula]

[0309] In a sealed vial, D20 (54 mg, 0.11 mmol) was dissolved in anhydrous DCM (1 mL). Trimethylsilyl iodide (0.08 mL, 0.55 mmol) was added and the reaction mixture was heated at reflux (50 °C) for 3 h. The mixture was quenched by the addition of methanol at 0 °C and then evaporated under reduced pressure. The residue was triturated with Et2O to give crude D28 (62 mg) as an orange solid, which was used in the next step without further purification. Method 1; Rt = 1.37 min; m / z = 425.25 (M+H) + .

[0310] Description D29: cis-N-(4-Fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide hydroiodide (D29) The compound was prepared according to the following scheme:

[0311] [Chemical formula]

[0312] Step A suspension of ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (70 mg, 0.260 mmol) and cis-ethyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate, (Enamine, catalog number EN300-754530) (56.2 mg, 0.299 mmol) in anhydrous acetonitrile (2 mL) was added anhydrous DIPEA (0.1 mL, 0.574 mmol) at room temperature. After 1.5 h, the mixture was diluted with DCM and washed with 5% citric acid solution. The organic layer was dried over Na2SO4 (anhydrous), filtered, and the solvent was removed under reduced pressure to give cis-ethyl 4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate as a pale yellow solid (162 mg). The compound is a cis racemic compound in the pyrrolidine ring (racemic compound of 3S,4S and 3R,4R). The crude product was purified by flash chromatography (petroleum ether / AcOEt) to give a white solid (101 mg). Method 1: Rt = 1.52 min, m / z = 422 (M+H) + 。

[0313] Step 2: To a solution of the compound obtained from Step 1 and 4-fluoro-3-methylaniline in anhydrous THF (2 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (5 eq) at room temperature. Upon completion of the reaction and standard workup, the intermediate product cis-ethyl 3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamide)-4-(hydroxymethyl)pyrrolidine-1-carboxylate was obtained and further reacted. Method 1: Rt = 1.83 min, m / z = 501 (M+H) + 。

[0314] Step 3 was carried out as for the synthesis of compound D21. Step 4 was carried out as described for the synthesis of D28 to give D29. Method 1: Rt = 1.36 min; m / z = 409.17 (M+H) + 。

[0315] Description D30: (3aR,10aR)-8-((4-Fluoro-3-methylphenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D30)

[0316]

Chem.

[0317] Procedure 1 Starting from D21, D30 was obtained in the same manner as described for compound D28. Method 1: Rt = 1.36 min; m / z = 409.37 (M+H) + 。

[0318] Procedure 2 The compound was prepared according to the following scheme:

[0319]

Chem.

[0320] Steps 1 - 6 were carried out starting from 2,2-dimethoxyethan-1-amine (094452, Fluorochem, CAS: 22483-09-6) and benzyl chloroformate according to the procedure reported in J. Med.Chem. 2007, 50, 5493 - 5508 to obtain (±) benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate. 1 H NMR (300 MHz, DMSO-d6+ TFA) δ ppm 2.55 - 2.68 (m, 1 H) 3.27 - 3.38 (m, 1 H) 3.43 - 3.67 (m, 5 H) 3.84 (br s, 1 H) 5.04 - 5.13 (m, 2 H) 7.29 - 7.41 (m, 5 H) 7.90 - 8.02 (br s, 2 H). Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) + .

[0321] Step 7: To a solution of the compound obtained from Step 6, (±)-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (11.52 g, 46.02 mmol) in acetone (16 mL) was added 2-methoxypropene (8.81 mL, 92.02 mmol) (174645, Sigma Aldrich, CAS: 116 - 11 - 0). The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure to remove volatiles. The crude product (13.38 g, 46.08.05 mmol) was taken up in anhydrous acetone (115 mL) and treated with (S)-2-hydroxy-2-phenylacetic acid (7.011 g, 46.08 mmol) (046847, Fluorochem, CAS: 17199 - 29 - 0). The mixture was cooled to -5 °C and stirred for 12 hours. The resulting white precipitate was filtered, washed three times with 60 mL of anhydrous acetone, and cooled at -5 °C to obtain benzyl (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylate [(S)-mandelate] as a white solid (6.2 g, y = 30%).

[0322] Step 8: Benzyl (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylate [(S)-mandelate] (500 mg, 1.13 mmol) was dissolved in 1 ml of absolute ethanol and H2SO4 (5% solution, 0.5 mL). The mixture was stirred at room temperature for 3 hours. The resulting mixture was treated with 2M NaOH (1 mL) solution and the ethanol was removed under reduced pressure. The aqueous residue was extracted with AcOEt (3 × 20 ml). Benzyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (245 mg, y = 87%) was used in the next step without further purification. Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) +

[0323] Step 9: To a solution of the compound obtained from Step 8, benzyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (217 mg, 0.870 mmol), N-ethyl-N-isopropylpropan-2-amine (0.6 mL, 3.47 mmol) and 4-fluoro-5-((4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (302.36 mg, 0.870 mmol) in 5 ml of absolute MeCN were added sequentially. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was diluted with EtOAc and washed with 5% citric acid solution and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The resulting crude material was purified by flash chromatography on silica gel (direct phase, eluent DCM / EtOAc) to give benzyl (3R,4R)-3-((4-fluoro-5-((4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (420 mg, y = 86%) as a white foamy substance. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 2.22 (s, 3 H) 2.30 - 2.43 (m, 1 H) 3.19 - 3.29 (m, 1 H) 3.29 - 3.51 (m, 4 H) 3.53 - 3.64 (m, 1 H) 3.70 - 3.92 (m, 4 H) 5.04 (d, J=4.22 Hz, 2 H) 7.10 (t, J=9.26 Hz, 1 H) 7.21 - 7.41 (m, 5 H) 7.43 - 7.54 (m, 2 H) 7.59 (br d, J=7.00 Hz, 1 H) 7.97 (d, J=6.88 Hz, 1 H) 9.99 (s, 1 H). Method 4; Rt = 2.04 min. m / z = 563 (M+H) + .

[0324] The enantiomeric ratio (ee > 99%) of the title compound was determined by chiral HPLC (HPCL conditions: DIACEL CHIRALPACK IG COLUMN; eluent: Phase A: H2O ultrapure grade 0.05% TFA, MeCN ultrapure grade 0.05% TFA; flow rate, 1.0 ml / min, UV, 270 nM); retention time of (S,S), 30 min; and retention time of (R,R), 45 min.

[0325] Step 10: In a sealed vial, cesium carbonate (604.58 mg, 1.84 mmol) was added to a solution of the compound obtained from Step 9 (415 mg, 0.740 mmol) in anhydrous DMF (2 ml). The resulting mixture was heated to 135 °C and stirred for 4 hours. Water (10 mL) and toluene (40 mL) were added, and the mixture was vigorously stirred for 5 minutes. The organic phase was collected, washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated. The resulting crude benzyl (3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-2(3H)-carboxylate 5,5-dioxide (397 mg, a crispy off-white solid) was used without further purification. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H) 2.87 - 3.22 (m, 2 H) 3.37 - 3.57 (m, 2 H) 3.66 - 3.86 (m, 4 H) 3.86 - 4.02 (m, 1 H) 4.36 - 4.52 (m, 1 H) 4.52 - 4.66 (m, 1 H) 4.98 - 5.20 (m, 2 H) 7.11 (t, J=9.45 Hz, 1 H) 7.29 - 7.42 (m, 5 H) 7.43 - 7.54 (m, 2 H) 7.54 - 7.66 (m, 1 H) 8.41 (br s, 1 H) 9.33 (s, 1 H). Method 4; Rt = 2.22 min. m / z = 543.24 (M+H) + .

[0326] Step 11: A solution of the compound obtained from Step 10 (960 mg, 1.77 mmol) was dissolved in anhydrous MeCN (12 mL, 0.230 mol). Trimethylsilyl iodide (0.53 mL, 3.72 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The mixture was then treated at 0 °C by the addition of methanol (1.2 mL), stirred at the same temperature for 10 minutes, and then evaporated under reduced pressure. The residue was taken up using a 5:1 mixture of Et2O / DCM (17 mL), then filtered and the solid was washed several times with Et2O to give crude D30 (833 mg, y = 87.8%) as a pale yellow solid, which was used in the next step without further purification. Method 4; Rt = 1.35 minutes. m / z = 409.24, 25 (M+H) + .

[0327] Described D31: (3aR,10aR)-8-((3-chloro-4-fluorophenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D31)

[0328] [Chemical Structure]

[0329] Starting from D22, it was prepared in the same manner as described for compound D28 to obtain D31. Method 1: Rt = 1.44 minutes; m / z = 429.30, 431.39 (M+H) + .

[0330] Procedure 2 The compound was prepared according to the following scheme:

[0331] [Chemical Structure]

[0332] Step 1: Starting from 2,2-dimethoxyethan-1-amine (094452, Fluorochem, CAS: 22483-09-6), (±)-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate was prepared according to the procedure reported in J. Med. Chem. 2007, 50, 5493-5508. 1 H NMR (300 MHz, DMSO-d6+ TFA) δ ppm 2.55 - 2.68 (m, 1 H) 3.27 - 3.38 (m, 1 H) 3.43 - 3.67 (m, 5 H) 3.84 (br s, 1 H) 5.04 - 5.13 (m, 2 H) 7.29 - 7.41 (m, 5 H) 7.90 - 8.02 (br s, 2 H). Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) + .

[0333] The compound (11.52 g, 46.02 mmol) in acetone (16 mL) was treated with 2-methoxypropene (8.81 mL, 92.02 mmol) (174645, Sigma Aldrich, CAS: 116-11-0). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure to remove volatile substances. The crude product (13.38 g, 46.08.05 mmol) was taken up in anhydrous acetone (115 mL) and treated with (S)-2-hydroxy-2-phenylacetic acid (7.011 g, 46.08 mmol) (046847, Fluorochem, CAS: 17199-29-0). The mixture was cooled to -5 °C and stirred for 12 h. The resulting white precipitate was filtered, washed three times with 60 mL of anhydrous acetone, and cooled at -5 °C to obtain benzyl (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylate [(S)-mandelate] as a white solid (6.2 g, y = 30%).

[0334] Step 2: Benzyl (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylate [(S)-mandelate] (500 mg, 1.13 mmol) was dissolved in 1 mL of anhydrous ethanol and H2SO4 (5% solution, 0.5 mL). The mixture was stirred at room temperature for 3 h. The resulting mixture was treated with 2 M NaOH (1 mL) solution and ethanol was removed under reduced pressure. The aqueous residue was extracted with AcOEt (3 × 20 mL). Benzyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (245 mg, y = 87%) was used in the next step without further purification. Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) +

[0335] Step 3: To a suspension of benzyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.83 g, 11.3 mmol) and DIPEA (4 mL, 22.96 mmol) in MeCN (40 mL) was added ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (3.05 g, 11.3 mmol) portionwise. The yellow solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, then diluted with EtOAc (100 mL) and washed with 5% aqueous citric acid (×2) and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material obtained was purified by flash chromatography on silica gel (eluent gradient from DCM / AcOEt: 5:5 to 100% EtoAc) to give ethyl 4-(N-((3R,4R)-1-((benzyloxy)carbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (4.05 g, y = 74%) as an off-white foamy solid. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.27 (q, J = 6.60 Hz, 3 H) 2.31 - 2.43 (m, 1 H) 3.12 - 3.27 (m, 1 H) 3.27 - 3.48 (m, 4 H) 3.49 - 3.60 (m, 1 H) 3.67 - 3.94 (m, 4 H) 4.13 - 4.38 (m, 2 H) 4.92 - 5.16 (m, 2 H) 7.28 - 7.44 (m, 5 H) 7.56 (d, J = 4.58 Hz, 1 H) 7.99 (br d, J = 7.90 Hz, 1 H). Method 1; Rt = 1.80 min. m / z = 484.4 (M+H) + .

[0336] Step 4: To a solution of ethyl 4-(N-((3R,4R)-1-((benzyloxy)carbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (110. mg, 0.230 mmol) and 3-chloro-4-fluoroaniline (0.03 mL, 0.250 mmol) in anhydrous THF (1.8 mL) was added 1N lithium bis(trimethylsilyl)amide in toluene (1.15 mL, 1.15 mmol) at room temperature for 1 hour. Complete conversion was shown by UPLC-MS analysis. The reaction mixture was diluted with toluene, cooled to 0 °C, quenched with 2M aqueous HCl, and then stirred at room temperature for 10 minutes. The two phases were separated, and the organic phase was washed with 2M aqueous HCl and saturated NaHCO3, then dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting crude material was used in the next step without further purification. Method 1; Rt = 2.11 min. m / z = 583.29 (M+H) + 。

[0337] Step 5: A solution of the crude benzyl (3R,4R)-3-((5-((3-chloro-4-fluorophenyl)carbamoyl)-4-fluoro-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (142.92 mg, 0.250 mmol) obtained from Step 4 in anhydrous DMF (4 mL) was added with cesium carbonate (199.68 mg, 0.610 mmol). The vial was sealed, the mixture was heated to 135 °C and stirred at the same temperature for 4 h. EtOAc and water were added, the organic phase was washed again with water (×2), dried over Na2SO4, filtered and evaporated. The obtained crude substance was purified by flash chromatography on silica gel (gradient from 100% DCM to DCM / EtOAc 70 / 30) to obtain the desired compound. Method 1; Rt = 2.30 min. m / z = 563.30 (M+H) + .

[0338] Step 6: The benzyl (3aR,10aR)-8-((3-chloro-4-fluorophenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (100 mg, 0.180 mmol) obtained from Step 5 was dissolved in anhydrous MeCN (2.5 mL, 0.048 mol). Trimethylsilyl iodide (80 mL, 0.370 mmo) was added and the mixture was stirred at room temperature for 30 min. The mixture was quenched at 0 °C by the addition of methanol (1 mL), stirred at the same temperature for 10 min and then evaporated under reduced pressure. The obtained crude D31 was used in the next step without further purification. Method 1: Rt = 1.44 min; m / z = 429.30 (M+H) + .

[0339] Description D32: (3aR,10aR)-7-Methyl-8-((3,4,5-trifluorophenyl)carbamoyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D32)

[0340] [Chemical Structure]

[0341] Starting from D23, D32 was obtained in the same manner as described for compound D28. Method 1: Rt = 1.46 min; m / z = 431.39 (M+H) + + .<0(002026>

[0342] Description D33: (3aR,10aR)-8-((3-cyano-4-fluorophenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D33)

[0343] [Chemical Structure]

[0344] Starting from D24, D33 was obtained in the same manner as described for compound D28. Method 1: Rt = 1.31 min; m / z = 420.38 (M+H) + + .

[0345] Description D34: cis-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide hydroiodide (D34)

[0346] [Chemical Structure]

[0347] Starting from D26, it was prepared in the same manner as described for compound D28 to obtain D34. 1 H NMR (300 MHz, DMSO-d6 + TFA ) δ ppm 1.29 (s, 3 H), 2.23 (s, 3 H), 2.97 - 3.27 (m, 3 H), 3.81 (s, 3 H), 3.99 (s, 2 H), 4.17 - 4.28 (m, 1 H), 4.34 (d, J = 11.65 Hz, 1 H), 7.12 (t, J = 9.22 Hz, 1 H), 7.40 - 7.48 (m, 1 H), 7.49 (s, 1 H), 7.53 - 7.65 (m, 1 H), 8.42 (d, J = 9.72 Hz, 1 H), 9.15 (br s, 2 H), 9.37 (s, 1 H). Method 1: Rt = 1.41 min; m / z = 422.14 (M+H) + .

[0348] Described D35: cis-N-(4-Fluoro-3-methylphenyl)-3a,7-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide hydrochloride (D35)

[0349]

Chemical Structure

[0350] D27 (0.062 mg, 0.11 mmol) was dissolved in MeOH (15 mL), and hydrogenation was carried out at 25 °C using an H-CUBE apparatus (registered trademark of ThalesNano) equipped with a 10% Pd / C mini-cartridge (THS01111, ThalesNano) at a H2 pressure of 10 bar and a flow rate of 0.8 mL / min. The cartridge was thoroughly washed with MeOH and 0.5 N HCl in MeOH. The solvent was removed by evaporation, and the residue was treated with 3 N HCl (3 mL) in MeOH. After evaporation, D35 (0.052 g, 0.113 mmol, quantitative yield). Method 1; Rt: 1.27 min; m / z: 423.22 (M+H) + 。

[0351] Described D36: Methyl 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-yl)-2-oxoacetate (D36)

[0352]

Chem.

[0353] To a solution of D30 (500 mg, 0.930 mmol) in anhydrous MeCN (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.229 mL, 1.28 mmol). The solution was cooled to 0 °C, and methyl 2-chloro-2-oxoacetate (0.930 mmol, 0.344 mL) (151440, Sigma Aldrich, CAS: 5781-53-3), which had been previously dissolved in anhydrous MeCN (1 mL), was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes and then quenched by the addition of 5% citric acid (1 mL) and diluted with DCM and water. The organic phase was further washed with 1N HCl and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The crude material was stripped using DCM and finally petroleum ether to give D36 (390 mg, y = 85%) as a yellow solid, which was used in the next step without purification. 1 H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.98 - 3.12 (m, 1H), 3.13 - 4.12 (m, 11H), 4.44 - 4.68 (m, 2H), 7.11 (t, J = 9.08 Hz, 1H), 7.44 - 7.54 (m, 2H), 7.55 - 7.63 (m, 1H), 8.47 (br d, J = 9.72 Hz, 1H), 9.35 (s, 1H). Method 1: Rt = 1.85 min, m / z = 495 (M+H) + .

[0354] Described D37: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-yl)-2-oxoacetic acid (D37)

[0355]

Chem.

[0356] A solution of D36 (337 mg, 0.680 mmol) in anhydrous THF (1 mL, 0.012 mol) was added dropwise at room temperature to a previously prepared solution of sodium hydroxide (81.78 mg, 2.04 mmol) in water (1 mL, 0.056 mol). After 5 minutes, the reaction was monitored by UPLC / MS and complete conversion was observed. The solution was cooled to 0 °C and quenched by adding 4 M HCl, forming a white precipitate. The reaction mixture was diluted with AcOEt and the two phases were separated. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give D37 (320 mg, yield = 97.7%) as a white solid, which was used in the next synthetic step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.96 - 3.10 (m, 1H), 3.11 - 4.11 (m, 8H), 4.43 - 4.69 (m, 2H), 7.11 (t, J = 9.22 Hz, 1H), 7.43 - 7.53 (m, 2H), 7.54 - 7.63 (m, 1H), 8.48 (dd, J = 9.81, 1.65 Hz, 1H), 9.35 (s, 1H), 14.06 (br s, 1H). Method 1: Rt = 1.61 min, m / z = 481.24 (M+H) + .

[0357] Described D38: Methyl 2 - ((3 - methyloxetan - 3 - yl)amino)-2 - oxoacetate (D38)

[0358]

Chemical Structure

[0359] To a solution of 3-methyl-3-oxetanamine (206 mg, 2.36 mmol) (318252, Fluorochem, CAS: 874473-14-0) and N-ethyl-N-isopropylpropan-2-amine (0.41 mL, 2.36 mmol) in DCM (2 mL, 0.031 mol) was added methyl 2-chloro-2-oxoacetate (0.22 mL, 2.36 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 30 minutes and then quenched with ice. The organic phase was separated using a phase separator and then washed with 1N HCl (2 mL) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated to give D38 (278 mg, 1.61 mmol) as a pale yellow solid, which was used as such in the next synthetic step. Method 2: Rt = 1.21 min, m / z = 174.14 (M+H) + .

[0360] Described D39: Sodium 2-((3-methyloxetan-3-yl)amino)-2-oxoacetate (D39)

[0361] [Chemical formula]

[0362] To a solution of D38 (507 mg, 2.93 mmol) in THF (2 mL, 0.025 mol) was added sodium hydroxide (117.11 mg, 2.93 mmol) dissolved in water (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and a white precipitate formed. The reaction mixture was diluted with diethyl ether, the precipitate was filtered off, and washed with diethyl ether. The product was dried under a vacuum pump for 1 hour to give D39 as a white powder. The presence of the title product was indicated by UPLC / MS analysis of the mother liquor. The mother liquor was evaporated, treated with diethyl ether, and filtered to give a second batch of crude product D39 (300 mg, 1.66 mmol, yield = 56.6%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.41 - 1.55 (m, 3 H), 4.26 (d, J=6.51 Hz, 2 H), 4.63 (d, J=6.24 Hz, 2 H), 8.65 (br s, 1 H). Method 14: Rt = 0.87 min; m / z=160.06 (M+H) + .

[0363] Description D40: Methyl (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D40)

[0364]

Chem.

[0365] To a solution of (2R)-1,1,1-trifluoro-2-propanamine hydrochloride (1:1) (500 mg, 3.34 mmol) (U23940, Aurum Pharmaceuticals, CAS: 177469-12-4) and N-ethyl-N-isopropylpropan-2-amine (1.16 mL, 6.69 mmol) in anhydrous DCM (3 mL, 0.047 mol), methyl 2-chloro-2-oxoacetate (0.31 mL, 3.34 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes and then quenched with ice and water. The organic phase was washed with 1N HCl (3 × 20 mL) and brine. The organic phase was dried over Na2SO4 (anhydrous), then filtered and concentrated to give D40 (567 mg, yield = 85%) as a colorless solid, which was used as such in the next synthetic step. Method 1: Rt = 1.12 min, m / z=200.15 (M+H) + 。

[0366] Description D41: Sodium (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D41)

[0367]

Chem.

[0368] A solution of D40 (567 mg, 2.85 mmol) in THF (2 mL, 0.025 mol) was added with a solution of sodium hydroxide (113.89 mg, 2.85 mmol) in water (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, diluted with toluene (30 mL), and evaporated under reduced pressure to obtain a white powder. The product was further dried under a vacuum pump overnight to obtain D41 (562 mg, yield = 95%) as a white powder. Method 13: Rt = 1.25 min, m / z = 130.08 (M+H) + 。

[0369] Described D42: Methyl 2-(cyclopropylamino)-2-oxoacetate (D42)

[0370]

Chem.

[0371] To a solution of cyclopropylamine (1.46 mL, 21 mmol) in DCM (15 mL, 0.18 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.05 mL, 17.5 mmol), methyl 2-chloro-2-oxoacetate (1.61 mL, 17.5 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with ice. The organic phase was washed with 1N HCl (2 mL) and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain methyl 2-(cyclopropylamino)-2-oxoacetate as a pale yellow solid. The presence of the title product was indicated by UPLC / MS analysis of the aqueous phase. To recover the product from the aqueous phase, it was concentrated to dryness, extracted with ethyl acetate to obtain a second batch of methyl 2-(cyclopropylamino)-2-oxoacetate. The two batches were combined to obtain D42 (1.869 g, yield = 73%). 11H NMR (300 MHz, DMSO-d6) δ 0.56 - 0.69 (m, 3H), 2.74 (br d, J = 3.94 Hz, 1H), 3.76 (s, 3H), 8.95 (br s, 1H). Method 1: Rt = 0.66 min, m / z = 143.96 (M + H) + .

[0372] Description D43: Sodium 2-(cyclopropylamino)-2-oxoacetate (D43)

[0373]

Chem.

[0374] A solution of sodium hydroxide (337.55 mg, 8.44 mmol) in water (2 mL) was added to a solution of D42 (1.21 g, 8.44 mmol) in THF (4 mL, 0.049 mol) at room temperature. The reaction mixture was stirred at the same temperature overnight and then concentrated under reduced pressure. The solid residue was taken up, sonicated, and triturated with toluene. The product was dried under a vacuum pump for 1 hour to give D43 (984 mg, 6.51 mmol) as a white powder. Method 13: Rt = 0.78 min; m / z = 130.11 (M + H) + 。

[0375] Description D44: cis-Methyl 2-(8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-yl)-2-oxoacetate (D44)

[0376]

Chem.

[0377] Starting from D29, it was prepared in the same manner as described for compound D36. 11H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.97 - 3.25 (m, 2H), 3.26 - 4.09 (m, 10H), 4.44 - 4.68 (m, 2H), 7.06 - 7.16 (m, 1H), 7.47 (br s, 2H), 7.58 (br s, 1H), 8.47 (br d, J = 9.72 Hz, 1H), 9.35 (s, 1H). Method 3: Rt = 1.85 min. m / z = 495.22 (M + H) + .

[0378] Description D45: cis-methyl 2-(7-methyl-5,5-dioxide-8-((3,4,5-trifluorophenyl)carbamoyl)-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-yl)-2-oxoacetate (D45) The compound was prepared according to the following scheme:

[0379]

Chem.

[0380] Steps 1 - 4: cis-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide hydroiodide was prepared as shown in Steps 1 and 4 of the procedure for the synthesis of D29, but using 3,4,5-trifluoroaniline instead of 4-fluoro-3-methylaniline. Method 3: Rt = 1.50 min. m / z = 431.39 (M + H) + .

[0381] Step 5 The crude compound (237 mg, 0.420 mmol) synthesized according to Steps 1 to 4 was dissolved in 11 ml of anhydrous MeCN, and N-ethyl-N-isopropylpropan-2-amine (0.227 mL, 1.28 mmol) was added. The solution was cooled to 0 °C, and methyl 2-chloro-2-oxoacetate (0.039 mL) dissolved in 2 ml of anhydrous MeCN was added dropwise. The reaction mixture was stirred at 0 °C for 20 minutes and then quenched by adding 5 ml of 5% citric acid and diluted with water (5 mL) and EtOAc (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid, which was used without any further purification. Method 3: Rt = 1.95 min. m / z = 517.10 (M+H) + 。

[0382] Description D46: trans-N-(4-Fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide hydrochloride (D46) The compound was prepared according to the following scheme:

[0383]

Chemical formula

[0384] Step 1: A solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate (12.5 g, 79.6 mmol) in anhydrous DMF (125 mL) cooled to 0 °C under a nitrogen atmosphere was added sodium hydride (60 wt% in mineral oil, 3.7 g, 92.5 mmol) portionwise over 30 minutes. The reaction mixture was stirred for an additional 20 minutes, then iodomethane (5.8 mL, 93.2 mmol) was added dropwise over 30 minutes. The mixture was stirred at the same temperature for an additional 30 minutes, then quenched with 2N HCl (20 mL). The reaction mixture was poured into water (120 mL) and toluene (650 mL), and the mixture was stirred vigorously for 10 minutes. The two phases were separated, and the organic phase was washed with water (250 mL) and brine (250 mL), dried over Na2SO4 (anhydrous), and filtered. After evaporation of the solvent, ethyl 3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (13.6 g) was obtained as a pale yellow oil and used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.11 Hz, 3 H), 3.78 (s, 3 H), 4.23 (q, J=7.06 Hz, 2 H), 5.99 (d, J=3.03 Hz, 1 H), 7.00 (dd, J=5.27, 3.07 Hz, 1 H).

[0385] Step 2: Ethyl 3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (13.6 g, 79.5 mmol) and 4-fluoro-3-methylaniline (10.3 g, 82.3 mmol) prepared in Step 1 were dissolved in anhydrous toluene (50 mL). LiHMDS (140 mL, 1 M in toluene, 140 mmol) was added dropwise over 30 minutes, and the reaction mixture was stirred at room temperature for an additional 30 minutes. The reaction mixture was cooled to 0 °C and quenched slowly with 2N HCl (200 mL), diluted with water (200 mL) and toluene (200 mL), and stirred at room temperature for 20 minutes. The two phases were separated, and the organic phase was washed with saturated NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4 (anhydrous), and filtered. After evaporation of the solvent, 3-fluoro-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide (19.8 g) was obtained as a light brown solid and used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H), 3.76 (s, 3 H), 6.01 (d, J=3.03 Hz, 1 H), 6.91 (dd, J=5.27, 3.07 Hz, 1 H), 7.08 (t, J=9.22 Hz, 1 H), 7.35 - 7.53 (m, 1 H), 7.59 (dd, J=7.06, 2.20 Hz, 1 H), 9.50 (br s, 1 H).

[0386] Step 3: A solution of 3-fluoro-N-(4-fluoro-3-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide (19.8 g, 79.5 mmol), prepared in Step 2, in anhydrous DCM (90 mL) cooled to 0 °C under a nitrogen atmosphere was added dropwise with chlorosulfonic acid (5.7 mL, 85.6 mmol) dissolved in anhydrous DCM (120 mL) over 90 minutes. The reaction mixture was stirred at the same temperature for an additional 30 minutes, then the precipitate formed was filtered and washed several times with Et2O. 4-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (23.1 g, 88% yield over 3 steps), obtained as a pale grey solid, was dried under vacuum overnight and used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H), 3.70 (s, 3 H), 6.93 (d, J=5.04 Hz, 1 H), 7.07 (t, J=9.22 Hz, 1 H), 7.44 - 7.52 (m, 1 H), 7.60 (dd, J=7.06, 2.20 Hz, 1 H), 9.64 (s, 1 H).

[0387] Step 4: Anhydrous DMF (0.35 mL, 4.51 mmol) was added to a suspension of 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (14.9 g, 45.1 mmol) prepared in Step 3 in thionyl chloride (112 mL). The reaction mixture was heated to 75 °C and stirred at the same temperature for 45 minutes. The brown solution was cooled to room temperature, diluted with toluene (200 mL), and slowly poured into a mixture of toluene (200 mL) and ice (500 mL) with vigorous stirring. The two-phase system was stirred for 20 minutes, the two phases were separated, the organic phase was washed with ice-water (200 mL) and brine (200 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated under reduced pressure. The residue was purified by silica (eluent petroleum ether / AcOEt gradient) to give 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (13.9 g, 88% yield) as an off-white powder. 1 H NMR (300 MHz, CDCl3) δ ppm 2.31 (s, 3 H), 4.06 (s, 3 H), 7.03 (t, J = 8.89 Hz, 1 H), 7.26 - 7.36 (m, 2 H), 7.39 - 7.46 (m, 1 H), 7.72 (br d, J = 8.16 Hz, 1 H).

[0388] Step 5: To a solution of trans-1-tert-butyl-3-ethyl-4-aminopyrrolidine-1,3-dicarboxylate (200 mg, 0.77 mmol) (Fluorochem, 317896, CAS: 362489-56-3) in MeCN (1 mL) was added DIPEA (0.27 mL, 1.55 mmol), followed by 4-fluoro-5-((4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (270 mg, 0.77 mmol) prepared in Step 4. The reaction was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 5% citric acid. The organic layer was dried over Na2SO4 (anhydrous), filtered and evaporated to give trans-1-(tert-butyl) 3-ethyl 4-((4-fluoro-5-((4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)pyrrolidine-1,3-dicarboxylate (450 mg, 0.789 mmol) as a white solid and used without any further purification in the next step. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.05 - 1.23 (m, 3 H), 1.38 (br s, 9 H), 2.18 - 2.27 (m, 3 H), 2.92 - 3.18 (m, 2 H), 3.19 - 3.42 (m, 1 H), 3.43 - 3.65 (m, 2 H), 3.80 (s, 3 H), 3.88 - 4.11 (m, 3 H), 7.11 (t, J=9.17 Hz, 1 H), 7.42 - 7.54 (m, 2 H), 7.54 - 7.66 (m, 1 H), 8.26 (br d, J=7.24 Hz, 1 H), 10.02 (s, 1 H). Method 1; Rt: 2.26 min; m / z: 571.13 (M+H) + .

[0389] Step 6: The intermediate obtained from Step 5 (370 mg, 0.7 mmol) was dissolved in THF (5 mL) and treated with 1 M LiAlH4 in THF (946 μL, 0.946 mmol), added in portions of approximately 200 μL over 5 minutes. After 15 minutes, the reaction was quenched by slowly adding water (2 mL) and stirred for 10 minutes. A saturated solution of Rochelle salt (sodium potassium tartrate tetrahydrate) (10 mL) was then added, followed by EtOAc (20 mL), and the reaction mixture was stirred for an additional 20 minutes. The resulting mixture was poured into a separatory funnel and the aqueous layer was extracted once with EtOAc. The combined organic extracts were dried over Na2SO4 (anhydrous), filtered, and finally evaporated in vacuo to give trans-tert-butyl 3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (370 mg, 0.7 mmol) as a white solid. Method 1; Rt: 2.26 min; m / z: 529.19 (M+H) + .

[0390] Step 7: The intermediate obtained in Step 6 (0.13 g, 0.25 mmol) was dissolved in DMF (2.46 mL), treated once with cesium carbonate (0.24 g, 0.74 mmol), and heated at 130 °C for 2 hours by microwave irradiation. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and finally evaporated. The residue was purified by flash chromatography (eluent DCM / EtOAc) and triturated in DEE / DCM to give trans-tert-butyl 8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2(3H)-carboxylate 5,5-dioxide (55 mg, 0.106 mmol) as a white solid. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H), 2.23 (s, 3 H), 2.55 - 2.66 (m, 1 H), 2.81 - 2.93 (m, 1 H), 2.94 - 3.10 (m, 1 H), 3.35 - 3.48 (m, 1 H), 3.73 - 3.90 (m, 4 H), 3.93 - 4.14 (m, 2 H), 4.22 (br dd, J=11.14, 4.45 Hz, 1 H), 6.88 - 6.89 (m, 1 H), 7.11 (t, J=9.26 Hz, 1 H), 7.42 - 7.55 (m, 2 H), 7.56 - 7.70 (m, 2 H), 9.51 (br s, 1 H). Method 3: Rt = 3.74 min; m / z = 509.28.

[0391] Step 8: A solution of the intermediate (44 mg, 0.08 mmol) prepared in Step 7 in DCM (1 mL) was treated with 3M HCl in MeOH (0.45 mL, 1.35 mmol) all at once, and the resulting yellow solution was stirred at room temperature for 2 hours. The solvent was then removed to afford D46 (37 mg, 0.083 mmol) in quantitative yield. 1 1H NMR (300 MHz, DMSO-d6 + TFA ) δ ppm 2.23 (d, J=1.01 Hz, 3 H) 2.57 - 2.70 (m, 1 H) 2.79 - 3.03 (m, 2 H) 3.19 - 3.32 (m, 1 H) 3.55 - 3.77 (m, 1 H) 3.82 (s, 3 H) 4.07 (br d, J=9.17 Hz, 2 H) 4.12 - 4.33 (m, 1 H) 7.11 (t, J=9.22 Hz, 1 H) 7.43 - 7.57 (m, 3 H) 7.62 (dd, J=7.06, 2.20 Hz, 1 H) 8.85 - 9.11 (m, 2 H) 9.68 (s, 1 H) Method 1; Rt: 1.32 min. m / z: 409.24 (M+H)+

[0392] Description D47: Methyl 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-2(3H)-yl)-2-oxoacetate (D47)

[0393] [Chemical formula]

[0394] To a solution of D28 (230 mg, 0.42 mmol) in MeCN (5 mL) was added DIPEA (0.15 mL, 0.83 mmol). The solution was cooled to 0 °C and methyl 2-chloro-2-oxoacetate (0.04 mL, 0.42 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30 minutes, then quenched by the addition of 5% citric acid solution and diluted with DCM. The organic phase was washed twice more with 5% citric acid solution, then dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude D47 (197 mg), which was used in the next step without further purification. Method 1; Rt = 1.87 minutes. m / z = 511.23 (M+H) + .

[0395] Description D48: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-2(3H)-yl)-2-oxoacetic acid (D48)

[0396] [Chemical formula]

[0397] A solution of D47 (158 mg, 0.31 mmol) in THF (3 mL) was added to 1N NaOH solution (0.77 mL, 0.77 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, acidified to pH = 3 using 1N HCl solution, and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain crude D48 (160 mg), which was used in the next step without further purification. Method 1; Rt = 1.67 min. m / z = 497.18 (M+H) + .

[0398] Described D49: Ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D49)

[0399] [Chemical formula]

[0400] To a solution of 3,3-difluoroazetidine hydrochloride (100.2 mg, 0.77 mmol) and DIPEA (0.26 mL, 1.49 mmol) in DCM (4 mL), ethoxycarbonyl chloride (0.08 mL, 0.70 mmol) was added at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 hour, then quenched with ice and water and diluted with DCM. The organic phase was washed twice with 1N HCl solution. The organic phase was dried over Na2SO4, then filtered and concentrated to obtain D49 (113 mg) as a pale orange solid, which was used as such in the next synthetic step. Method 2; Rt = 2.40. m / z = 194.12 (M+H) + .

[0401] Described D50: Ethyl (S)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D50)

[0402] [Chemical formula]

[0403] (2S)-1,1,1-Trifluoro-2-propanamine hydrochloride was used instead of 3,3-difluoroazetidine hydrochloride and prepared in the same manner as described for compound D49 to obtain D50 ethyl (S)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate as a colorless oil. Method 2; Rt = 2.84 min. m / z = 214.34 (M+H) + 。

[0404] Described D51: (3aR,10aR)-8-((3,4-difluorophenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D51)

[0405]

Chem.

[0406] 3,4-Difluoroaniline was used instead of 3-chloro-4-fluoroaniline and prepared in the same manner as described for compound D31 (procedure 2) to obtain D51 as a dark yellow solid, which was used in the next step without further purification. Method 1; Rt = 1.34 min. m / z = 413.36 (M+H) + 。

[0407] Described D52: (3aR,10aR)-8-((3-(difluoromethyl)-4-fluorophenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D52)

[0408]

Chem.

[0409] Using 3-(difluoromethyl)-4-fluoroaniline instead of 3-chloro-4-fluoroaniline, it was prepared in the same manner as described for compound D31 (procedure 2) to obtain D52 as a solid, which was used in the next step without further purification. Method 1; Rt = 1.31 min. m / z = 445.37 (M+H) + 。

[0410] Description of D53: (3aR,10aR)-8-((4-Fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-2-ium 5,5-dioxide iodide (D53)

[0411]

Chemical formula

[0412] Using 4-fluoro-3-(trifluoromethyl)aniline instead of 3-chloro-4-fluoroaniline, it was prepared in the same manner as described for compound D31 (procedure 2) to obtain D53 as a solid, which was used in the next step without further purification. Method 1; Rt = 1.51 min. m / z = 463.41 (M+H) + 。

[0413] Description of D54: Ethyl 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-6,7-dimethyl-5,5-dioxide-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazin-2(3H)-yl)-2-oxoacetate (D54)

[0414]

Chemical formula

[0415] Step 1: To a suspension of D30 (509 mg, 0.950 mmol) and triethylamine (0.32 mL, 2.28 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (270 mg, 1.24 mmol) dissolved in 5 mL of DCM. The pale yellow solution was stirred at room temperature for 12 h (a white precipitate formed). The reaction mixture was diluted with DCM (30 mL) and washed with 0.5 M HCl (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give tert-butyl (3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-2(3H)-carboxylate 5,5-dioxide as a white foamy substance and used without further purification. Method 1; Rt = 2.19 min. m / z = 509 (M+H) + .

[0416] Step 2: To a solution of the intermediate obtained from Step 1 (450 mg, 0.880 mmol) in a mixture of DCM / MeCN 8:1 (18 mL) was added N-bromosuccinimide (189.0 mg, 1.06 mmol). The orange solution was stirred at room temperature for 4 h until it turned pale yellow, then diluted with DCM (20 mL) and saturated solution of NaHCO3 (30 mL) and stirred at room temperature for 30 min. The two phases were separated, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude obtained was purified by flash chromatography on silica with a gradient of eluent from DCM / EtOAc 9:1 to 8:2. The pure fractions were combined and concentrated to give tert-butyl (3aR,10aR)-6-bromo-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-2(3H)-carboxylate 5,5-dioxide as a white foamy substance. Method 1; Rt = 2.28 min. m / z = 587.4 (M+H) + . 11H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9 H) 2.21 - 2.28 (m, 3 H) 2.72 - 2.99 (m, 1 H) 3.06 (q, J=9.17 Hz, 1 H) 3.34 - 3.41 (m, 2 H) 3.54 - 3.77 (m, 1 H) 3.80 (s, 3 H) 3.99 (br t, J=10.73 Hz, 1 H) 4.27 - 4.43 (m, 2 H) 0.00 (t, J=8.99 Hz, 1 H) 7.44 - 7.54 (m, 1 H) 7.54 - 7.66 (m, 1 H) 8.55 (br s, 1 H) 9.62 (br s, 1 H).

[0417] Step 3: The intermediate obtained from Step 2 (100 mg, 0.170 mmol), palladium-tetrakis(triphenylphosphine) (29.5 mg, 0.030 mmol) and cesium carbonate (195.3 mg, 0.600 mmol) were weighed and placed in a vial, which was sealed under a nitrogen atmosphere for 5 minutes. Then, dioxane (3 mL), water (0.3 mL) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.1 mL, 0.680 mmol) were added, and the mixture was stirred at 130 °C for 3 hours. The reaction mixture was diluted with toluene (30 ml) and saturated solution of NaHCO3 (20 ml) and stirred for 30 minutes. The two phases were separated, the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using an eluent starting from DCM / EtOAc 9:1 to 6:4. The pure fractions were combined and concentrated to give tert-butyl (3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-6,7-dimethyl-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-2(3H)-carboxylate 5,5-dioxide as a colorless oil. Method 1; Rt = 2.22 min. m / z = 523.31 (M+H) + .

[0418] Step 4: To a solution of the intermediate (63.35 mg, 0.120 mmol) obtained from Step 3 in DCM (3 mL), 3N HCl in MeOH (0.8 mL, 2.42 mmol) was slowly added at room temperature. The pale yellow solution was stirred at room temperature for 3 hours until 4% of SM was detected, and then the solution was concentrated under reduced pressure to obtain D54 as a pale yellow solid. Method 1; Rt = 1.38 min. m / z = 423 (M+H) + 。

[0419] Described D55: Sodium 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D55)

[0420]

Chemical formula

[0421] Prepared in the same manner as described for compound D43 starting from D49. Method 6; Rt = 0.92 min.

[0422] Described D56: Sodium (S)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D56)

[0423]

Chemical formula

[0424] Prepared in the same manner as described for compound D43 starting from D50. Method 6; Rt = 1.34 min.

[0425] Described D57: Ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D57)

[0426]

Chemical formula

[0427] Using 2,2,2-trifluoroethylamine hydrochloride instead of cyclopropanamine, it was prepared in the same manner as described for compound D42 to obtain ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate D57 as a white solid, which was used as such in the next synthetic step. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (t, J = 7.11 Hz, 3 H) 3.83 - 4.08 (m, 2 H) 4.27 (q, J = 7.12 Hz, 2 H) 9.35 - 9.70 (m, 1 H). Method 6; Rt = 2.32 min. m / z = 200.2 (M+H) + .

[0428] Description D58: Sodium 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D58)

[0429]

Chemical formula

[0430] Starting from D57, it was prepared in the same manner as described for compound D43. Method 6; Rt = 1.22 min. m / z = 172.1 (M+H) + 。

[0431] Description D59: Ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D59)

[0432]

Chemical formula

[0433] Using 2,2,2-trifluoro-1,1-dimethylethylamine hydrochloride instead of cyclopropanamine, it was prepared in the same manner as described for compound D42 to obtain ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate D59 as a colorless oil, which was used as such in the next synthetic step. Method 6; Rt = 3.54 min. m / z = 228.13 (M+H) + 。

[0434] Description D60: Sodium 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D60)

[0435]

Chemical formula

[0436] Starting from D59, it was prepared in the same manner as described for compound D43. Method 6; Rt = 1.07 min. m / z = 200.15 (M+H) + 。

[0437] Description D61: tert-Butyl (3R,4R)-1-benzyl-4-(benzyl((S)-1-phenylethyl)amino)-3-methylpyrrolidine-3-carboxylate (D61)

[0438]

Chemical formula

[0439] A two-neck round-bottom flask (100 mL) equipped with a magnetic stirrer and a thermometer was evacuated with nitrogen and filled with (S)-(-)-N-benzyl-1-phenylethylamine (0.64 mL, 3.07 mmol). THF (25 mL, 0.308 mol) was added at room temperature under a nitrogen atmosphere, and the resulting solution was stirred at room temperature for 5 minutes. The yellow solution was cooled to -78 °C using a dry ice / acetone bath. While maintaining the temperature below -70 °C, n-butyllithium (1.9 mL, 3.04 mmol) was added over 30 minutes. The purple solution was stirred at -78 °C for 1 hour and 15 minutes. While maintaining the internal temperature below -73 °C, a pre-formed solution of tert-butyl 1-(phenylmethyl)-2,5-dihydropyrrole-3-carboxylate (Org. Biom. Chem., 2004, 2, 2763 - 2776) (500 mg, 1.93 mmol) in THF (5 mL, 0.062 mol) was added over 2 hours. The resulting orange solution was stirred at this temperature for 3 hours. A solution of iodomethane (187.24 μL, 3.01 mmol) in THF (1 mL) was added over 15 minutes, and the internal temperature was below -70 °C. After 10 minutes, the cooling bath was removed, and the reaction mixture was warmed to -30 °C in about 20 minutes, then quenched with NH4Cl (saturated solution), dried over anhydrous Na2SO4, filtered, and evaporated to obtain a crude residue (about 500 mg). Purification by silica gel chromatography (EtOAc / petroleum ether) gave D61 (500 mg, 1.0316 mmol). Method 15; Rt = 6.58 minutes. m / z = 485.19 (M+H) + 。

[0440] Described D62: Di-tert-butyl (3R,4R)-4-amino-3-methylpyrrolidine-1,3-dicarboxylate (D62)

[0441]

Chem.

[0442] A mixture of tert-butyl (3R,4R)-3-methyl-4-[[(1S)-1-phenylethyl]-(phenylmethyl)amino]-1-(phenylmethyl)pyrrolidine-3-carboxylate (D61, 377 mg, 0.780 mmol) and di-tert-butyl dicarbonate (169.76 mg, 0.780 mmol) in methanol (40 mL, 0.987 mol) was hydrogenated by an H-CUBE apparatus (cartridge type 10% Pd / C, 5 bar, flow rate 0.7 mL / min, T = 25 °C). Working at 10 bar, complete deprotection is extremely slow. The solvent was removed and the apparatus was washed with ethanol. The substrate was dissolved in 9 / 1 EtOH / H2O (40 mL) and further hydrogenated by UPLC at 50 °C and 10 bar until completion (about 3 runs) to give compound D62 (200 mg, 0.67 mmol). 1 H NMR (300 MHz, DMSO-d 6 + TFA ) δ ppm 1.19 (s, 3 H) 1.27 (s, 9 H) 1.31 (s, 9 H) 2.85 - 3.11 (m, 1 H) 3.30 (br s, 1 H) 3.41 - 3.73 (m, 3 H) 8.12 (br s, 2 H) 11.28 (br s, 3 H)

[0443] Described D63: (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide hydrochloride (D63)

[0444]

Chemical Structure

[0445] In Step 5, Intermediate D62 was used instead of trans-1-tert-butyl-3-ethyl-4-aminopyrrolidine-1,3-dicarboxylate and obtained as reported for Intermediate D46. Method 10; Rt = 1.35 min. m / z = 423.42 (M+H) +

[0446] Description D64: tert-butyl (3S,4S)-1-benzyl-4-(benzyl((S)-1-phenylethyl)amino)-3-fluoropyrrolidine-3-carboxylate (D64)

[0447]

Chemical formula

[0448] Starting from tert-butyl 1-(phenylmethyl)-2,5-dihydropyrrole-3-carboxylate (Org. Biom. Chem., 2004, 2, 2763 - 2776; 500 mg, 1.928 mmol), and using a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonimide (Sigma Aldrich, catalog number 392715; 960 mg, 3.0 mmol) in THF (7.9 mL) instead of methyl iodide, it was synthesized as reported for D61 to obtain D64 (250 mg, 0.512 mmol). 1 H NMR (300 MHz, chloroform-d) δ ppm 1.29 (d, J = 6.97 Hz, 3 H) 1.50 (s, 9 H) 2.32 (t, J = 9.54 Hz, 1 H) 2.72 (br t, J = 7.70 Hz, 1 H) 2.80 - 3.15 (m, 2 H) 3.21 - 3.54 (m, 3 H) 3.77 (ddd, J = 25.03, 10.18, 6.51 Hz, 1 H) 3.92 (d, J = 15.31 Hz, 1 H) 4.19 (q, J = 6.82 Hz, 1 H) 7.08 - 7.36 (m, 15 H). 1919F NMR (300 MHz, chloroform-d) δ ppm -142 (s, 1 F). Method 1; Rt = 2.07 min. m / z = 489.61 (M+H)+.

[0449] Description D65: Di-tert-butyl (3S,4S)-4-amino-3-fluoropyrrolidine-1,3-dicarboxylate (D65)

[0450]

Chem.

[0451] Starting from D64 (480 mg, 0.982 mmol), it was synthesized as reported for D62 to obtain D65 (140 mg, 0.460 mmol). Method 1; Rt = 1.33 min. m / z = 305.28 (M+H) + 。

[0452] Description D66: (3aS,10aS)-N-(4-fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide hydrochloride (D66)

[0453]

Chem.

[0454] In step 5, using D65 (179 mg, 0.29 mmol) instead of trans-1-tert-butyl-3-ethyl-4-aminopyrrolidine-1,3-dicarboxylate, it was synthesized as reported for D46. The reaction gave D66 (17.5 mg, 0.038 mmol). Method 1; Rt = 1.32 min. m / z = 447.33 (M+Na) +

[0455] (Example E1) cis-2-(2-(Dimethylamino)-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E1)

[0456] [Chemical formula]

[0457] cis-7-Methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide hydroiodide (25 mg, 0.054 mmol), N,N-dimethyloxamic acid (7.0 mg, 0.060 mmol) (Fluorochem, catalog number 023520), and HATU (22.5 mg, 0.059 mmol) were dissolved in anhydrous DMF (0.5 mL). Anhydrous DIPEA (0.025 mL, 0.144 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. The mixture was evaporated under reduced pressure to give a brown solid, which was purified using preparative HPLC-MS (H2O / CH3CN + 0.1% TFA) (13.02 mg). 1 H NMR (300 MHz, DMSO-d6+TFA) δ ppm 2.83 - 2.96 (m, 6 H), 2.99 - 3.25 (m, 2 H), 3.33 - 3.55 (m, 2 H), 3.76 - 4.00 (m, 5 H), 4.45 - 4.69 (m, 2 H), 7.50 (s, 1 H), 7.59 - 7.76 (m, 2 H), 8.47 - 8.59 (m, 1 H), 9.63 - 9.69 (m, 1 H). Method 3: Rt = 3.09 min; m / z = 530.47 (M+H) + .

[0458] (Example E2) cis-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E2)

[0459] [Chemical Structure]

[0460] To a mixture of D29 (29 mg, 0.050 mmol), 2-(2,3-dihydro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (20.56 mg, 0.050 mmol) and D39 (14.69 mg, 0.080 mmol) in DMF (1.5 mL, 0.019 mol), N-ethyl-N-isopropylpropan-2-amine (0.03 mL, 0.160 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hour. Then it was diluted with ethyl acetate and washed with a small amount of water (7 × 5 mL), 5% citric acid (2 × 15 mL) and brine. The organic phase was dried over Na2SO4 (anhydrous), then filtered and concentrated under reduced pressure. The product was purified by preparative HPLC-MS (H2O / CH3CN + 0.1% HCOOH) to obtain E2 (2.03 mg, 0.004 mmol). 11H NMR (300 MHz, DMSO-d6) δ 1.52 (d, J=6.14 Hz, 3H), 2.24 (s, 3H), 2.91 - 3.13 (m, 1H), 3.14 - 3.66 (m, 2H), 3.74 - 4.14 (s, 6H), 4.23 - 4.39 (m, 2H), 4.42 - 4.56 (m, 1H), 4.57 - 4.73 (m, 3H), 7.11 (t, J=9.26 Hz, 1H), 7.45 - 7.54 (m, 2H), 7.56 - 7.64 (m, 1H), 8.41 (br s, 1H), 9.23 (br d, J=8.07 Hz, 1H), 9.35 (br d, J=5.23 Hz, 1H). Method 3: Rt = 3.03 min; m / z = 550.40 (M+H) + .

[0461] (Example E3) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E3)

[0462]

Chemical formula

[0463] Starting from D30 and D39, it was prepared in the same manner as described for compound E2. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E3 (92.16 mg). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.24 Hz, 3 H), 2.24 (s, 3 H), 2.89 - 3.13 (m, 1 H), 3.20 (br t, J=11.10 Hz, 1 H), 3.42 - 3.66 (m, 2 H), 3.74 - 4.14 (m, 6 H), 4.25 - 4.36 (m, 2 H), 4.41 - 4.55 (m, 1 H), 4.57 - 4.68 (m, 3 H), 7.11 (t, J=9.17 Hz, 1 H), 7.46 - 7.55 (m, 2 H), 7.55 - 7.62 (m, 1 H), 8.41 (br s, 1 H), 9.22 (d, J=8.34 Hz, 1 H), 9.35 (d, J=5.04 Hz, 1 H). Method 3: Rt = 3.03 min; m / z = 550.40 (M+H) + .

[0464] (Example E4) (3aR,10aR)-7-Methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E4)

[0465]

Chemical Structure

[0466] Starting from D32 and D39, it was prepared in the same manner as described for compound E2. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E4 (22 mg) as a white solid. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.33 Hz, 3 H), 2.88 - 3.13 (m, 1 H), 3.14 - 3.68 (m, 2 H), 3.81 (s, 3 H), 3.83 - 4.15 (m, 3 H), 4.22 - 4.37 (m, 2 H), 4.41 - 4.55 (m, 1 H), 4.56 - 4.74 (m, 3 H), 7.52 (s, 1 H), 7.60 - 7.83 (m, 2 H), 8.34 - 8.53 (m, 1 H), 9.23 (d, J=7.70 Hz, 1 H), 9.67 (d, J=3.58 Hz, 1 H). Method 3; Rt = 3.20 min; m / z = 572.35 (M+H) + .

[0467] (Example E5) (3aR,10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E5)

[0468]

Chemical Structure

[0469] Starting from D31 and D39, it was prepared in the same manner as described for compound E2. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E5 as an off-white solid. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.42 Hz, 3 H), 2.84 - 3.13 (m, 1 H), 3.41 - 3.68 (m, 2 H), 3.72 - 4.19 (m, 6 H), 4.24 - 4.37 (m, 2 H), 4.41 - 4.55 (m, 1 H), 4.56 - 4.71 (m, 3 H), 7.36 - 7.46 (m, 1 H), 7.49 (s, 1 H), 7.56 - 7.77 (m, 1 H), 7.89 - 8.06 (m, 1 H), 8.29 - 8.64 (m, 1 H), 9.23 (d, J=7.24 Hz, 1 H), 9.57 (d, J=4.77 Hz, 1 H). Method 3: Rt = 3.17 min; m / z = 570.39; 572.35 (M+H) + .

[0470] (Example E6) (3aR,10aR)-N-(3-Cyano-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E6)

[0471]

Chemical formula

[0472] Starting from D33 and D39, the crude product prepared in the same manner as described for compound E2 was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E6 as an off-white solid. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.42 Hz, 3 H), 2.86 - 3.13 (m, 1 H), 3.15 - 3.69 (m, 1 H), 3.48 (br s, 2 H), 3.72 - 4.18 (m, 7 H), 4.23 - 4.38 (m, 2 H), 4.41 - 4.56 (m, 1 H), 4.56 - 4.74 (m, 3 H), 7.46 - 7.63 (m, 2 H), 7.95 - 8.11 (m, 1 H), 8.19 (ddd, J=5.64, 4.54, 2.75 Hz, 1 H), 8.27 - 8.59 (m, 1 H), 9.23 (d, J=7.06 Hz, 1 H), 9.68 (d, J=4.13 Hz, 1 H). Method 3: Rt = 2.88 min; m / z = 561.34 (M+H) + .

[0473] (Example E7) (3aR,10aR)-2-(2-(tert-Butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E7)

[0474] [Chemical formula]

[0475] A solution of D37 (30 mg, 0.060 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (30.38 mg, 0.070 mmol), and DIPEA (25 μL, 0.140 mmol) in anhydrous DMF (2.5 mL, 0.032 mol) was added with tert-butylamine (0.02 mL, 0.190 mmol) at room temperature, and the reaction mixture was stirred under the same conditions for 4 hours. The reaction mixture was diluted with EtOAc (25 mL) and 20 mL of water + 1 mL of 1N HCl. After phase separation, the organic layer was washed with brine. The organic portion was dried over Na2SO4 (anhydrous), filtered, and concentrated under reduced pressure. The residue was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E7 as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (d, J = 7.70 Hz, 9 H), 2.24 (s, 3 H), 2.91 - 3.09 (m, 1 H), 3.12 - 3.65 (m, 2 H), 3.71 - 4.08 (m, 6 H), 4.43 - 4.56 (m, 1 H), 4.61 (br dd, J = 11.10, 3.85 Hz, 1 H), 7.11 (t, J = 9.20 Hz, 1 H), 7.42 - 7.55 (m, 2 H), 7.59 (br s, 1 H), 7.97 (d, J = 14.12 Hz, 1 H), 8.37 - 8.49 (m, 1 H), 9.34 (d, J = 5.41 Hz, 1 H). Method 3: Rt = 3.44 min; m / z = 536.42 (M+H) + .

[0476] (Example E8) (3aR,10aR)-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E8)

[0477] [Chemical formula]

[0478] Cyclopropanamine was used instead of tert-butylamine and prepared in the same manner as described for Compound E7 to obtain E8. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain 15.69 mg of an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.51 - 0.70 (m, 4 H), 2.21 - 2.27 (m, 3 H), 2.66 - 2.83 (m, 1 H), 2.91 - 3.11 (m, 1 H), 3.14 - 3.64 (m, 2 H), 3.73 - 4.13 (m, 6 H), 4.41 - 4.55 (m, 1 H), 4.55 - 4.67 (m, 1 H), 7.11 (t, J = 9.17 Hz, 1 H), 7.45 - 7.54 (m, 2 H), 7.56 - 7.62 (m, 1 H), 8.41 (dd, J = 9.90, 2.66 Hz, 1 H), 8.70 (dd, J = 9.90, 4.95 Hz, 1 H), 9.34 (d, J = 3.94 Hz, 1 H). Method 3: Rt = 3.12 min; m / z = 520.26 (M+H) + .

[0479] (Example E9) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E9)

[0480] [Chemical formula]

[0481] Instead of tert-butylamine, (2R)-1,1,1-trifluoro-2-propanamine hydrochloride (Fluorochem, catalog number 093835) was used and prepared in the same manner as described for Compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E9. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 6.88 Hz, 3 H), 2.24 (s, 3 H), 2.92 - 3.13 (m, 1 H), 3.15 - 3.68 (m, 2 H), 3.78 - 4.09 (m, 6 H), 4.43 - 4.56 (m, 1 H), 4.55 - 4.73 (m, 2 H), 7.11 (t, J = 9.17 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.54 - 7.64 (m, 1 H), 8.37 - 8.53 (m, 1 H), 9.21 - 9.31 (m, 1 H), 9.31 - 9.39 (m, 1 H). Method 3: Rt = 3.48 min; m / z = 576.33 (M+H) + .

[0482] (Example E10) cis-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E10)

[0483]

Chemical Structure

[0484] A mixture of D44 (50 mg, 0.1 mmol) and methylamine 2M in THF (0.76 mL, 1.52 mmol) was stirred at 50 °C for 30 min. The solvent was removed under reduced pressure and the crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E10. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H), 2.57 - 2.75 (m, 3 H), 2.91 - 3.08 (m, 1 H), 3.20 - 3.65 (m, 2 H), 3.75 - 4.11 (m, 6 H), 4.42 - 4.53 (m, 1 H), 4.54 - 4.68 (m, 1 H), 7.11 (t, J = 9.20 Hz, 1 H), 7.43 - 7.52 (m, 2 H), 7.56 - 7.63 (m, 1 H), 8.41 (s, 1 H), 8.61 (br s, 1 H), 9.34 (d, J = 3.40 Hz, 1 H). Method 3: Rt = 2.94 min; m / z = 494.21 (M+H) + .

[0485] (Example E11) cis-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E11)

[0486]

Chemical formula

[0487] Using NH3 (7N solution in MeOH) instead of methylamine, it was prepared in the same manner as described for compound E10. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E11. 11H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H) 2.92 - 3.10 (m, 1 H) 3.19 - 3.63 (m, 2 H) 3.76 - 4.11 (m, 6 H) 4.42 - 4.54 (m, 1 H) 4.55 - 4.66 (m, 1 H) 7.11 (t, J=9.17 Hz, 1 H) 7.45 - 7.55 (m, 2 H) 7.55 - 7.62 (m, 1 H) 7.69 (br d, J=11.00 Hz, 1 H) 7.97 (br d, J=5.14 Hz, 1 H) 8.42 (br s, 1 H) 9.34 (d, J=3.58 Hz, 1 H). Method 3: Rt = 2.81 min. m / z = 480.29 (M+H)+.

[0488] (Example E12) cis-7-Methyl-2-(2-(methylamino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E12)

[0489] [Chemical formula]

[0490] Starting from D45, it was prepared in the same manner as described for compound E10 using 2M methanamine in THF. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E12. 11H NMR (300 MHz, DMSO-d6) δ ppm 2.65 (dd, J = 7.11, 4.91 Hz, 3 H), 2.92 - 3.10 (m, 1 H), 3.19 - 3.67 (m, 2 H), 3.79 - 4.08 (m, 6 H), 4.41 - 4.54 (m, 1 H), 4.56 - 4.68 (m, 1 H), 7.51 (s, 1 H), 7.64 - 7.74 (m, 2 H), 8.42 (br s, 1 H), 8.61 (br t, J = 5.55 Hz, 1 H), 9.64 - 9.69 (m, 1 H). Method 3: Rt = 3.14 min; m / z = 516.09 (M+H) + .

[0491] (Example E13) cis-2-(2-Amino-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E13)

[0492]

Chemical Structure

[0493] Starting from D45, and using NH3 (7N solution in MeOH), it was prepared in the same manner as described for compound E10. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E13. 11H NMR (300 MHz, DMSO-d6) δ ppm 2.94 - 3.07 (m, 1 H), 3.18 - 3.61 (m, 2 H), 3.79 - 4.11 (m, 6 H), 4.49 (m, 1 H), 4.55 - 4.67 (m, 1 H), 7.51 (s, 1 H), 7.63 - 7.75 (m, 3 H), 7.97 (br d, J=5.14 Hz, 1 H), 8.44 (br s, 1 H), 9.67 (s, 1 H). Method 3: Rt = 3.01 min; m / z = 502.18 (M+H) + .

[0494] (Example E14) (3aR,10aR)-2-(2-((3,3-Difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E14)

[0495]

Chemical Structure

[0496] Using 3,3-difluorocyclobutaneamine hydrochloride (Fluorochem, catalog number 091836) instead of tert-butylamine, it was prepared in the same manner as described for compound E7. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E14. 11H NMR (300 MHz, DMSO-d6) δ ppm 2.22 - 2.28 (m, 3 H), 2.63 - 3.12 (m, 6 H), 3.15 - 3.70 (m, 2 H), 3.73 - 4.21 (m, 6 H), 4.40 - 4.70 (m, 2 H), 7.11 (t, J=9.22 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.59 (dt, J=6.74, 3.32 Hz, 1 H), 8.40 (m, 1 H), 9.23 (t, J=6.65 Hz, 1 H), 9.35 (d, J=4.77 Hz, 1 H). Method 3: Rt = 3.41 min; m / z = 570.25 (M+H) + .

[0497] (Example E15) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E15)

[0498]

Chem.

[0499] (2S)-1,1,1-Trifluoro-2-propanamine hydrochloride (Fluorochem, catalog number 093836) was used instead of tert-butylamine and prepared in the same manner as described for compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E15. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J=5.59 Hz, 3 H), 2.24 (s, 3 H), 2.95 - 3.13 (m, 1 H), 3.16 - 3.68 (m, 2 H), 3.78 - 4.13 (m, 6 H), 4.62 (m, 3 H), 7.11 (t, J=9.12 Hz, 1 H), 7.45 - 7.54 (m, 2 H), 7.56 - 7.62 (m, 1 H), 8.44 (br s, 1 H), 9.21 - 9.32 (m, 1 H), 9.32 - 9.38 (m, 1 H). Method 3: Rt = 3.51 min; m / z = 576.13 (M+H) + .

[0500] (Example E16) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isobutylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E16)

[0501]

Chemical Structure

[0502] Prepared in the same manner as described for compound E7, using 2-methylpropan-1-amine instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E16. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (t, J=6.56 Hz, 6 H), 1.77 (dd, J=13.75, 6.88 Hz, 1 H), 2.24 (s, 3 H), 2.95 (br d, J=7.89 Hz, 3 H), 3.20 - 3.67 (m, 2 H), 3.76 - 3.83 (m, 3 H), 3.83 - 4.13 (m, 3 H), 4.49 (br s, 1 H), 4.56 - 4.70 (m, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.59 (dt, J=6.79, 3.39 Hz, 1 H), 8.32 - 8.55 (m, 1 H), 8.64 (dt, J=9.40, 6.17 Hz, 1 H), 9.34 (d, J=7.15 Hz, 1 H). Method 3: Rt = 3.45 min; m / z = 536.21 (M+H) + .

[0503] (Example E17) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E17)

[0504]

Chem.

[0505] Using 2,2,2-trifluoroethane-1-amine hydrochloride (180386, Sigma Aldrich, CAS: 373-88-6) instead of tert-butylamine, it was prepared in the same manner as described for Compound E7. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E17. 11H NMR (300 MHz, DMSO-d6) δ ppm 2.18 - 2.27 (m, 3 H), 2.90 - 3.15 (m, 1 H), 3.20 - 3.65 (m, 2 H), 3.81 (s, 3 H), 3.83 - 4.16 (m, 5 H), 4.36 - 4.78 (m, 2 H), 7.11 (t, J=9.17 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.55 - 7.64 (m, 1 H), 8.43 (br s, 1 H), 9.13 - 9.50 (m, 2 H). Method 3: Rt = 3.41 min. m / z = 562.15 (M+H)+.

[0506] (Example E18) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E18)

[0507]

Chemical formula

[0508] 1-Methylcyclopropanamine hydrochloride (092116, Sigma Aldrich, CAS: 88887-87-0) was used instead of tert-butylamine and prepared in the same manner as described for Compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E18. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.52 - 0.73 (m, 4 H), 1.29 (d, J=7.06 Hz, 3 H), 2.24 (s, 3 H), 2.89 - 3.09 (m, 1 H), 3.16 - 3.60 (m, 2 H), 3.74 - 4.09 (m, 6 H), 4.42 - 4.55 (m, 1 H), 4.57 - 4.66 (m, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.45 - 7.53 (m, 2 H), 7.54 - 7.62 (m, 1 H), 8.40 (br s, 1 H), 8.80 (d, J=14.86 Hz, 1 H), 9.34 (d, J=4.68 Hz, 1 H). Method 3; Rt = 3.25 min; m / z = 534.26 (M+H) + .

[0509] (Example E19) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E19)

[0510] [Chemical Structure]

[0511] Using 1-trifluoromethyl-cyclopropylamine hydrochloride (093841, Sigma Aldrich, CAS: 112738-67-7) instead of tert-butylamine, it was prepared in the same manner as described for compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E19. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.94 - 1.19 (m, 2 H), 1.19 - 1.34 (m, 2 H), 2.24 (s, 3 H), 2.86 - 3.10 (m, 1 H), 3.11 - 3.65 (m, 2 H), 3.81 (s, 3 H), 3.83 - 4.13 (m, 3 H), 4.40 - 4.55 (m, 1 H), 4.56 - 4.74 (m, 1 H), 7.11 (t, J=9.26 Hz, 1 H), 7.42 - 7.55 (m, 2 H), 7.55 - 7.65 (m, 1 H), 8.31 - 8.49 (m, 1 H), 9.34 (d, J=7.34 Hz, 1 H), 9.47 (d, J=13.57 Hz, 1 H). Method 3: Rt = 3.51 min; m / z = 588.19 (M+H) + .

[0512] (Example E20) (3aR,10aR)-2-(2-((Cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E20)

[0513] [Chemical formula]

[0514] Prepared in the same manner as described for Compound E7, using cyclopropanemethylamine (Sigma Aldrich, Catalog No. 08460) instead of tert-butylamine. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E20. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.18 (broad t, J = 4.81 Hz, 2 H), 0.39 (broad t, J = 6.05 Hz, 2 H), 0.89 - 1.05 (m, 1 H), 2.23 (s, 3 H), 2.99 (q, J = 6.85 Hz, 3 H), 3.12 - 3.66 (m, 2 H), 3.76 - 4.16 (m, 6 H), 4.48 (broad d, J = 5.32 Hz, 1 H), 4.61 (dt, J = 11.55, 5.59 Hz, 1 H), 7.10 (t, J = 9.17 Hz, 1 H), 7.43 - 7.54 (m, 2 H), 7.55 - 7.62 (m, 1 H), 8.41 (broad d, J = 6.05 Hz, 1 H), 8.67 - 8.77 (m, 1 H), 9.34 (d, J = 5.69 Hz, 1 H). Method 3: Rt = 3.34 min; m / z = 534.26 (M + H) + .

[0515] (Example E21) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isopropylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E21)

[0516] [Chemical Structure]

[0517] Using isopropylamine (Sigma Aldrich, catalog number 471291) instead of tert-butylamine, it was prepared in the same manner as described for compound E). The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E21. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=6.65 Hz, 6 H), 2.24 (s, 3 H), 2.91 - 3.10 (m, 1 H), 3.18 - 3.63 (m, 2 H), 3.78 - 4.09 (m, 7 H), 4.49 (m, 1 H), 4.54 - 4.66 (m, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.46 - 7.54 (m, 2 H), 7.54 - 7.62 (m, 1 H), 8.38 - 8.51 (m, 2 H), 9.34 (d, J=5.69 Hz, 1 H). Method 3: Rt = 3.25 min; m / z = 522.23 (M+H) + .

[0518] (Example E22) (3aR,10aR)-2-(2-(Cyclobutylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E22)

[0519]

Chem.

[0520] Using cyclobutylamine hydrochloride (Sigma Aldrich, catalog number 59271) instead of tert-butylamine, it was prepared in the same manner as described for compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E22. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.55 - 1.70 (m, 2 H), 1.99 - 2.19 (m, 4 H), 2.20 - 2.28 (m, 3 H), 2.89 - 3.11 (m, 1 H), 3.19 - 3.75 (m, 2 H), 3.77 - 4.08 (m, 6 H), 4.23 (dt, J=16.99, 8.42 Hz, 1 H), 4.42 - 4.53 (m, 1 H), 4.53 - 4.66 (m, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 7.55 - 7.63 (m, 1 H), 8.41 (br s, 1 H), 8.89 (t, J=8.30 Hz, 1 H), 9.34 (d, J=5.50 Hz, 1 H). Method 3: Rt = 3.37 min; m / z = 534.26 (M+H) + .

[0521] (Example E23) (3aR,10aR)-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E23)

[0522]

Chem.

[0523] Starting from D28 and D43, it was prepared in the same manner as described for compound E2. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E23 as a white solid. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 0.46 - 0.59 (m, 2 H), 0.59 - 0.70 (m, 2 H), 2.23 (s, 3 H), 2.30 - 2.43 (m, 1 H), 2.57 - 2.81 (m, 2 H), 2.95 - 3.61 (m, 3 H), 3.72 (s, 3 H), 3.75 - 4.09 (m, 2 H), 4.68 - 4.88 (m, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.44 - 7.60 (m, 2 H), 7.66 (br d, J=6.42 Hz, 1 H), 8.08 - 8.24 (m, 1 H), 8.67 (dd, J=15.50, 4.95 Hz, 1 H), 10.33 (d, J=2.38 Hz, 1 H).. Method 3; Rt = 3.17 min; m / z = 536.18 (M+H) + .

[0524] (Example E24) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E24)

[0525]

Chem.

[0526] Starting from D28 and D41, it was prepared in the same manner as described for compound E2. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E24 as a white solid. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.30 (t, J=6.74 Hz, 3 H), 2.23 (s, 3 H), 2.29 - 2.44 (m, 1 H), 2.60 - 2.79 (m, 1 H), 3.02 - 3.44 (m, 2 H), 3.46 - 3.65 (m, 1 H), 3.72 (s, 3 H), 3.75 - 4.09 (m, 2 H), 4.47 - 4.71 (m, 1 H), 4.71 - 4.87 (m, 1 H), 7.11 (t, J=9.12 Hz, 1 H), 7.46 - 7.61 (m, 2 H), 7.66 (br d, J=6.79 Hz, 1 H), 8.11 - 8.30 (m, 1 H), 9.24 (t, J=9.81 Hz, 1 H), 10.33 (d, J=4.49 Hz, 1 H). Method 3; Rt = 3.59 min; m / z = 592.13 (M+H) + .

[0527] (Example E25) cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E25)

[0528] [Chemical formula]

[0529] Starting from D34 and D43, it was prepared in the same manner as described for compound E2. The crude material was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to obtain E25. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 0.48 - 0.74 (m, 4 H), 1.27 (d, J=4.95 Hz, 3 H), 2.24 (s, 3 H), 2.65 - 2.84 (m, 1 H), 3.27 (br d, J=7.52 Hz, 1 H), 3.49 - 4.30 (m, 8 H), 4.36 (d, J=11.37 Hz, 1 H), 7.11 (t, J=9.22 Hz, 1 H), 7.36 - 7.50 (m, 2 H), 7.52 - 7.65 (m, 1 H), 8.46 (dd, J=9.49, 3.71 Hz, 1 H), 8.71 (t, J=4.40 Hz, 1 H), 9.33 (d, J=4.86 Hz, 1 H). Method 3; Rt = 3.30 min; m / z = 534.23 (M+H) + .

[0530] (Example E26) Cis-N-(4-Fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E26)

[0531]

Chem.

[0532] Starting from D34 and D41, it was prepared in the same manner as described for compound E2. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E26. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.19 - 1.40 (m, 6H), 2.24 (s, 3H), 3.18 - 3.41 (m, 1H), 3.42 - 3.88 (m, 5H), 3.91 - 4.31 (m, 3H), 4.37 (br d, J = 11.55 Hz, 1H), 4.48 - 4.80 (m, 1H), 7.12 (t, J = 9.22 Hz, 1H), 7.36 - 7.51 (m, 2H), 7.51 - 7.68 (m, 1H), 8.35 - 8.64 (m, 1H), 9.08 - 9.50 (m, 2H). Method 3: Rt = 3.68 min. m / z = 590.19. (M+H) + .

[0533] (Example E27) Cis-N-(4-Fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E27)

[0534]

Chemical Structure

[0535] Starting from D35 and D41, it was prepared in the same manner as described for compound E2. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E27. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.09 - 1.34 (m, 4 H), 1.35 - 1.58 (m, 3 H), 2.24 (s, 3 H), 3.17 - 3.74 (m, 3 H), 3.75 - 4.00 (m, 4 H), 4.16 - 4.75 (m, 3 H), 7.10 (t, J = 9.08 Hz, 1 H), 7.41 - 7.67 (m, 3 H), 8.03 - 8.21 (m, 1 H), 9.17 - 9.28 (m, 1 H), 9.28 - 9.41 (m, 1 H). Method 3: Rt = 3.58 min; m / z = 590.19 (M + H) + .

[0536] (Example E28) cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E28)

[0537]

Chemical formula

[0538] Starting from D35 and D43, it was prepared in the same manner as described for compound E2. The crude product was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E28. 11H NMR (300 MHz, DMSO-d6) δ ppm 0.43 - 0.71 (m, 4 H), 1.08 - 1.30 (m, 1 H), 1.33 - 1.49 (m, 3 H), 2.17 - 2.26 (m, 3 H), 2.63 - 2.71 (m, 1 H), 3.17 - 3.51 (m, 1 H), 3.54 - 3.78 (m, 2 H), 3.78 - 3.87 (m, 3 H), 3.87 - 4.00 (m, 1 H), 4.13 - 4.65 (m, 2 H), 7.09 (t, J=9.22 Hz, 1 H), 7.44 - 7.54 (m, 2 H), 7.54 - 7.65 (m, 1 H), 8.10 (d, J=2.48 Hz, 1 H), 8.65 (t, J=4.36 Hz, 1 H), 9.31 (d, J=4.86 Hz, 1 H). Method 3; Rt = 3.18 min; m / z = 534.23.

[0539] (Example E29) (3aR,10aR)-2-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E29)

[0540] [Chemical formula]

[0541] E29 was obtained by preparing it in the same manner as described for compound E7, using 3,3-difluoroazetidine hydrochloride (Fluorochem, catalog number 013896) instead of tert-butylamine. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 2.23 (s, 3 H), 2.91 - 3.10 (m, 1 H), 3.13 - 3.64 (m, 2 H), 3.74 - 4.08 (m, 6 H), 4.36 - 4.54 (m, 3 H), 4.56 - 4.80 (m, 3 H), 7.08 (t, J=9.12 Hz, 1 H), 7.44 - 7.53 (m, 2 H), 7.57 (br d, J=6.60 Hz, 1 H), 8.37 (br d, J=9.54 Hz, 1 H), 9.32 (s, 1 H). Method 3; Rt = 3.31 min; m / z = 556.20 (M+H) + .

[0542] (Example E30) trans-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E30)

[0543] [Chemical formula]

[0544] A mixture of D46 (21.5 mg, 0.050 mmol) and D41 (15.01 mg, 0.07 mmol) in DMF (1 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (25.25 μL, 0.14 mmol) all at once to obtain a brown solution. PyBop (37.72 mg, 0.07 mmol) was obtained, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 mL×3). The combined organic extracts were washed with brine and 5% citric acid (aqueous solution), dried over Na2SO4, filtered, and evaporated. The residue was purified by Fraction-Lynx (H2O / CH3CN+1‰TFA).1 1H NMR (300 MHz, DMSO-d6 +TFA) δ ppm 1.09 - 1.42 (m, 4 H) 2.23 (s, 3 H) 2.57 - 2.71 (m, 1 H) 2.98 - 3.30 (m, 1 H) 3.33 - 3.70 (m, 1 H) 3.74 - 3.92 (m, 3 H) 3.94 - 4.39 (m, 4 H) 4.41 - 4.77 (m, 1 H) 7.01 - 7.16 (m, 1 H) 7.43 - 7.55 (m, 2 H) 7.55 - 7.65 (m, 1 H) 7.66 - 7.82 (m, 1 H) 9.25 (br dd, J=9.03, 2.80 Hz, 1 H) 9.51 (br d, J=9.63 Hz, 1 H). Method 3; Rt: 3.46 min. m / z: 576.33 (M+H)+.

[0545] (Example E31) trans-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E31)

[0546] [Chemical Structure]

[0547] A mixture of D46 (21.5 mg, 0.050 mmol) and D43 (10.95 mg, 0.070 mmol) in DMF (1 mL, 0.013 mol) was treated with N-ethyl-N-isopropylpropan-2-amine (25.25 μL, 0.140 mmol) all at once to obtain a brown solution. PyBop (37.72 mg, 0.070 mmol) was added all at once and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 mL × 3). The combined organic extracts were washed with brine and 5% citric acid (aqueous solution), dried over Na2SO4 (anhydrous), filtered, and evaporated. The residue was purified by Fraction-Lynx (H2O / CH3CN + 1‰ TFA). 1 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37 - 0.77 (m, 4 H) 2.24 (d, J = 0.92 Hz, 3 H) 2.63 - 2.77 (m, 1 H) 2.97 - 3.67 (m, 3 H) 3.83 (s, 3 H) 3.88 - 4.40 (m, 5 H) 7.11 (t, J = 9.22 Hz, 1 H) 7.44 - 7.55 (m, 2 H) 7.56 - 7.78 (m, 2 H) 8.68 (dd, J = 7.06, 5.14 Hz, 1 H) 9.51 (d, J = 8.53 Hz, 1 H). Method 3; Rt: 3.06 min. m / z: 520.21 (M+H)+.

[0548] (Example E32) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E32)

[0549] [[ID=I2]]

Chemical Structure

[0550] Using 2,2,2-trifluoro-1,1-dimethyl-ethylamine hydrochloride (Fluorochem, catalog number 033026) instead of tert-butylamine, it was prepared in the same manner as described for Compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E32 as a white powder. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.53 (br d, J = 6.14 Hz, 6 H) 2.22 (s, 3 H) 2.89 - 3.65 (m, 3 H) 3.69 - 4.12 (m, 6 H) 4.41 - 4.73 (m, 2 H) 7.08 (br t, J = 9.40 Hz, 1 H) 7.38 - 7.68 (m, 3 H) 8.35 - 8.54 (m, 2 H) 9.32 (br d, J = 8.25 Hz, 1 H). Method 3; Rt = 3.67 min. m / z = 590.31 (M+H) + .

[0551] (Example E33) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclobutyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E33)

[0552]

Chemical Structure

[0553] Using 1-(trifluoromethyl)cyclobutylamine (Fluorochem, catalog number 075973) instead of tert-butylamine, it was prepared in the same manner as described for compound E7. The crude material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to obtain E33 as a white powder. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.77 - 1.99 (m, 2 H) 2.20 (s, 3 H) 2.34 - 2.51 (m, 4 H) 2.89 - 3.12 (m, 1 H) 3.13 - 3.67 (m, 2 H) 3.73 - 4.10 (m, 6 H) 4.41 - 4.69 (m, 2 H) 6.97 - 7.08 (m, 1 H) 7.40 (s, 1 H) 7.42 - 7.58 (m, 2 H) 8.41 (br t, J = 10.18 Hz, 1 H) 9.22 (br d, J = 12.29 Hz, 1 H) 9.35 (br d, J = 8.16 Hz, 1 H). Method 3; Rt = 3.67 min. m / z = 602.20 (M+H)+.

[0554] (Example E34) (3aR,10aR)-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E34)

[0555] [[ID=ll]]

Chem.

[0556] A mixture of crude D47 (21.1 mg, 0.04 mmol) and 7N NH3 in MeOH (1 mL, 7.0 mmol) was stirred at 50 °C for 1 h. The solvent was removed under reduced pressure, and the resulting crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH), and after lyophilization, E34 (15 mg) was obtained as a white solid.1 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.23 (s, 3 H) 2.30 - 2.44 (m, 1 H) 2.56 - 2.71 (m, 1 H) 2.98 - 3.41 (m, 2 H) 3.42 - 3.60 (m, 1 H) 3.72 (s, 3 H) 3.74 - 4.09 (m, 2 H) 4.68 - 4.88 (m, 1 H) 7.10 (t, J = 9.08 Hz, 1 H) 7.45 - 7.60 (m, 2 H) 7.60 - 7.76 (m, 2 H) 7.95 (d, J = 11.92 Hz, 1 H) 8.19 (q, J = 4.77 Hz, 1 H) 10.21 - 10.45 (m, 1 H). Method 3; Rt = 2.88 min. m / z = 496.30 (M + H) + .

[0557] (Example E35) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E35)

[0558]

Chem.

[0559] Starting from D47, using 2M NH2CH3 in THF instead of 7N NH3 in MeOH, it was prepared in the same manner as described for E34. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E35 (13 mg) as a white solid. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.23 (s, 3 H) 2.29 - 2.43 (m, 1 H) 2.55 - 2.70 (m, 4 H) 2.98 - 3.61 (m, 3 H) 3.71 (s, 3 H) 3.73 - 4.09 (m, 2 H) 4.65 - 4.88 (m, 1 H) 7.10 (t, J = 9.35 Hz, 1 H) 7.43 - 7.61 (m, 2 H) 7.62 - 7.73 (m, 1 H) 8.18 (d, J = 10.09 Hz, 1 H) 8.46 - 8.72 (m, 1 H) 10.21 - 10.45 (m, 1 H). Method 3; Rt = 3.00 min. m / z = 510.14 (M + H) + .

[0560] (Example E36) (3aR,10aR)-2-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E36)

[0561] [Chemical formula]

[0562] To a suspension of D28 (35 mg, 0.06 mmol) and D49 (14.8 mg, 0.08 mmol) in ethanol (1 mL), DBU (0.02 mL, 0.13 mmol) was added, and the resulting solution was stirred at room temperature for 1 hour. 1N HCl solution was added to the reaction mixture until a white solid precipitated. Then, EtOAc was added and the phases were separated. The aqueous layer was extracted again with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The obtained crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH), and after lyophilization, E36 was obtained as a white solid. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.23 (s, 3 H) 2.28 - 2.46 (m, 1 H) 2.58 - 2.71 (m, 1 H) 2.99 - 3.39 (m, 2 H) 3.41 - 3.57 (m, 1 H) 3.72 (s, 3 H) 3.74 - 4.07 (m, 2 H) 4.43 (q, J = 12.29 Hz, 2 H) 4.56 - 4.87 (m, 3 H) 7.11 (t, J = 9.08 Hz, 1 H) 7.44 - 7.61 (m, 2 H) 7.66 (br d, J = 6.33 Hz, 1 H) 8.05 - 8.30 (m, 1 H) 10.33 (s, 1 H). Method 3; Rt = 3.35 min. m / z = 572.21 (M+H) + .

[0563] (Example E37) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E37)

[0564]

Chem.

[0565] D50 was used instead of ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate and prepared in the same manner as described for compound E36. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E36 (35 mg) as a white solid. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.21 - 1.39 (m, 3 H) 2.23 (s, 3 H) 2.27 - 2.45 (m, 1 H) 2.59 - 2.82 (m, 1 H) 3.04 - 3.42 (m, 2 H) 3.43 - 3.61 (m, 1 H) 3.72 (s, 3 H) 3.75 - 4.08 (m, 2 H) 4.46 - 4.72 (m, 1 H) 4.73 - 4.91 (m, 1 H) 7.11 (t, J = 9.00 Hz, 1 H) 7.45 - 7.61 (m, 2 H) 7.66 (br d, J = 6.69 Hz, 1 H) 8.22 (d, J = 9.10 Hz, 1 H) 9.25 (dd, J = 25.40, 8.89 Hz, 1 H) 10.33 (br s, 1 H). Method 3; Rt = 3.57 min. m / z = 592.27 (M + H) + .

[0566] (Example E38) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide (E38)

[0567] [Chemical formula]

[0568] To a solution of D48 (30 mg, 0.060 mmol) in anhydrous DMF (0.8 mL), 2,2,2-trifluoroethylamine hydrochloride (12.3 mg, 0.09 mmol) was added, followed by anhydrous DIPEA (0.05 mL, 0.30 mmol) under N2 atmosphere. To the stirred solution, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.09 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Water and EtOAc were added and then the organic layer was washed with 5% aqueous citric acid solution (×2) and water. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The obtained crude was E38 (19 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6+TFA) δ ppm 2.23 (s, 3 H) 2.30 - 2.44 (m, 1 H) 2.60 - 2.73 (m, 1 H) 3.02 - 3.41 (m, 2 H) 3.42 - 3.65 (m, 1 H) 3.72 (s, 3 H) 3.75 - 4.15 (m, 4 H) 4.68 - 4.90 (m, 1 H) 7.10 (t, J=9.17 Hz, 1 H) 7.43 - 7.61 (m, 2 H) 7.62 - 7.74 (m, 1 H) 8.20 (dd, J=9.63, 6.42 Hz, 1 H) 9.11 - 9.45 (m, 1 H) 10.32 (d, J=4.58 Hz, 1 H). Method 3; Rt = 3.47 min. m / z = 578.22 (M+H) + .

[0569] (Example E39) (3aR,10aR)-2-(2-((Cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E39)

[0570]

Chemical formula

[0571] Cyclopropylmethylamine was used instead of 2,2,2-trifluoroethylamine hydrochloride and prepared in the same manner as described for Compound E38. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E39 (26 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 0.05 - 0.26 (m, 2 H) 0.29 - 0.46 (m, 2 H) 0.82 - 1.06 (m, 1 H) 2.22 (s, 3 H) 2.29 - 2.42 (m, 1 H) 2.57 - 2.70 (m, 1 H) 2.85 - 3.02 (m, 2 H) 3.04 - 3.39 (m, 2 H) 3.41 - 3.61 (m, 1 H) 3.71 (s, 3 H) 3.74 - 4.08 (m, 2 H) 4.67 - 4.92 (m, 1 H) 7.09 (t, J = 9.17 Hz, 1 H) 7.40 - 7.60 (m, 2 H) 7.60 - 7.76 (m, 1 H) 8.18 (dd, J = 9.90, 5.96 Hz, 1 H) 8.54 - 8.80 (m, 1 H) 10.32 (d, J = 3.39 Hz, 1 H). Method 3; Rt = 3.39 min. m / z = 550.19 (M+H) + .

[0572] (Example E40) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E40)

[0573]

Chemical Structure

[0574] Using 1-methylcyclopropanamine hydrochloride instead of 2,2,2-trifluoroethylamine hydrochloride, it was prepared in the same manner as described for Compound E38. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E40 (28 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 0.42 - 0.59 (m, 2 H) 0.61 - 0.76 (m, 2 H) 1.28 (d, J = 7.61 Hz, 3 H) 2.23 (s, 3 H) 2.30 - 2.44 (m, 1 H) 2.56 - 2.71 (m, 1 H) 3.20 (s, 2 H) 3.39 - 3.59 (m, 1 H) 3.62 - 4.05 (m, 5 H) 4.58 - 4.89 (m, 1 H) 7.10 (t, J = 9.35 Hz, 1 H) 7.43 - 7.60 (m, 2 H) 7.62 - 7.74 (m, 1 H) 8.17 (t, J = 9.54 Hz, 1 H) 8.77 (d, J = 21.37 Hz, 1 H) 10.32 (d, J = 3.03 Hz, 1 H). Method 3; Rt = 3.31 min. m / z = 550.26 (M + H) + .

[0575] (Example E41) (3aR,10aR)-2-(2-((3,3-Difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E41)

[0576]

Chemical formula

[0577] Using 3,3-difluorocyclobutaneamine hydrochloride instead of 2,2,2-trifluoroethylamine hydrochloride, it was prepared in the same manner as described for Compound E38. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E41 (24 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6+TFA) δ ppm 2.23 (s, 3 H) 2.30 - 2.44 (m, 1 H) 2.62 - 2.98 (m, 5 H) 3.02 - 3.43 (m, 2 H) 3.44 - 3.62 (m, 1 H) 3.72 (s, 3 H) 3.75 - 4.22 (m, 3 H) 4.62 - 4.89 (m, 1 H) 7.10 (t, J=9.12 Hz, 1 H) 7.46 - 7.61 (m, 2 H) 7.66 (br d, J=6.42 Hz, 1 H) 8.14 - 8.23 (m, 1 H) 9.21 (dd, J=12.01, 7.34 Hz, 1 H) 10.32 (d, J=2.84 Hz, 1 H). Method 3; Rt = 3.46 min. m / z = 586.33 (M+H) + .

[0578] (Example E42) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide (E42)

[0579]

Chem.

[0580] 3-Methyl-3-oxetanamine was used instead of 2,2,2-trifluoroethylamine hydrochloride and prepared in the same manner as described for Compound E38. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E42. Method 1; Rt = 1.79 min. m / z = 566.13 (M+H) + 。

[0581] (Example E43) (3aR,10aR)-N-(3-Chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E43)

[0582]

Chemical formula

[0583] To a solution of crude D31 (71.68 mg, 0.130 mmol) and D40 (33.2 mg, 0.160 mmol) in ethanol (2 mL) was added DBU (0.03 mL, 0.190 mmol), and the resulting yellow solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E43. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J=6.97 Hz, 3 H) 2.93 - 3.13 (m, 1 H) 3.20 (br t, J =11.46 Hz, 1 H) 3.36 - 3.67 (m, 2 H) 3.81 - 4.09 (m, 5 H) 4.44 - 4.70 (m, 3 H) 7.41 (t, J =9.03 Hz, 1 H) 7.50 (s, 1 H) 7.61 - 7.69 (m, 1 H) 7.99 (ddd, J =6.79, 4.03, 2.66 Hz, 1 H) 8.49 (br d, J =8.80 Hz, 1 H) 9.28 (br d, J =7.43 Hz, 1 H) 9.57 (d, J =10.18 Hz, 1 H). Method 3; Rt = 3.67 min. m / z = 596.39 (M+H) + .

[0584] (Example E44) (3aR,10aR)-N-(3,4-Difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E44)

[0585] [Chemical formula]

[0586] Compound E44 was prepared in the same manner starting from D51 instead of D31 as described for compound E43. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E44. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.30 (t, J=6.97 Hz, 3 H) 2.86 - 3.12 (m, 1 H) 3.14 - 3.68 (m, 2 H) 3.81 (s, 3 H) 3.82 - 4.12 (m, 3 H) 4.42 - 4.55 (m, 1 H) 4.57 - 4.72 (m, 2 H) 7.30 - 7.47 (m, 2 H) 7.48 (s, 1 H) 7.75 - 7.95 (m, 1 H) 8.35 - 8.56 (m, 1 H) 9.16 - 9.33 (m, 1 H) 9.56 (d, J=9.72 Hz, 1 H). Method 3; Rt = 3.51 min. m / z = 580.29 (M+H)+.

[0587] (Example E45) (3aR,10aR)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E45)

[0588] [Chemical Structure Diagram]

[0589] Starting from D52 instead of D31, it was prepared in the same manner as described for compound E43. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E45. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.06 Hz, 3 H) 2.90 - 3.13 (m, 1 H) 3.15 - 3.70 (m, 2 H) 3.78 - 4.09 (m, 6 H) 4.44 - 4.68 (m, 3 H) 6.97 - 7.40 (m, 2 H) 7.47 (s, 1 H) 7.79 (br dd, J =7.70, 3.58 Hz, 1 H) 8.02 - 8.09 (m, 1 H) 8.45 (dd, J =16.87, 9.90 Hz, 1 H) 9.18 - 9.30 (m, 1 H) 9.60 (d, J =9.63 Hz, 1 H). Method 3; Rt = 3.51 min. m / z = 612.39 (M+H)+.

[0590] (Example E46) (3aR,10aR)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E46)

[0591] [Chemical formula]

[0592] Starting from D53 instead of D31, it was prepared in the same manner as described for compound E43. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E46. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (t, J = 7.11 Hz, 3 H) 2.88 - 3.14 (m, 1 H) 3.14 - 3.70 (m, 2 H) 3.81 (s, 3 H) 3.82 - 4.11 (m, 3 H) 4.43 - 4.55 (m, 1 H) 4.56 - 4.73 (m, 2 H) 7.36 - 7.62 (m, 2 H) 7.87 - 8.00 (m, 1 H) 8.14 - 8.25 (m, 1 H) 8.35 - 8.56 (m, 1 H) 9.17 - 9.32 (m, 1 H) 9.71 (d, J = 9.45 Hz, 1 H). Method 3; Rt = 3.75 min. m / z = 630.33 (M + H)+.

[0593] (Example E47) (3aR,10aR)-6-chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E47)

[0594] [Chemical Structure]

[0595] A solution of E43 (15 mg, 0.030 mmol) in DCM (2.1 mL) cooled to 0 °C was added dropwise with sulfuryl dichloride (2.3 μL, 0.030 mmol) pre-dissolved in DCM (0.4 mL) at 0 °C over 1 minute. The reaction mixture was left to reach room temperature and stirred for 3 hours. UPLC / MS showed less than 50% conversion. Additional sulfuryl dichloride (2 μL) dissolved in DCM (0.4 mL) was added and the reaction mixture was stirred at room temperature for a further 2 hours. The reaction was quenched with water (0.5 mL) and then concentrated under reduced pressure and purified directly by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to afford E47.1 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 - 1.40 (m, 3 H) 2.84 - 3.06 (m, 1 H) 3.17 - 3.70 (m, 2 H) 3.73 - 4.16 (m, 6 H) 4.26 - 4.50 (m, 2 H) 4.52 - 4.74 (m, 1 H) 7.42 (s, 1 H) 7.58 - 7.74 (m, 1 H) 7.88 - 8.10 (m, 1 H) 8.48 - 8.92 (m, 1 H) 9.11 - 9.54 (m, 1 H) 9.71 - 9.99 (m, 1 H). Method 3; Rt: 3.82. m / z: 630.63 (M+H) + .

[0596] (Example E48) (3aR,10aR)-6-chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E48)

[0597]

Chem.

[0598] Starting from E44, it was prepared in the same manner as described for compound E47. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E48. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.26 - 1.38 (m, 3 H) 2.81 - 3.05 (m, 1 H) 3.33 (m, 2 H) 3.71 - 4.14 (m, 6 H) 4.33 - 4.51 (m, 2 H) 4.52 - 4.76 (m, 1 H) 7.27 - 7.58 (m, 2 H) 7.68 - 7.96 (m, 1 H) 8.32 - 8.91 (m, 1 H) 9.27 (br s, 1 H) 9.82 (d, J=7.70 Hz, 1 H). Method 3; Rt: 3.67. m / z: 614.42 (M+H) + .

[0599] (Example E49) (3aR,10aR)-6-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E49)

[0600] [Chemical formula]

[0601] Starting from E45, it was prepared in the same manner as described for compound E47. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E49. 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (t, J = 7.20 Hz, 3 H) 2.79 - 3.08 (m, 1 H) 3.14 - 3.72 (m, 2 H) 3.72 - 4.17 (m, 6 H) 4.34 - 4.51 (m, 2 H) 4.51 - 4.75 (m, 1 H) 6.91 - 7.49 (m, 2 H) 7.80 (br dd, J = 7.93, 3.81 Hz, 1 H) 8.03 (br s, 1 H) 8.67 (dd, J = 18.75, 9.86 Hz, 1 H) 9.24 (t, J = 8.53 Hz, 1 H) 9.86 (d, J = 8.25 Hz, 1 H). Method 3; Rt: 3.66. m / z: 646.43 (M + H) + .

[0602] (Example E50) (3aR,10aR)-6-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E50)

[0603] [Chemical Structure Diagram]

[0604] Starting from E46, it was prepared in the same manner as described for compound E47. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E50. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.22 - 1.40 (m, 3 H) 2.85 - 3.03 (m, 1 H) 3.17 - 3.67 (m, 2 H) 3.69 - 4.13 (m, 6 H) 4.34 - 4.53 (m, 2 H) 4.53 - 4.75 (m, 1 H) 7.49 - 7.57 (m, 1 H) 7.89 - 8.03 (m, 1 H) 8.13 - 8.26 (m, 1 H) 8.49 - 8.88 (m, 1 H) 9.19 - 9.41 (m, 1 H) 9.91 - 10.06 (m, 1 H). Method 3; Rt: 3.89. m / z: 664.46 (M+H) + .

[0605] (Example E51) (3aR,10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E51)

[0606]

Chemical Structure

[0607] Starting from E9, it was prepared in the same manner as described for compound E47. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E51. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.36 - 1.48 (m, 3 H) 2.33 - 2.38 (m, 3 H) 2.94 - 3.15 (m, 1 H) 3.29 - 3.77 (m, 2 H) 3.87 - 4.19 (m, 6 H) 4.47 - 4.62 (m, 2 H) 4.64 - 4.85 (m, 1 H) 7.23 (t, J=9.17 Hz, 1 H) 7.57 - 7.72 (m, 2 H) 8.67 (s, 1 H) 9.32 - 9.48 (m, 1 H) 9.65 - 9.77 (m, 1 H). Method 3; Rt: 3.69. m / z: 610.44 (M+H) + .

[0608] (Example E52) (3aR,10aR)-6-Bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide (E52)

[0609] [Chemical formula]

[0610] To a solution of E9 (97 mg, 0.170 mmol) in CHCl3 (3.2 ml) was added N-bromosuccinimide (32.11 mg, 0.180 mmol), and the colorless solution was stirred at room temperature overnight. The crude material was diluted with DCM (20 ml) and saturated solution of NaHCO3 (20 ml), and stirred at room temperature for 30 minutes. The two phases were separated, the organic layer was washed with brine, dried over Na2SO4 (anhydrous), filtered, and concentrated. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E52. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 7.06 Hz, 3 H) 2.24 (s, 3 H) 2.90 (td, J = 9.28, 5.09 Hz, 1 H) 3.19 - 3.69 (m, 2 H) 3.79 - 3.91 (m, 4 H) 3.96 - 4.12 (m, 2 H) 4.30 - 4.51 (m, 2 H) 4.52 - 4.71 (m, 1 H) 7.12 (t, J = 9.22 Hz, 1 H) 7.45 - 7.54 (m, 1 H) 7.54 - 7.63 (m, 1 H) 8.61 (br dd, J = 18.94, 9.40 Hz, 1 H) 9.26 (br t, J = 8.16 Hz, 1 H) 9.61 (d, J = 7.52 Hz, 1 H). Method 3; Rt: 3.71. m / z: 656.4 (M+H) + .

[0611] (Example E53) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide (E53)

[0612]

Chemical Structure

[0613] Starting from D54 instead of D31, it was prepared in the same manner as described for compound E43. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E53. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.34 Hz, 3 H) 2.24 (s, 3 H) 2.43 (s, 3 H) 2.84 - 3.05 (m, 1 H) 3.14 - 3.63 (m, 2 H) 3.67 - 3.76 (m, 3 H) 3.78 - 4.09 (m, 3 H) 4.37 - 4.54 (m, 2 H) 4.63 (br s, 1 H) 7.11 (t, J=9.17 Hz, 1 H) 7.40 - 7.53 (m, 1 H) 7.54 - 7.65 (m, 1 H) 8.36 - 8.60 (m, 1 H) 9.19 - 9.36 (m, 1 H) 9.36 - 9.47 (m, 1 H). Method 3; Rt: 3.58. m / z: 590.4 (M+H) + .

[0614] (Example E54) trans-8-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E54)

[0615] [Chemical Structure]

[0616] A solution of trans-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide hydrochloride (prepared as described in WO2020030781; 30 mg, 0.070 mmol), D43 (10.97 mg, 0.080 mmol) and DIPEA (34.2 μL, 0.200 mmol) in anhydrous DMF (0.5 mL) was added with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 37.6 mg, 0.080 mmol). The dark yellow solution was stirred at room temperature for 90 minutes and monitored by UPLC / MS. The reaction mixture was diluted with water (400 μL), acidified with formic acid (50 μL) and purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH) to give E54 (21.6 mg, 0.04 mmol). 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.43 - 0.56 (m, 2 H) 0.58 - 0.72 (m, 2 H) 1.40 - 1.66 (m, 1 H) 1.76 - 2.01 (m, 2 H) 2.25 (s, 3 H) 2.64 - 2.79 (m, 2 H) 3.04 - 3.20 (m, 1 H) 3.69 - 3.82 (m, 2 H) 3.82 - 3.88 (m, 3 H) 4.20 - 4.46 (m, 3 H) 7.12 (t, J=9.22 Hz, 1 H) 7.45 - 7.52 (m, 2 H) 7.54 - 7.62 (m, 1 H) 8.05 (br t, J=8.90 Hz, 1 H) 8.76 (d, J=4.40 Hz, 1 H) 9.27 (d, J=9.63 Hz, 1 H). Method 3; Rt: 3.01 min. m / z: 534 (M+H) + .

[0617] (Example E55) trans-8-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E55)

[0618] [Chemical formula]

[0619] D55 was used instead of D43 and prepared in the same manner as described for compound E54. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to give E55. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.42 - 1.68 (m, 1 H) 1.80 - 2.03 (m, 2 H) 2.25 (s, 3 H) 2.63 - 2.91 (m, 1 H) 3.08 - 3.25 (m, 1 H) 3.69 - 3.96 (m, 5 H) 4.20 - 4.72 (m, 7 H) 7.12 (t, J=9.17 Hz, 1 H) 7.42 - 7.53 (m, 2 H) 7.54 - 7.66 (m, 1 H) 8.03 (br s, 1 H) 9.20 - 9.42 (m, 1 H). Method 3; Rt: 3.27 min. m / z: 570 (M+H) + .

[0620] (Example E56) trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E56)

[0621] [Chemical]

[0622] Using D56 instead of D43, it was prepared in the same manner as described for compound E54. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E56. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (t, J = 6.90 Hz, 3 H) 1.46 - 1.68 (m, 1 H) 1.79 - 2.04 (m, 2 H) 2.24 (br d, J = 6.24 Hz, 3 H) 2.72 (s, 1 H) 3.11 - 3.25 (m, 1 H) 3.60 - 3.79 (m, 2 H) 3.80 - 3.87 (m, 3 H) 4.18 - 4.26 (m, 1 H) 4.26 - 4.47 (m, 2 H) 4.65 (br s, 1 H) 7.06 - 7.16 (m, 1 H) 7.42 - 7.68 (m, 3 H) 8.07 (br s, 1 H) 9.23 - 9.31 (m, 1 H) 9.36 - 9.47 (m, 1 H). Method 3; Rt: 3.38 min. m / z: 590 (M+H) + .

[0623] (Example E57) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E57)

[0624] [Chemical]

[0625] Using D58 instead of D43, it was prepared in the same manner as described for compound E54. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E57. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.45 - 1.70 (m, 1 H) 1.78 - 2.06 (m, 2 H) 2.24 (br d, J=5.04 Hz, 3 H) 2.68 - 2.89 (m, 1 H) 3.17 (q, J=12.81 Hz, 1 H) 3.66 - 3.86 (m, 5 H) 3.94 - 4.09 (m, 2 H) 4.19 - 4.46 (m, 3 H) 7.11 (td, J=9.10, 6.46 Hz, 1 H) 7.42 - 7.66 (m, 3 H) 8.07 (br s, 1 H) 9.27 (d, J=7.60 Hz, 1 H) 9.42 - 9.55 (m, 1 H). Method 3; Rt: 3.28. m / z: 576 (M+H) + .

[0626] (Example E58) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E58)

[0627]

Chemical Structure

[0628] Using D60 instead of D43, it was prepared in the same manner as described for compound E54. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E58. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49 - 1.68 (m, 7 H) 1.84 - 2.06 (m, 2 H) 2.23 (d, J=7.43 Hz, 3 H) 2.63 - 2.84 (m, 1 H) 3.11 - 3.24 (m, 1 H) 3.52 - 3.66 (m, 1 H) 3.70 - 3.79 (m, 1 H) 3.83 (s, 3 H) 4.18 - 4.52 (m, 3 H) 7.03 - 7.18 (m, 1 H) 7.44 - 7.64 (m, 3 H) 8.08 (br s, 1 H) 8.82 - 8.92 (m, 1 H) 9.24 - 9.31 (m, 1 H). Method 3; Rt: 3.49. m / z: 604 (M+H) + .

[0629] (Example E59) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E59)

[0630]

Chemical Structure

[0631] Using D41 instead of D43, it was prepared in the same manner as described for compound E54. The crude material was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E59. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.22 - 1.34 (m, 3 H) 1.46 - 1.68 (m, 1 H) 1.81 - 2.05 (m, 2 H) 2.24 (br d, J=6.24 Hz, 3 H) 2.66 - 2.86 (m, 1 H) 3.07 - 3.25 (m, 1 H) 3.59 - 3.79 (m, 2 H) 3.83 (d, J=2.66 Hz, 3 H) 4.22 (br s, 3 H) 4.58 - 4.75 (m, 1 H) 7.06 - 7.16 (m, 1 H) 7.42 - 7.64 (m, 3 H) 8.07 (br s, 1 H) 9.21 - 9.33 (m, 1 H) 9.36 - 9.49 (m, 1 H). Method 3; Rt: 3.38. m / z: 590 (M+H) + .

[0632] (Example E60) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E60)

[0633] [Chemical formula]

[0634] A solution of cis-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide hydrochloride (prepared as described in WO2020030781) (33 mg, 0.07 mmol), D41 (19.36 mg, 0.090 mmol) and DIPEA (37.57 μL, 0.22 mmol) in anhydrous DMF (0.7 mL) was added with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 41.34 mg, 0.09 mmol). The resulting solution was stirred at room temperature for 1 hour and monitored by UPLC / MS. The reaction mixture was diluted with EtOAc and water, and the organic layer was washed with 5% citric acid solution (×2) and water. The organic portion was dried over Na2SO4, filtered, concentrated under reduced pressure, and then the residue was purified by preparative HPLC (H2O / CH3CN + 1‰ HCOOH) to give E60 (31 mg, 0.052 mmol). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.21 - 1.39 (m, 3 H) 1.39 - 1.68 (m, 2 H) 2.24 (s, 3 H) 2.54 - 2.79 (m, 1 H) 2.97 - 3.16 (m, 1 H) 3.43 - 3.80 (m, 3 H) 3.81 (s, 3 H) 4.05 - 4.26 (m, 1 H) 4.26 - 4.56 (m, 2 H) 4.57 - 4.85 (m, 1 H) 7.11 (t, J=9.17 Hz, 1 H) 7.39 - 7.47 (m, 1 H) 7.47 - 7.55 (m, 1 H) 7.55 - 7.63 (m, 1 H) 7.86 - 8.15 (m, 1 H) 8.90 - 9.26 (m, 1 H) 9.27 - 9.44 (m, 1 H). Method 3; Rt: 3.47. m / z: 590.4 (M+H) + .

[0635] (Example E61) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E61)

[0636]

Chemical Structure

[0637] Using D58 instead of D41, it was prepared in the same manner as described for compound E60. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E61. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.36 - 1.66 (m, 2 H) 2.24 (s, 3 H) 2.54 - 2.72 (m, 1 H) 3.01 - 3.14 (m, 1 H) 3.47 - 3.77 (m, 2 H) 3.81 (s, 3 H) 3.86 - 4.27 (m, 4 H) 4.27 - 4.60 (m, 2 H) 7.11 (t, J=9.17 Hz, 1 H) 7.39 - 7.47 (m, 1 H) 7.48 - 7.55 (m, 1 H) 7.55 - 7.63 (m, 1 H) 7.90 - 8.19 (m, 1 H) 9.07 - 9.28 (m, 1 H) 9.34 (s, 1 H). Method 3; Rt = 3.37 min. m / z = 576.4 (M+H) + .

[0638] (Example E62) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E62)

[0639] [Chemical Structure]

[0640] Using D60 instead of D41, it was prepared in the same manner as described for compound E60. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E62. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.24 - 1.52 (m, 2 H) 1.52 - 1.68 (m, 6 H) 2.24 (s, 3 H) 2.54 - 2.79 (m, 1 H) 2.99 - 3.14 (m, 1 H) 3.46 - 3.79 (m, 3 H) 3.81 (s, 3 H) 4.06 - 4.24 (m, 1 H) 4.25 - 4.41 (m, 1 H) 4.41 - 4.57 (m, 1 H) 7.11 (t, J = 9.26 Hz, 1 H) 7.45 (d, J = 5.78 Hz, 1 H) 7.47 - 7.55 (m, 1 H) 7.55 - 7.65 (m, 1 H) 7.80 - 8.15 (m, 1 H) 8.26 - 8.68 (m, 1 H) 9.34 (s, 1 H). Method 3; Rt = 3.57 min. m / z = 604.4 (M+H) + .

[0641] (Example E63) cis-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E63)

[0642] [Chemical Structure]

[0643] Using D55 instead of D41, it was prepared in the same manner as described for compound E60. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E63. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 - 1.65 (m, 2 H) 2.24 (s, 3 H) 2.63 - 2.80 (m, 1 H) 3.02 - 3.13 (m, 1 H) 3.47 - 3.73 (m, 2 H) 3.75 - 3.91 (m, 4 H) 4.10 - 4.42 (m, 2 H) 4.43 - 4.59 (m, 3 H) 4.60 - 4.69 (m, 1 H) 4.70 - 4.95 (m, 1 H) 7.11 (t, J = 9.26 Hz, 1 H) 7.44 - 7.55 (m, 2 H) 7.56 - 7.63 (m, 1 H) 7.86 - 8.22 (m, 1 H) 9.35 (s, 1 H). Method 3; Rt = 3.31 min. m / z = 570.45 (M+H) + .

[0644] (Example E64) cis-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E64)

[0645]

Chem.

[0646] Using D43 instead of D41, it was prepared in the same manner as described for compound E60. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E64. 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.45 - 0.54 (m, 1 H) 0.54 - 0.78 (m, 3 H) 1.24 - 1.66 (m, 2 H) 2.24 (s, 3 H) 2.55 - 2.78 (m, 2 H) 2.95 - 3.12 (m, 1 H) 3.35 - 3.56 (m, 1 H) 3.59 - 3.73 (m, 1 H) 3.74 - 3.96 (m, 4 H) 4.01 - 4.21 (m, 1 H) 4.24 - 4.43 (m, 1 H) 4.43 - 4.58 (m, 1 H) 7.11 (t, J = 9.08 Hz, 1 H) 7.38 - 7.47 (m, 1 H) 7.47 - 7.55 (m, 1 H) 7.55 - 7.63 (m, 1 H) 7.82 - 8.14 (m, 1 H) 8.23 - 8.69 (m, 1 H) 9.33 (s, 1 H). Method 3; Rt = 3.10 min. m / z = 534.39 (M+H)+ Exact mass: 533.17

[0647] (Example E65) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E65)

[0648]

Chem.

[0649] Using D56 instead of D41, it was prepared in the same manner as described for compound E60. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E65. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.22 - 1.38 (m, 3 H) 1.39 - 1.70 (m, 2 H) 2.24 (s, 3 H) 2.55 - 2.78 (m, 1 H) 3.02 - 3.18 (m, 1 H) 3.38 - 3.78 (m, 3 H) 3.81 (s, 3 H) 4.07 - 4.25 (m, 1 H) 4.27 - 4.55 (m, 2 H) 4.56 - 4.81 (m, 1 H) 7.11 (t, J = 9.22 Hz, 1 H) 7.40 - 7.47 (m, 1 H) 7.47 - 7.55 (m, 1 H) 7.55 - 7.63 (m, 1 H) 7.85 - 8.27 (m, 1 H) 8.92 - 9.26 (m, 1 H) 9.34 (br s, 1 H). Method 3; Rt = 3.47 min. m / z = 590.38 (M+H) + .

[0650] (Example E66) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E66)

[0651]

Chemical Structure

[0652] A solution of trans-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide hydrochloride (prepared as described in WO2020030781; 30 mg, 0.065 mmol), D41 (19.36 mg, 0.09 mmol) and DIPEA (0.035 mL, 0.20 mmol) in anhydrous DMF (0.7 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 38 mg, 0.086 mmol). The resulting solution was stirred at room temperature for 1 hour and monitored by UPLC / MS. The reaction mixture was diluted with EtOAc and water, and the organic layer was washed with 5% citric acid solution (×2) and water. The organic portion was dried over Na2SO4, filtered, concentrated under reduced pressure, and then the residue was purified by preparative HPLC (H2O / CH3CN + 1‰ HCOOH) to give E66. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.21 - 1.59 (m, 4 H) 1.70 - 1.87 (m, 1 H) 1.99 - 2.17 (m, 1 H) 2.18 - 2.28 (m, 3 H) 2.60 - 2.77 (m, 1 H) 2.99 - 3.19 (m, 1 H) 3.38 - 3.73 (m, 2 H) 3.73 - 3.91 (m, 3 H) 4.01 - 4.16 (m, 1 H) 4.24 - 4.44 (m, 2 H) 4.55 - 4.76 (m, 1 H) 7.09 (t, J=9.12 Hz, 1 H) 7.42 - 7.52 (m, 2 H) 7.52 - 7.61 (m, 1 H) 8.03 - 8.22 (m, 1 H) 9.22 - 9.44 (m, 2 H). Method 3; Rt = 3.41 min. m / z = 590.4 (M+H) + .

[0653] (Example E67) trans-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E67)

[0654]

Chem.

[0655] Using D43 instead of D41, it was prepared in the same manner as described for compound E66. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E67. 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.43 - 0.58 (m, 2 H) 0.59 - 0.70 (m, 2 H) 1.47 (br d, J = 3.85 Hz, 1 H) 1.76 (br d, J = 11.55 Hz, 1 H) 2.06 (br d, J = 5.78 Hz, 1 H) 2.23 (s, 3 H) 2.57 - 2.75 (m, 2 H) 2.97 - 3.11 (m, 1 H) 3.45 (br t, J = 10.36 Hz, 1 H) 3.66 - 3.88 (m, 4 H) 4.01 - 4.14 (m, 1 H) 4.22 - 4.40 (m, 2 H) 7.08 (t, J = 9.17 Hz, 1 H) 7.43 - 7.52 (m, 2 H) 7.56 (br d, J = 6.79 Hz, 1 H) 8.09 - 8.20 (m, 1 H) 8.73 (dd, J = 7.47, 4.45 Hz, 1 H) 9.27 (s, 1 H). Method 3; Rt = 3.04 min. m / z = 534.4 (M + H) + .

[0656] (Example E68) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E68)

[0657]

Chem.

[0658] Using D58 instead of D41, it was prepared in the same manner as described for compound E66. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E68. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.28 - 1.58 (m, 1 H) 1.77 (br d, J = 10.73 Hz, 1 H) 2.07 (br d, J = 6.14 Hz, 1 H) 2.23 (s, 3 H) 2.67 (br t, J = 11.92 Hz, 1 H) 3.08 (br d, J = 12.38 Hz, 1 H) 3.40 - 3.71 (m, 2 H) 3.82 (s, 3 H) 3.91 - 4.14 (m, 3 H) 4.25 - 4.41 (m, 2 H) 7.09 (t, J = 9.22 Hz, 1 H) 7.43 - 7.59 (m, 3 H) 8.06 - 8.23 (m, 1 H) 9.28 (s, 1 H) 9.37 - 9.48 (m, 1 H). Method 3; Rt = 3.32 min. m / z = 576.4 (M+H) + .

[0659] (Example E69) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E69)

[0660]

Chem.

[0661] Using D60 instead of D41, it was prepared in the same manner as described for compound E66. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E69. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.32 - 1.61 (m, 7 H) 1.75 (br d, J = 12.75 Hz, 1 H) 2.06 (br d, J = 8.44 Hz, 1 H) 2.23 (s, 3 H) 2.55 - 2.71 (m, 1 H) 3.06 (q, J = 12.23 Hz, 1 H) 3.43 - 3.71 (m, 2 H) 3.82 (s, 3 H) 4.00 - 4.11 (m, 1 H) 4.21 - 4.39 (m, 2 H) 7.08 (t, J = 9.12 Hz, 1 H) 7.43 - 7.52 (m, 2 H) 7.52 - 7.58 (m, 1 H) 8.08 - 8.20 (m, 1 H) 8.77 - 8.85 (m, 1 H) 9.28 (d, J = 3.94 Hz, 1 H). Method 3; Rt = 3.54 min. m / z = 604.5 (M+H) + .

[0662] (Example E70) trans-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E70)

[0663] [Chemical Structure]

[0664] Using D55 instead of D41, it was prepared in the same manner as described for compound E66. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E70. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.19 - 1.57 (m, 1 H) 1.71 - 1.87 (m, 1 H) 1.98 - 2.16 (m, 1 H) 2.22 (s, 3 H) 2.60 - 2.79 (m, 1 H) 2.98 - 3.20 (m, 1 H) 3.34 - 3.59 (m, 1 H) 3.76 - 3.98 (m, 4 H) 4.13 (br d, J = 5.41 Hz, 1 H) 4.20 - 4.71 (m, 6 H) 7.07 (t, J = 9.17 Hz, 1 H) 7.43 - 7.53 (m, 2 H) 7.55 (br d, J = 6.97 Hz, 1 H) 8.18 (br d, J = 8.80 Hz, 1 H) 9.28 (s, 1 H). Method 3; Rt = 3.29 min. m / z = 570.3 (M+H) + .

[0665] (Example E71) trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E71)

[0666] [Chemical Structure]

[0667] Using D56 instead of D41, it was prepared in the same manner as described for compound E66. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E71. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.22 - 1.52 (m, 4 H) 1.77 (br d, J=11.74 Hz, 1 H) 2.06 (br d, J=8.07 Hz, 1 H) 2.23 (s, 3 H) 2.66 (br t, J=11.78 Hz, 1 H) 3.00 - 3.16 (m, 1 H) 3.42 - 3.71 (m, 2 H) 3.82 (s, 3 H) 4.02 - 4.15 (m, 1 H) 4.25 - 4.42 (m, 2 H) 4.56 - 4.72 (m, 1 H) 7.08 (t, J=9.17 Hz, 1 H) 7.43 - 7.52 (m, 2 H) 7.52 - 7.59 (m, 1 H) 8.05 - 8.22 (m, 1 H) 9.26 - 9.40 (m, 2 H). Method 3; Rt = 3.42 min. m / z = 590.4 (M+H) + .

[0668] (Example E72) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide (E72)

[0669]

Chem.

[0670] To a solution of cis-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocin-1-carboxamide 4,4-dioxide hydrochloride (prepared as described in WO2020030781; 16 mg, 0.03 mmol), D41 (9.39 mg, 0.050 mmol) and DIPEA (18 μL, 0.10 mmol) in anhydrous DMF (0.5 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 20.05 mg, 0.050 mmol). The reaction mixture was stirred at room temperature for 4 h, then diluted with water (400 μL), acidified with formic acid (50 μL) and purified by Fraction-Lynx (H2O / CH3CN + 1‰ HCOOH). The organic portion was dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC (H2O / CH3CN + 1‰ HCOOH) to afford E72. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.15 - 1.34 (m, 3 H) 1.71 - 2.02 (m, 2 H) 2.23 (br d, J=3.76 Hz, 3 H) 2.35 - 2.46 (m, 1 H) 2.86 - 3.61 (m, 3 H) 3.78 - 4.07 (m, 5 H) 4.15 - 4.75 (m, 3 H) 7.04 - 7.14 (m, 1 H) 7.45 - 7.60 (m, 3 H) 8.28 - 8.37 (m, 1 H) 9.24 - 9.30 (m, 1 H) 9.32 - 9.42 (m, 1 H). Method 3; Rt: 3.41 m / z: 590.45 (M+H) + .

[0671] (Example E73) cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide (E73)

[0672] [Chemical Structure Diagram]

[0673] Using D58 instead of D41, it was prepared in the same manner as described for compound E72. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E73. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.69 - 2.31 (m, 4 H) 2.36 - 2.51 (m, 5 H) 2.82 - 3.67 (m, 3 H) 3.77 - 4.54 (m, 6 H) 7.07 (td, J=9.26, 5.59 Hz, 1 H) 7.42 - 7.60 (m, 2 H) 8.34 (br d, J=9.45 Hz, 1 H) 9.04 - 9.38 (m, 2 H) 9.38 - 9.49 (m, 1 H). Method 3; Rt: 3.31 m / z: 576.40 (M+H) + .

[0674] (Example E74) (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E74)

[0675]

Chemical Structure

[0676] Instead of cis-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide hydrochloride, D63 was used and compound E72 was prepared in the same manner as described. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E74. Method 3: Rt = 3.68 min. m / z = 590.2 (M+H) + 。

[0677] (Example E75) (3aS,10aS)-N-(4-Fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide (E75)

[0678]

Chem.

[0679] Instead of cis-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocine-1-carboxamide 4,4-dioxide hydrochloride, D66 was used and compound E72 was prepared in the same manner as described. The crude product was purified by preparative HPLC (H2O / CH3CN + 0.1% HCOOH) to obtain E75. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.27 - 1.38 (m, 3 H) 2.24 (d, J = 1.47 Hz, 3 H) 3.41 - 4.06 (m, 9 H) 4.18 - 4.96 (m, 6 H) 5.94 (br dd, J = 16.23, 3.76 Hz, 1 H) 7.11 (t, J = 9.17 Hz, 1 H) 7.41 - 7.67 (m, 3 H) 8.02 - 8.59 (m, 1 H) 9.18 (d, J = 2.20 Hz, 1 H) 9.34 (br dd, J = 17.65, 9.03 Hz, 1 H). Method 3; Rt = 3.41 min; m / z = 592.34. (M+H) + .

[0680] Biology Assay Cells and culture conditions The HepAD38 cell system (Ladner et al., Antimicrob Agents Chemother, 1997, 41, 1715 - 1720) was used for the HBV inhibition assay. HepAD38 is a subclone derived from the hepatoblastoma cell line HepG2 (ATCC® number: HB - 8065™), and expresses the HBV genome (genotype D subtype ayw) under the transcriptional control of a tetracycline - responsive promoter in the TET - OFF system: the addition of antibiotics belonging to the class of doxycycline and tetracycline suppresses HBV replication, while the removal of them switches on a process that enables the release of HBV virus particles in the cell supernatant. The HepAD38 cell line is maintained in DMEM / F12 supplemented with 10% fetal bovine serum, 1% glutamine, 1% penicillin / streptomycin, 0.4 mg / ml G418 and 0.3 μg / ml tetracycline. For the HBV inhibition assay, doxycycline - free medium is used to enable virion production.

[0681] The HepG2 cell line was used for the HBV genotype and core variant inhibition assay. The HepG2 cell line is maintained in DMEM supplemented with 10% fetal bovine serum, 1% glutamine and 1% penicillin / streptomycin.

[0682] Anti - HBV activity in vitro The in vitro HBV inhibition activity was performed in 96 - well plates. During the first (primary) screening, compounds were first tested in triplicate at concentrations of 0.02 μM, 0.1 μM, 0.5 μM and 1 μM. For the selected compounds, an 8 - point dose - response curve was obtained using a 1:2 serial dilution (starting from 0.01 μM, 0.1 μM, 0.4 μM or 5 μM depending on the degree of inhibition observed during the primary screening). From the dose - response curve, the half - maximal effective concentration (EC 50 ) can be calculated (see also below).

[0683] More specifically, usually, the compound dissolved in the DMSO storage solution was diluted to 2× the final desired concentration in 100 μl of the above medium (without doxycycline) and plated in a 96-well plate with three replicates.

[0684] Simultaneously, HepAD38 cells that had been thoroughly pre-washed with doxycycline-free medium to induce HBV production were suspended in 100 μl of doxycycline-free medium at 2×10 4 cells and added to each well of the plate to obtain a final assay volume of 200 μl.

[0685] The DMSO used for the storage solution and compound dilution was always present in the assay at a final concentration of 0.5%.

[0686] The plate was incubated at 37 °C for 96 hours and then subjected to a cell viability assay and extracellular HBV quantification to evaluate both the cytotoxic performance and antiviral agent activity of the compound.

[0687] Cytotoxicity was evaluated by a commercially available fluorescence assay that measures the metabolic activity of cells, which is directly related to cell viability (Cell Titer Blue, Promega). For each compound, cytotoxicity was evaluated at the same concentrations used to evaluate its anti-HBV activity. Anti-HBV activity was evaluated by quantification of extracellular HBV DNA using direct qPCR. Specifically, the supernatant was collected, centrifuged for cell debris clarification, and viral DNA was extracted from the virions by the addition of lysis buffer (1 mM 1,4-dithiothreitol, 0.2% sodium dodecyl sulfate) and incubated at 95 °C for 10 minutes. The sample was then diluted 1:40 and real-time PCR amplification was performed using a SYBR green assay (Power SYBR™ Green PCR Master Mix - Thermo Fisher Scientific) and specific HBV primers (HBV-DF: 5'-ATTTGTTCAGTGGTTCGTAGGG-3' (SEQ ID NO: 1), HBV-DR: 5'-CGGTAAAAAGGGACTCAAGATG-3' (SEQ ID NO: 2)).

[0688] The antiviral activity data of each compound are reported as the EC 50 value (see the legend of Table 1). Excel and Graphpad Prism programs are commonly used for data refinement and EC 50 calculation.

[0689] Antiviral effect against HBV genotypes A - E Regarding the antiviral effect against HBV genotypes A - E, HepG2 cell line and DNA plasmids expressing HBV genomes of different genotypes A - E were used. HepG2 cells were transiently transfected with plasmid DNA having an over - length genomic sequence of 1.1 - mer of each HBV genotype A - E cloned into the pcDNA3.1 / Zeo(-) vector as described in J Virol. 2010, 84, 3879 - 3888 (https: / / doi.org / 10.1128 / JVI.02528 - 09). Each plasmid contains 1.1×HBV genome under the control of the CMV promoter. The list of plasmids used is as follows: pcDNA3.1 - HBV1.1 - A2 (HBV genotype A2), pcDNA3.1 - HBV1.1 - B2 (HBV genotype B2), pcDNA3.1 - HBV1.1 - C2 (HBV genotype C2), pcDNA3.1 - HBV1.1 - D (HBV genotype D, described as p26 in the above reference), pcDNA3.1 - HBV1.1 - E (HBV genotype E). The method for generating plasmids is well - known in the art (e.g., as in Viruses 2020, 12, 353, doi:10.3390 / v12030353; Antiviral Research 144 (2017) 205 - 215, http: / / dx.doi.org / 10.1016 / j.antiviral.2017.06.016), and the selection of a suitable method is not a limitation of the present invention.

[0690] HepG2 cells were seeded at 2*10 4Cells were seeded at a density of 50 cells / well and incubated overnight at 37°C. The next day, cells were transfected with HBV plasmid (100 ng / well) using Lipofectamine 3000 reagent (Thermo Fisher Scientific) according to the manufacturer's instructions. After 5 hours of transfection, the mixture was harvested and cells were treated with the compound serially diluted with 0.5% DMSO at 8-point dose response as previously described. After incubation with the compound at 37°C for 96 hours, the supernatant was collected, centrifuged for cell debris clarification, and incubated with DNase I amplification grade 1 unit / 50 μl (Sigma) for 1 hour at 37°C to enable digestion of plasmid input. Extracellular HBV DNA quantification was performed using direct qPCR as previously described. To avoid non-specific detection of HBV plasmid and to confirm plasmid digestion, specific primers designed across the plasmid backbone and HBV sequence were added as controls (HBV-CNT-gt-F: 5'-AACTCCGCCCCATTGACGCAAA-3' (SEQ ID NO: 3), HBV-CNT-gt-R: 5'-AAAGCCACCCAAGGCACAGCTT-3' (SEQ ID NO: 4)). Antiviral activity data for each genotype were reported as the average value. Furthermore, the observed 50 and the ratio between that of genotype D used as the reference genotype (see results, legend of Table 2) were 50 corresponded to the 50 shift value. Excel and Graphpad Prism programs were commonly used for data refinement and 50 calculation.

[0691] Antiviral effect against naturally occurring core variants The test procedure for the antiviral effect against HBV core protein variants was the same as that previously described for the antiviral effect against HBV genotypes A - E. Based on its ability to reduce the potency of currently developing CAM (literature data), various core point mutants (F23Y, F110I, I105T, L37Q, T33N, T33P, T128I, V124G, Y118F) were selected and introduced into a plasmid containing the HBV genome of genotype D (the above - mentioned, pcDNA3.1 - HBV1.1 - D). By site - directed mutagenesis of the parental plasmid pcDNA3.1 - HBV1.1 - D (p26 in J Virol. 2010, 84, 3879 - 3888), the following list of plasmids was generated: pcDNA3.1 - HBV1.1 - D - CoreF23Y, pcDNA3.1 - HBV1.1 - D - CoreF110I, pcDNA3.1 - HBV1.1 - D - Core I105T, pcDNA3.1 - HBV1.1 - D - CoreL37Q, pcDNA3.1 - HBV1.1 - D - CoreT33N, pcDNA3.1 - HBV1.1 - D - CoreT33P, pcDNA3.1 - HBV1.1 - D - CoreT128I, pcDNA3.1 - HBV1.1 - D - CoreV124G, pcDNA3.1 - HBV1.1 - D - CoreY118F (the point mutations in the nucleotide codons for the indicated core amino acid substitutions are as follows: TTC / TAC for F23Y, TTT / ATT for F110I, ATT / ACT for I105T, CTG / CAG for L37Q, ACC / AAC for T33N, ACC / CCC for T33P, ACT / ATT for T128I, GTG / GGG for V124G, TAT / TTT for Y118F). The antiviral activity data for each variant were reported as the EC 50 mean and EC 50 shift (see the legend of Table 1 for results). For data refinement and EC 50 calculation, Excel and Graphpad Prism programs are commonly used.

[0692] Results The exemplified compounds presented herein were tested in the above assay. All compounds did not exhibit significant cytotoxicity at all concentrations of the dose-response curve (maximum test dose of 0.01 μM, 0.1 μM, 0.4 μM, or 5 μM, depending on compound potency).

[0693] The results of HBV inhibition are reported in Table 1 below.

[0694]

Table 1A

[0695]

Table 1B

[0696]

Table 1C

[0697]

Table 1D

[0698]

Table 1E

[0699]

Table 1F

[0700]

Table 1G

[0701] The data in Table 1 demonstrate that the compounds of the present invention are all extremely potent inhibitors of HBV replication and always have EC50 values in the nanomolar range.

[0702] Antiviral effect against HBV genotypes A - E Compound E15 was selected as a representative compound to evaluate the antiviral activity of the class of compounds of the present invention against HBV genotypes A - E. The antiviral activity data for each genotype are reported as the EC 50 mean value and the EC 50 shift compared to genotype D. Transient transfection of HepG2 cells using plasmids with different HBV genotypes showed that compound E15 behaved as a pan - genotype (A to E) anti - HBV agent. As shown by the EC 50 values and the relative EC 50 shift from genotype D, minimal variation in anti - HBV activity was observed across genotypes A - E.

[0703]

Table 2

[0704] Antiviral effect against naturally occurring core variants The representative compound E15, which shows an EC 50 shift ≥ 2 against known CAM (literature data), was tested against a panel of nine variants of the HBV core protein. The compounds of the present invention showed low / medium nanomolar EC 50 against each mutant, including the most resistant variant T33N (associated with a high potency shift compared to other CAM). All HBV variants remained sensitive to inhibition by E15 and had an average EC 50 fold change in the range of 0.7 - 29.5 times compared to those obtained from the wild - type (genotype D). These data demonstrate that the compounds of the present invention have broad - spectrum activity and are active against wild - type HBV and several mutants that can be resistant to other CAM. The EC 50 values and the relative EC 50 shift against the wild - type are included in Table 3.

[0705]

Table 3

Claims

1. General formula (I): 【Chemical 1】 [wherein, Cy is aryl, A is C-R 3 or N, and X is O or S, Y is methylene, Y' and Y'' are methylene or ethylene, Y''' is a single bond, R 1 is H or C 1～6 is alkyl, R 2 is selected from H, OH, and C 1～6 alkyl, and R 3 is selected from H, C 1～6 alkyl, and halogen, R 5 is H or C 1～6 and is alkyl, or R 2 and R 5 together form a C 1～6 alkanediyl bridge, R 6 is selected from H, C 1～6 alkyl, C 3～8 cycloalkyl, C 3～8 heterocycloalkyl, C 1～6 alkylaryl, C 1～6 alkylheteroaryl and C 1～6 alkyl-C 3～8 cycloalkyl, and each of the C 1～6 alkyl, C 3～8 cycloalkyl, C 3～8 heterocycloalkyl, C 1～6 alkylaryl, C 1～6 alkylheteroaryl or C 1～6 alkyl-C 3～8 cycloalkyl may each be substituted with one or more substituents independently selected from OH, halogen, haloC 1～6 alkyl, cyano and NH 2 and may be substituted accordingly. R 7 and R 8 each of which is - hydrogen, -OH, halogen, CN, NH 2 , NH(R 9 ), N(R 9 ), 2 , haloC 1～6 alkyl, aryl, heteroaryl, one or more substituents each independently selected from the group consisting of 3- to 7-membered saturated rings and 5- to 7-membered partially saturated rings, optionally substituted C 1～12 alkyl, wherein each of said saturated or partially saturated rings may contain one or more heteroatoms selected from the group consisting of O, N and S, and each of said aryl, heteroaryl, 3- to 7-membered saturated ring or 5- to 7-membered partially saturated ring is OH, halogen, C 1～6 alkyl, haloC 1～6 alkyl, CN, haloC 1～6 alkoxy and C 1～6 alkoxy, optionally substituted with one or more substituents each independently selected therefrom, C 1～12 alkyl, - aryl or heteroaryl, each of said aryl or heteroaryl being optionally substituted with one or more substituents independently selected from OH, halogen, haloC 1～6 alkyl, CN, haloC 1～6 alkoxy and C 1～6 alkoxy, and aryl or heteroaryl optionally substituted with one or more substituents independently selected from each of the foregoing, and A 3- to 8-membered saturated or partially saturated cyclic or bicyclic ring which may contain one or more heteroatoms each independently selected from the group consisting of O, S, and N, and which is substituted with one, two or more substituents each independently selected from the group consisting of OH, halogen, CN, C 1～6 alkyl, hydroxy C 1～6 alkyl, C(O)OR 9 、C(O)R 9 、halo C 1～6 alkyl, halo C 1～6 alkoxy and C 1～6 alkoxy, and which may be substituted with one, two or more substituents each independently selected from the group consisting of OH, halogen, CN, C are independently selected from, or R 7 and R 8 together with the nitrogen atom to which they are attached form a cyclic amine selected from aziridine, azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine and piperazine, each of said cyclic amines being optionally substituted with one or more substituents independently selected from the group consisting of OH, halogen, CN, C 1～6 alkyl, hydroxy C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy and C 1～6 alkoxy, and may be substituted with one or more substituents independently selected from the group consisting of Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, halogen, CN, C 1～6 alkyl, C 1～6 alkoxy, haloC 1～6 alkyl, haloC 1～6 alkoxy, C(O)OR 9 , C(O)R 9 , NH 2 , NH(R 9 ), N(R 9 ) 2 , C(O)N(R 9 ) 2 , SO 2 N(R 9 ) 2 , and NHCON(R 9 ) 2 and are each independently selected from the group consisting of Each R 9 is independently selected from H, C 1～6 alkyl, halo C 1～6 alkyl, C 1～6 alkylaryl, C 1～6 alkylheteroaryl and C 1～6 alkyl-C 3～8 cycloalkyl a compound represented by or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

2. Formula (I-A): 【Chemical 2】 [wherein, Cy, X, Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , Ra, Rb, Rc, and Rd are the same as defined in claim 1 a compound represented by, the compound according to Claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

3. Formula (I-B): [Chemical 3] [wherein, Cy, X, Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , Ra, Rb, Rc, and Rd are the same as defined in claim 1 a compound represented by, the compound according to Claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

4. Formula (II-A), Formula (III-A) or Formula (III-B): 【Chemical 4】 [wherein, X is O or S, R 2 is H, C 1～6 alkyl or OH, and R 3 is H, C 1～6 alkyl or halogen, and R 4 is H and Cy, R 1 , R 5 , R 6 , R 7 , R 8 , Ra, Rb, Rc, and Rd are as defined in claim 1 a compound represented by, the compound according to Claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

5. Cy is phenyl, R 1 is CH 3 and R 3 is H, methyl, chlorine or bromine, and R 5 is hydrogen or methyl, and R 6 is hydrogen, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

6. R 7 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, and a group represented by the following formula 【Chemical Formula 7】 selected from the group consisting of, and / or R 8 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, and a group represented by the following formula [Chemical 8] selected from the group consisting of, the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

7. - cis-2-(2-(dimethylamino)-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - cis-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-7-Methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-cyano-4-fluorophenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - cis N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - cis-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - cis-7-Methyl-2-(2-(methylamino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - cis-2-(2-Amino-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((3,3-Difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isobutylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-2-(2-(isopropylamino)-2-oxoacetyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(Cyclobutylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - cis-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - Trans-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - Trans-2-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((1-(trifluoromethyl)cyclobutyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-Amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((Cyclopropylmethyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7-methyl-2-(2-((1-methylcyclopropyl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-2-(2-((3,3-difluorocyclobutyl)amino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocin-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-Chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-6-bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - (3aR,10aR)-N-(4-fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; - trans-8-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocine-1-carboxamide 4,4-dioxide; - trans-8-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazocine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-7-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-7-(2-(3,3-Difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - trans-N-(4-Fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - cis-N-(4-Fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazine-1-carboxamide 4,4-dioxide; - (3aR,10aR)-N-(4-Fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; and - (3aS,10aS)-N-(4-Fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazocine-8-carboxamide 5,5-dioxide; The compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, selected from the group consisting of.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

9. The pharmaceutical composition according to claim 8 for the treatment and / or prevention of HBV infection.

10. The pharmaceutical composition according to claim 8 for the treatment and / or prevention of HBV infection, chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, or inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and / or liver injury resulting from HBV infection.

11. Treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or reduction of viral load associated with HBV infection in an individual in need thereof, and / or reduction of recurrence of HBV infection in an individual in need thereof, and / or induction of remission of liver injury resulting from HBV infection in an individual in need thereof, and / or prophylactic treatment of HBV infection in an individual suffering from potential HBV infection, the pharmaceutical composition according to claim 8.

12. The pharmaceutical composition according to claim 10, wherein the HBV infection, chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, or inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and / or liver injury resulting from HBV infection is caused by HBV of any genotype including genotype A, B, C, D or E, and / or is caused by a drug-resistant HBV mutant.

13. The pharmaceutical composition according to any one of claims 8 to 12, further comprising at least one additional therapeutic agent.

14. The at least one additional therapeutic agent is a therapeutic vaccine, an RNA interference therapeutic agent / antisense oligonucleotide, an immunomodulatory substance, a STING agonist, a RIG-I modulator, an NKT modulator, an IL agonist, an interleukin or another immunologically active protein, a therapeutic and prophylactic vaccine, an immune checkpoint modulator / inhibitor, an HBV entry inhibitor, a cccDNA modulator, an inhibitor of HBV protein expression, a drug targeting HBV RNA, a capsid assembly inhibitor / modulator, a core or X protein targeting agent, a nucleotide analogue, a nucleoside analogue, interferon or a modified interferon, an HBV antiviral agent of a distinct or unknown mechanism, a cyclophilin inhibitor, an sAg release inhibitor, an HBV polymerase inhibitor, a dinucleotide, a SMAC inhibitor, an HDV targeting agent, a virus maturation inhibitor, a reverse transcriptase inhibitor, an HBV RNA destabilizing agent or another small molecule inhibitor of HBV protein expression, and combinations thereof, the pharmaceutical composition according to claim 13.

15. The therapeutic vaccine is selected from HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (HB-110E), CVI-HBV-002, RG7944 (INO-1800), TG-1050, FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204, NU-500, INX-102-00557, HBV MVA, and PepTcell; the RNA interference therapeutic agent is selected from TKM-HBV (ARB-1467), ARB-1740, ARC-520, ARC-521, BB-HB-331, REP-2139, ALN-HBV, ALN-PDL, LUNAR-HBV, GS3228836, and GS3389404; the immunomodulatory substance is a TLR agonist; the RIG-I modulator is SB-9200; the IL agonist or other immunomodulatory protein is INO-9112 or recombinant IL12; the immune checkpoint modulator / inhibitor is BMS-936558 (Opdivo (nivolumab)) or pembrolizumab; the HBV entry inhibitor is Myrcludex B, IVIG-Tonrol, or GC-1102; the cccDNA modulator is selected from direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, and inhibitors of cccDNA transcription; the capsid assembly inhibitor / modulator, core or protein targeting agent, direct cccDNA inhibitor, inhibitor of cccDNA formation or maintenance, or cccDNA epigenetic modifier is BAY 41-4109, NVRSelected from 3-778, GLS-4, NZ-4 (W28F), Y101, ARB-423, ARB-199, ARB-596, AB-506, JNJ-56136379, ASMB-101 (AB-V102), ASMB-103, CHR-101, CC-31326, AT-130, EP-027367 and RO7049389, wherein the interferon or modified interferon is interferon alpha (IFN-α), pegylated interferon alpha (PEG-IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, peginterferon alpha-2a (Pegasys), interferon alpha-2b (Intron A), recombinant interferon alpha-2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, peginterferon beta-1a, interferon delta, interferon lambda (IFN-λ), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon alphacon-1, interferon alpha-n1, interferon alpha-n3, albuinterferon alpha-2b, BLX-883, DA-3021, PI101 (also known as AOP2014), PEG-infergen, Belerofon, INTEFEN-IFN, albumin / interferon alpha 2a fusion protein, rHSA-IFN alpha 2a, rHSA-IFN alpha 2b, PEG-IFN-SA, and interferon alpha biobetter, wherein the HBV antiviral agent of the above-mentioned distinct or unknown mechanism is selected from AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), its analogs, REP-9AC (REP-2055), REP-9AC' (REP-2139), REP-2165, and HBV-0259, wherein the cyclophilin inhibitor is selected from OCB-030 (NVP-018), SCY-635, SCY-575, and CPI-431-32, wherein the HBV polymerase inhibitor is selected from entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevudine, besifovir, adefovir (hepsera), tenofovir, tenofovir disoproxil fumarate (Viread), tenofovir alafenamide fumarate (TAF), tenofovir disoproxil orotate (DA-2802), tenofovir disoproxil aspartate (CKD-390), AGX-1009, and CMX157, wherein the dinucleotide is SB9200, wherein the SMAC inhibitor is birinapant, wherein the HDV targeting agent is lonafarnib, and wherein the HBV RNA destabilizing agent or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452, the pharmaceutical composition according to claim 14.

16. The pharmaceutical composition according to any one of claims 8 to 15, comprising at least one pharmaceutically acceptable excipient.

17. A is C-R 3 wherein Y' and Y'' are both methylene, Y''' is a single bond, R 1 is methyl, R 6 is H, Cy, X, Y, R 2 , R 3 , R 5 , R 7 , R 8 , Ra, Rb, Rc and Rd are as defined in claim 1, a process for synthesizing a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, comprising 【Chemical Formula 9】 - reacting a compound of formula (5a) wherein m and n are 1 with a compound of formula (8a) or a compound of formula (8b) A method comprising.

18. A is C-R 3 wherein Y' and Y'' are both methylene, Y''' is a single bond, R 1 is methyl, R 6 is H, Cy, X, Y, R 2 , R 3 , R 5 , R 7 , R 8 , Ra, Rb, Rc and Rd are as defined in claim 1, a process for preparing a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, 【Chemical Formula 10】 - A method comprising the step of reacting a compound of formula (6) in which m and n are 1 with an amine of formula NHR 7 R 8 .

19. A is C-R 3 wherein Y' and Y'' are both methylene, Y''' is a single bond, R 1 is methyl, R 6 is H, Cy, X, Y, R 2 , R 3 , R 5 , R 7 , R 8 , Ra, Rb, Rc and Rd are as defined in claim 1, a process for synthesizing a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, 【Chemical 11】 - A method comprising the step of reacting a compound of formula (7) wherein m and n are 1 with an amine of formula NHR 7 R 8 .

20. The method according to claim 18, comprising reacting the compound of formula (5a) according to claim 17 with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (6) according to claim 18.

21. A process according to claim 19, comprising the step of hydrolyzing the compound of formula (6) according to claim 18 in the presence of a base to obtain the compound of formula (7) according to claim 19.

22. Formula (9), which is a compound of general formula (I) according to claims 17 to 21: 【Chemical 12】 [Wherein, Cy, X, Y, R 2 , R 5 , R 7 , R 8 , Ra, Rb, Rc, and Rd are the same as defined in claim 1, m and n are 1, and R 3 = H], the compound is reacted with sulfur dichloride in a dichloromethane solvent to obtain a compound of formula (9) wherein R 3 = Cl. The method according to any one of claims 17 to 21, comprising the step of

23. Formula (9), which is a compound of general formula (I) according to claims 17 to 21: 【Chemical 13】 [wherein Cy, X, Y, R 2 , R 5 , R 7 , R 8 , Ra, Rb, Rc, and Rd are the same as defined in claim 1, m and n are 1, and R 3 =H], the compound is reacted with N-bromosuccinimide in a chloroform solvent to obtain a compound of formula (9) wherein R 3 =Br. The method according to any one of claims 17 to 21, comprising the step of

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