Oxamide substituted hepatitis B virus tricyclic inhibitors

Abstract

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

Description

Technical Field

[0001] The present invention relates to compounds as hepatitis B virus (HBV) inhibitors. The compounds of the present invention can be used alone or in combination with other agents to treat, improve, prevent or cure HBV infection and related conditions. The present invention also relates to pharmaceutical compositions containing the compounds. Background of the Invention

[0003] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the family Hepadnaviridae that is transmitted through contact with infected blood and body fluids and causes acute and chronic necrotizing inflammatory liver disease of varying severity (Guidotti LG, Chisari FV. Annual Review of Disease Pathogenesis (Annu Rev Pathol). 2006; 1: 23-61). The HBV lipid envelope contains three in-frame viral envelope proteins (large, medium, and small), each of which has a hepatitis B virus surface antigen (HBsAg) determinant cluster (Seeger C, Mason WS. Virology. 2015 May; 479-480: 672-86). The envelope encloses a protein shell or capsid, which is composed of 240 monomers of the core protein, each of which has a hepatitis B virus core antigen (HBcAg or Cp) determinant cluster. The capsid, in turn, surrounds a partially double-stranded, relaxed circular DNA (rcDNA) form of the viral genome, as well as the viral polymerase molecule. After entering susceptible cells (i.e., hepatocytes) through the interaction of the large envelope protein with specific receptors on the hepatocyte membrane, the capsid is released into the cytoplasm and transported at the nuclear membrane. The rcDNA is then released into the nucleus and repaired by the cellular polymerase into an additional "mini-chromosome" called covalently closed circular DNA (cccDNA), which represents the viral transcription template. The negative strand of the viral DNA encodes 3.5, 2.4, 2.1, and 0.7 kb mRNA species, which are translated into the structural (envelope and core) and non-structural (polymerase, pre-core, and X) proteins of the virus. After transport to the cytoplasm, one of the 3.5 kb RNAs (called the pregenomic RNA) is selectively packaged into the nascent capsid by interacting with the core and polymerase proteins translated from their respective mRNAs. Within these capsids, the viral polymerase reverse transcribes the pregenomic RNA into a single negative (-) strand DNA molecule that serves as a template for viral polymerase-mediated DNA positive (+) strand synthesis, and the cohesive structure of the linear DNA intermediates converts them into relaxed circular double-stranded molecules. A portion of these "mature" capsids containing HBV DNA are transported back to the nucleus, where second strand synthesis is completed and the ends of the two strands are connected, resulting in the amplification of the cccDNA pool. Another portion of the capsid binds to viral envelope proteins that have been independently translated and translocated to the membrane of the endoplasmic reticulum (ER)-like structure. After binding, the enveloped capsid enters the ER lumen and leaves the cell as an infectious virion to begin a new infection cycle.

[0004] Therefore, HBV core protein and related capsids are important components and regulators of the HBV life cycle. The full-length core protein Cp183 or its N-terminal domain Cp149 mainly assembles into T=4 icosahedral capsids. Due to its key role in capsid assembly, pregenomic RNA packaging and cccDNA maintenance, it is not surprising that HBV core protein and related capsids are widely considered to be attractive antiviral targets (Durantel D, Zoulim F; J Hepatol. 2016 Apr; 64(1 Suppl): S117-S131).

[0005] According to the World Health Organization (WHO), HBV infection is one of the major medical scourges of our time. As a sexually transmitted disease that is also transmitted through intravenous drug abuse and from mother to baby at birth, more than one-third of the world's population is infected with HBV at some point in their life (Burns GS, Thompson AJ; Cold Spring Harb Perspect Med. 2014 Oct 30;4(12)). Although the majority of these individuals have successfully cleared the virus, more than 250 million remain persistently infected, and nearly 900,000 of them die each year from complications of chronic infection (i.e., cirrhosis and / or hepatocellular carcinoma). HBV infection is highly endemic in sub-Saharan Africa, the Pacific region, and particularly Asia. Regions with high rates of chronic HBV infection also include the Middle East, the Indian subcontinent, South and Central America, and eastern and southern central Europe. The number of chronic carriers has also been steadily increasing in the Western world in recent years, largely due to an influx of immigrants from endemic regions. Furthermore, HBV is a helper virus for hepatitis delta virus (HDV), and it should be noted that the more than 15 million people co-infected with HBV and HDV are at increased risk for rapid progression to cirrhosis and hepatic decompensation (Hughes, SA et al., Lancet 2011, 378, 73-85).

[0006] Well-tolerated vaccines that generate HBsAg-neutralizing antibodies are effective in preventing de novo HBV infection but have no therapeutic potential for the millions of people who are already persistently infected (Zoulim, Durantel D; Cold Spring Harb Perspect Med. 2015 Apr 1;5(4)). Treatment for these people relies primarily on direct-acting antiviral (DAA) drugs (e.g., tenofovir, lamivudine, adefovir, entecavir, or telbivudine), which suppress viral production but do not eradicate HBV from the liver, requiring lifelong treatment. Some patients still receive pegylated interferon-α (PEG-IFN-α)-based therapy, which has the advantages of limited treatment duration and high HBsAg seroconversion rates, but is associated with significant side effects. As a result, the number of patients receiving PEG-IFN-α is gradually decreasing.

[0007] Different chemical classes of inhibitors targeting the encapsidation process of HBV (also called capsid assembly modulators or CAMs) are under development, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs). For example, Novira Therapeutics recently demonstrated using a humanized mouse model of HBV infection that a combination of CAM and PEG-IFN-α had higher antiviral activity than previously observed with DAAs. NVR3-778 is the first member of this class of CAMs, showing significant reductions in both HBV DNA and serum HBV RNA in a Phase 1b proof-of-concept clinical study. The compound was recently discontinued. The compound JNJ-56136379 (or JNJ-6379), developed by Janssen, recently showed potent antiviral activity and is currently entering Phase 2 clinical trials.

[0008] WO2013 / 006394 published on January 10, 2013 relates to a subclass of sulfamoyl-aryl amides having the general formula A, which can be used to treat hepatitis B virus (HBV) infection:

[0009]

[0010] WO2013 / 096744 published on June 26, 2013 relates to sulfamoyl-aryl amides of formula B having anti-HBV activity:

[0011]

[0012] WO2014 / 106019 published on July 3, 2014 relates to compounds of formula C, which can be used as nucleocapsid assembly inhibitors to treat viruses, particularly but not exclusively, including HBV pregenomic RNA encapsidation inhibitors for the treatment of hepatitis B virus (HBV) infection and related conditions:

[0013]

[0014] 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 having anti-HBV activity.

[0015] WO2015 / 120178 published on August 13, 2015 relates to sulfamoyl-arylamide compounds for use in combination therapy with peginterferon alpha-2a or another interferon analog for the treatment of HBV infection.

[0016] WO2016 / 089990 published on June 9, 2016 relates to sulfonated alkyl and pyridyl trans-sulfonamide compounds for HBV treatment.

[0017] US2016185748 published on June 30, 2016 relates to pyridyl trans-sulfonamides for HBV treatment.

[0018] US2016151375 published on June 2, 2016 relates to sulfonated alkyl compounds for HBV treatment.

[0019] WO2017 / 001655A1 published on January 5, 2017 relates to cyclized sulfamoyl arylamide derivatives having the following structure:

[0020]

[0021] Potential problems encountered with HBV direct-acting antivirals are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility, and / or off-target activity, and to date, no compounds from any of the above structural classes have been approved as drugs for the treatment of HBV patients.

[0022] There is a need for additional HBV inhibitors that may overcome at least one of these disadvantages or possess other advantages, such as increased efficacy, increased bioavailability, or increased safety period. SUMMARY OF THE INVENTION

[0024] The present invention provides a small molecule drug obtained by chemically modifying a known sulfonyl arylamide derivative. In particular, the compound of the present invention is characterized by a fused tricyclic core structure, which includes a pyrrole ring and carries an oxalamide substituent at a specific position of the fused tricyclic core. The chemical type found in the present invention leads to a potent HBV inhibitor with improved pharmacokinetic properties, good kinetic solubility, stability in mouse and human hepatocytes, low in vivo clearance and positive liver-to-plasma concentration. In view of the key role of the liver in metabolic regulation and the fact that it is the main tissue affected by hepatitis B disease, designing HBV inhibitors with liver-selective distribution characteristics is an important strategy for developing safe candidate drugs (Tu M. et al., Current Topics in Medicinal Chemistry, 2013, 13, 857-866). The compound of the present invention also has pan-genotype activity, so it shows minimal changes in anti-HBV activity between genotypes AE, and is active against wild-type HBV and several variants that may be resistant to other CAMs. DETAILED DESCRIPTION

[0025] The compounds of the present invention are inhibitors of hepatitis B virus (HBV).

[0026] Therefore, one of the objects of the present invention is the compounds of general formula (I):

[0027]

[0028] in:

[0029] Cy is aryl or heteroaryl;

[0030] A is C-R3 or N;

[0031] X is O, S, NH, SO, SO2 or a single bond;

[0032] Y, Y', Y" and Y'" are each independently C optionally substituted with one or more R4 1-6 Alkanediyl or C 2-7 alkenediyl, or a single bond;

[0033] R1 is H or C 1-6 alkyl;

[0034] R2 is selected from H, OH, halogen and C 1-6 alkyl;

[0035] R3 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl and halogen;

[0036] R4 is selected from H, OH, C 1-6 Alkyl, C 3-8 Cycloalkyl and halogen, or two pairs of R4 together with the atoms to which they are attached form a spiro-C 3-8 Cycloalkyl or spiro-C 3-8 Heterocycloalkyl;

[0037] R5 is H or C 1-6 alkyl;

[0038] Or R2 and R5 together form C 1-6 Alkanediyl bridge;

[0039] R6 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl and C 1-6 Alkyl-C 3-8 Cycloalkyl, wherein each of the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl or C 1-6 Alkyl-C 3-8 The cycloalkyl group is optionally substituted with each independently selected from OH, halogen, halo 1-6 Alkyl, cyano and NH2 are substituted with one or more substituents;

[0040] Each of R7 and R8 is independently selected from:

[0041] -hydrogen;

[0042] -C 1-12 Alkyl, which is optionally substituted by one or more substituents each independently selected from the group consisting of OH, halogen, CN, NH2, NH(R9), N(R9)2, halo 1-6 alkyl, aryl, heteroaryl, 3-7 membered saturated ring and 5-7 membered partially saturated ring, each of the saturated or partially saturated ring optionally contains one or more heteroatoms selected from O, N and S, and each of the aryl, heteroaryl, 3-7 membered saturated ring or 5-7 membered partially saturated ring is optionally substituted by one or more each independently selected from OH, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, CN, halogenated C 1-6 Alkoxy and C 1-6 substituted by an alkoxy substituent;

[0043] - aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of OH, halogen, halogenated C 1-6 Alkyl, CN, halogenated C 1-6 Alkoxy and C 1-6 Alkoxy; and

[0044] - a 3-8 membered saturated or partially saturated ring or bicyclic ring, which optionally contains one or more heteroatoms each independently selected from O, N and S, and the 3-8 membered saturated or partially saturated ring or bicyclic ring is optionally substituted by 1, 2 or more substituents each independently selected from the following group: OH, halogen, CN, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C(O)OR9, C(O)R9, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and C 1-6 Alkoxy;

[0045] or R7 and R8 together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of aziridine, azetidine, pyrrolidine, piperidine, azetidine, morpholine, thiomorpholine and piperazine, each of which is optionally substituted by one or more each independently selected from OH, halogen, CN, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and C 1-6 substituted by an alkoxy substituent;

[0046] Ra, Rb, Rc and Rd are each independently selected from hydrogen, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C(O)OR9, C(O)R9, NH2, NH(R9), N(R9)2, C(O)N(R9)2, SO2N(R9)2, NHCON(R9)2;

[0047] Each R9 is independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl and C 1-6 Alkyl-C 3-8 Cycloalkyl;

[0048] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0049] In a particular embodiment, R2 is selected from H, OH and C1-6 Alkyl; Ra, Rb, Rc and Rd are each independently selected from hydrogen, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy, C(O)OR9, C(O)R9, NH2, NH(R9) and N(R9)2; and each R9 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl and C 1-6 Alkyl-C 3-8 Cycloalkyl.

[0050] Preferably, Cy is aryl. Preferably, X is O or S. Preferably, Y is methylenediyl, Y' and Y" are methylenediyl or ethylenediyl and Y'" is a single bond.

[0051] Preferably, R2 is H, C 1-6 Alkyl or OH and R3 is H or C 1-6 Alkyl or halogen.

[0052] In one embodiment, the present invention relates to compounds of formula (IA):

[0053]

[0054] or a compound of formula (IB):

[0055]

[0056] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof. In particular, in Formula IA, R2 is H or C 1-6 Alkyl; R3 is H, C 1-6 Alkyl or halogen and the remaining substituents are as defined above.

[0057] In a preferred embodiment, the compound of the present invention has the formula (II-A), (III-A) or (III-B):

[0058]

[0059]

[0060] in:

[0061] X is O, S, NH, SO, SO2;

[0062] R2 is H, C 1-6 Alkyl or OH;

[0063] R3 is H, C 1-6 Alkyl or halogen;

[0064] Each R4 is independently selected from H, OH, C 1-6 Alkyl, C 3-8 Cycloalkyl and halogen, or two R4 together with the atoms to which they are attached form a spiro-C 3-8 Cycloalkyl or spiro-C 3-8 Heterocycloalkyl;

[0065] The remaining substituents are as defined above;

[0066] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0067] Another embodiment of the present invention relates to compounds of formula (II-B):

[0068]

[0069] in:

[0070] represents a single bond or a double bond;

[0071] R2 is H or C 1-6 alkyl;

[0072] R3 is H, C 1-6 Alkyl or halogen;

[0073] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0074] In a further preferred embodiment of the compound of Formula (I), (IA), (IB), (II-A), (II-B), (III-A), (III-B) or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, Cy is phenyl, R1 is CH3, R3 is H, methyl, chloro or bromo, R5 is hydrogen or methyl and R6 is hydrogen.

[0075] Another embodiment of the present invention relates to compounds of Formula (I), Formula (IA), Formula (IB), Formula (II-A), Formula (II-B), Formula (III-A), Formula (III-B), or pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof, wherein:

[0076] R7 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl,

[0077] and / or

[0078] R8 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl

[0079]

[0080] Preferably, in any compound of formula (I), (IA), (IB), (II-A), (II-B), (III-A) or (III-B), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, Cy is aryl (particularly phenyl).

[0081] Preferably, in any compound of formula (I), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, A is C-R3.

[0082] Preferably, in the compound of formula (I), (IA), (IB), (II-A), (III-A) or (III-B), or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, X is O or S.

[0083] Preferably, in any compound of formula (I), (IA) or (IB), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, Y is C 1-6 Alkanediyl (especially methylenediyl).

[0084] Preferably, in any compound of formula (I), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, Y' and / or Y" is C 1-6 Alkanediyl (especially methylenediyl).

[0085] Preferably, in any compound of formula (I), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, Y'" is a single bond.

[0086] Preferably, in any compound of formula (I), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, Y, Y', Y" is C 1-6 alkanediyl (especially methylenediyl) and Y'' is a single bond.

[0087] Preferably, in the compound of formula (I), (IA), (IB), (II-A), (II-B), (III-A) or (III-B), or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, R1 is C 1-6 Alkyl (especially methyl).

[0088] Preferably, in the compounds of formula (I), (IA), (IB), (II-A), (II-B), (III-A) or (III-B), or in pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof as defined above, R2 is H or C 1-6 Alkyl (especially methyl).

[0089] Preferably, in the compound of formula (I), (IA), (II-A), (II-B), (III-A) or (III-B), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, R3 is H, methyl, bromine, fluorine or chlorine, more preferably R3 is H, methyl or chlorine.

[0090] Preferably, in the compound of formula (I), (IA), (II-A), (II-B), (III-A) or (III-B), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, R5 is H or C 1-6 Alkyl (especially methyl);

[0091] Preferably, in the compound of formula (I), (IA), (II-A), (II-B), (III-A) or (III-B), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, R6 is H.

[0092] Preferably, in the compound of formula (I), (IA), (II-A), (II-B), (III-A) or (III-B), or in a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof as defined above, R7 and R8 are independently selected from:

[0093] -hydrogen;

[0094] -C 1-12 Alkyl (especially C 1-4 alkyl, preferably methyl, ethyl, isopropyl, tert-butyl or isobutyl), which is optionally substituted by one or more each independently selected from halogen (especially fluorine), halo 1-6 alkyl (especially trifluoromethyl) and a 3-7 membered saturated ring optionally containing an oxygen atom (especially oxetanyl, cyclopropyl or cyclobutyl), and

[0095] - a 3-8 membered saturated or partially unsaturated ring or bicyclic ring, which optionally contains an oxygen atom (especially oxetanyl, cyclopropyl or cyclobutyl), which is optionally substituted by one or more each independently selected from C1-6 alkyl (especially methyl), halogen (especially fluorine) and halo C 1-6substituted by an alkyl (especially trifluoromethyl) substituent,

[0096] Or R7 and R8 together with the nitrogen atom to which they are attached form an azetidine optionally substituted by one or more halogens, particularly fluorine.

[0097] Preferably, in any compound as defined above, its pharmaceutically acceptable salt, tautomer, solvate or stereoisomer, Ra, Rb, Rc, and Rd are each independently selected from hydrogen, halogen (especially fluorine or chlorine), C 1-6 Alkyl (especially methyl) and CN.

[0098] In a preferred embodiment, the present invention provides compounds of general formula (I) as defined above, wherein:

[0099] Cy is aryl (especially phenyl);

[0100] A is C-R3;

[0101] X is O or S;

[0102] Y, Y', Y" are C 1-6 (especially methylenediyl);

[0103] Y'' is a single bond;

[0104] R1 is C 1-6 Alkyl (especially methyl);

[0105] R2 is H or C 1-6 Alkyl (especially methyl);

[0106] R3 is H, methyl or chloro;

[0107] R5 is H or C 1-6 Alkyl (especially methyl);

[0108] R6 is H;

[0109] R7 and R8 are independently selected from:

[0110] -hydrogen;

[0111] -C 1-12 Alkyl (especially C 1-4 alkyl, preferably methyl, ethyl, isopropyl, tert-butyl or isobutyl), which is optionally substituted by one or more each independently selected from halogen (especially fluorine), halo 1-6 alkyl (especially trifluoromethyl) and a 3-7 membered saturated ring optionally containing an oxygen atom (especially oxetanyl, cyclopropyl or cyclobutyl), and

[0112] - a 3- to 8-membered saturated or partially unsaturated ring or bicyclic ring, which optionally contains an oxygen atom (especially oxetanyl, cyclopropyl or cyclobutyl), which is optionally replaced by one or more each independently selected from C 1-6 Alkyl (especially methyl), halogen (especially fluorine) and halogenated C 1-6 substituted by an alkyl (especially trifluoromethyl) substituent,

[0113] or R7 and R8 together with the nitrogen atom to which they are attached form an azetidine optionally substituted with one or more halogens (particularly fluorine);

[0114] Ra, Rb, Rc, and Rd are each independently selected from hydrogen, halogen (particularly fluorine or chlorine), C 1-6 Alkyl (especially methyl), halogenated C 1-6 Alkyl (especially CF3 or CHF2) and CN.

[0115] Still preferably, the compounds of the present invention are selected from:

[0116] -cis-2-(2-(dimethylamino)-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,

[0117] 4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0118] -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,

[0119] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0120] -(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:

[0121] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0122] -(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,

[0123] 4-b: 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0124] -(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:

[0125] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0126] -(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:

[0127] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0128] -(3aR,10aR)-2-(2-(tert-butylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,

[0129] 3,3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0130] -(3aR,10aR)-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl

[0131] -2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]

[0132] Oxathiazepine-8-carboxamide 5,5-dioxide;

[0133] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:

[0134] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0135] -cis-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,3a,4,

[0136] 10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine

[0137] -8-Carboxamide 5,5-dioxide;

[0138] -cis-2-(2-amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,3a,4,

[0139] 10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine

[0140] -8-Carboxamide 5,5-dioxide;

[0141] -cis-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-N-(3,4,5-trifluorophenyl)-2,3,3a,

[0142] 4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0143] -cis-2-(2-amino-2-oxoacetyl)-7-methyl-N-(3,4,5-trifluorophenyl)-2,3,3a,4,

[0144] 10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine

[0145] -8-Carboxamide 5,5-dioxide;

[0146] -(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,

[0147] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0148] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:

[0149] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0150] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-2-(2-(isobutylamino)-2-oxoacetyl)-7-methyl-2,

[0151] 3,3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0152] -(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,

[0153] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0154] -(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,

[0155] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0156] -(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,

[0157] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0158] -(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,

[0159] 5] Oxathiazepine-8-carboxamide 5,5-dioxide;

[0160] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-2-(2-(isopropylamino)-2-oxoacetyl)-7-methyl-2,

[0161] 3,3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0162] -(3aR,10aR)-2-(2-(cyclobutylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,

[0163] 3,3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0164] -(3aR,10aR)-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl

[0165] -2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]

[0166] Dithiazepine-8-carboxamide 5,5-dioxide;

[0167] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:

[0168] 3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide;

[0169] -cis-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl

[0170] -2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]

[0171] Oxathiazepine-8-carboxamide 5,5-dioxide;

[0172] -cis-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:

[0173] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0174] -cis-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:

[0175] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0176] -cis-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2,

[0177] 3,3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0178] -(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′,

[0179] 4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0180] -trans-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,

[0181] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0182] -trans-2-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,

[0183] 3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0184] -(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,

[0185] 4-b: 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0186] -(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,

[0187] 4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0188] -(3aR,10aR)-2-(2-amino-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-7-methyl-2,3,

[0189] 3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide;

[0190] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-(methylamino)-2-oxoacetyl)-2,3,

[0191] 3a,4,10,10a-Hexahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide;

[0192] -(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′,

[0193] 4'-g][1,6,2]dithiazoline-8-carboxamide 5,5-dioxide;

[0194] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-c:

[0195] 3',4'-g][1,6,2]dithiazoline-8-carboxamide 5,5-dioxide;

[0196] -(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,

[0197] 6,2] dithiazepine-8-carboxamide 5,5-dioxide;

[0198] -(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,

[0199] 2] dithiazepine-8-carboxamide 5,5-dioxide;

[0200] -(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,

[0201] 6,2] dithiazepine-8-carboxamide 5,5-dioxide;

[0202] -(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,

[0203] 6,2] dithiazepine-8-carboxamide 5,5-dioxide;

[0204] -(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:

[0205] 3',4'-g][1,6,2]dithiazocin-8-carboxamide 5,5-dioxide;

[0206] -(3aR,10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3′,

[0207] 4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0208] -(3aR,10aR)-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane

[0209] -2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:

[0210] 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0211] -(3aR,10aR)-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-

[0212] (trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0213] -(3aR,10aR)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0214] -(3aR,10aR)-6-chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,

[0215] 4-b: 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0216] -(3aR,10aR)-6-chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,

[0217] 4-b: 3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0218] -(3aR,10aR)-6-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,

[0219] 1-(1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0220] -(3aR,10aR)-6-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,

[0221] 1-(1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0222] -(3aR,10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0223] -(3aR,10aR)-6-bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0224] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0225] -trans-8-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,

[0226] 6,7,8,9,9a,10-Octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0227] -trans-8-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)

[0228] -2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,4-b][1,

[0229] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0230] -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,

[0231] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0232] -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,

[0233] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0234] - 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]oxathiazepine-1-carboxamide 4,4-dioxide;

[0235] -trans-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[4,3-f]pyrrolo[3,

[0236] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0237] -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,

[0238] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0239] -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,

[0240] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0241] -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]oxathiazepine-1-carboxamide 4,4-dioxide;

[0242] -cis-7-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)

[0243] -2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,

[0244] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0245] -cis-7-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,

[0246] 6,7,8,9,9a,10-Octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0247] -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,

[0248] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0249] -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,

[0250] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0251] -trans-7-(2-(cyclopropylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-2-methyl-5,5a,

[0252] 6,7,8,9,9a,10-Octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0253] -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,

[0254] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0255] - 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]oxathiazepine-1-carboxamide 4,4-dioxide;

[0256] -trans-7-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)

[0257] -2-methyl-5,5a,6,7,8,9,9a,10-octahydro-2H-pyrido[3,4-f]pyrrolo[3,4-b][1,

[0258] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0259] -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,

[0260] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0261] -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,

[0262] 4-b][1,4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0263] -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,

[0264] 4,5]oxathiazepine-1-carboxamide 4,4-dioxide;

[0265] -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,

[0266] 1-(1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrole

[0267] and [3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; and -(3aS,10aS)-N-(4-fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2-(2-oxo-2-(((R)-1,1,

[0268] 1-(1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide;

[0269] or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

[0270] Preferably, the compound as defined above or its pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer is used for medical purposes. Still preferably, the compound as defined above or its pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer is used to treat and / or prevent HBV infection and / or conditions associated with HBV infection. Preferably, the "condition associated with HBV infection" is selected from chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation caused by hepatitis B virus infection, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage.

[0271] Even more preferably, the compound as defined above or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof is used for treating, eradicating, reducing, slowing or inhibiting HBV infection in an individual in need thereof, and / or reducing the viral load associated with HBV infection in an individual in need thereof, and / or reducing the recurrence of HBV infection in an individual in need thereof, and / or inducing remission of liver damage caused by HBV infection in an individual in need thereof, and / or for the prophylactic treatment of HBV infection in an individual with latent HBV infection.

[0272] Preferably, the HBV infection and / or the condition associated with HBV infection is caused by any genotype of HBV (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.

[0273] Preferred compounds show greater than 50% inhibition of HBV at the concentrations tested (1.0 micromolar to 0.1 micromolar) and / or an EC value less than 0.5 micromolar as defined below. 50 HBV inhibition refers to the inhibition of HBV expression and replication. The inhibitory activity of the compounds of the present invention can be determined as described below. Preferably, the compounds of the present invention target the HBV core protein and misdirect capsid assembly, thus acting as capsid assembly modulators / inhibitors (CAMs) and leading to the inhibition of HBV replication and virion production.

[0274] Preferably, the compound as defined above or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof is used in combination with at least one additional therapeutic agent. Preferably, the combined use comprises the administration of at least one additional therapeutic agent.

[0275] The object of the present invention is a pharmaceutical composition comprising a compound as defined above or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient.

[0276] Preferably, at least one additional therapeutic agent is selected from the group consisting of therapeutic vaccines; RNA interference therapeutics / antisense oligonucleotides; immunomodulators; STING agonists; RIG-I modulators; NKT modulators; IL agonists; interleukins or other immune activating proteins; therapeutic and prophylactic vaccines; immune checkpoint regulators / inhibitors; HBV entry inhibitors; cccDNA regulators; HBV protein expression inhibitors; substances targeting HBV RNA; capsid assembly inhibitors / modulators; core or X protein targeting agents; nucleotide analogs; nucleoside analogs; interferons or modified interferons; HBV antivirals with different 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 destabilizers or other small molecule inhibitors of HBV protein expression; or a combination thereof.

[0277] Preferably, the therapeutic vaccine is selected from: HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX110 (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, HBVMVA and PepTcell.

[0278] 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.

[0279] Preferably, the immunomodulator 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 ([3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetic acid methyl ester) and ARB-1598.

[0280] Preferably, the RIG-1 modulator is SB-9200. Preferably, the IL agonist or other immune activating protein is INO-9112 or recombinant IL12. Preferably, the immune checkpoint regulator / inhibitor is BMS-936558 (Opdivo (nivolumab)) or pembrolizumab. Preferably, the HBV entry inhibitor is MyRcludex B, IVIG-TonRol or GC-1102.

[0281] Preferably, the cccDNA modulator is selected from: a direct cccDNA inhibitor, an inhibitor of cccDNA formation or maintenance, a cccDNA epigenetic modifier and a cccDNA transcription inhibitor.

[0282] 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: BAY41-4109, NVR3-778, 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.

[0283] Preferably, the interferon or modified interferon is selected from the group consisting of interferon alpha (IFN-α), pegylated interferon alpha (PEG-IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, pegylated interferon alpha-2a (Pegasys), interferon alpha-2b (intron A), recombinant interferon alpha-2b, interferon alpha-2b interferon alpha-2b, PEGylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, PEGylated interferon beta-1a, interferon delta, interferon lambda (IFN-λ), PEGylated interferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon Alfacon-1, interferon alpha-nl, interferon alpha-n3, alb-interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-stemfugen, Belerofon, INTEFEN-IFN, albumin / interferon alpha 2a fusion protein, rHSA-IFNα2a, rHSA-IFNα2b, PEG-IFN-SA, and interferon alpha biobetter. Particularly preferred are: pegylated interferon α-2a, pegylated interferon α-2b, glycosylated interferon α-2b, pegylated interferon β-1a and pegylated interferon λ-1. More particularly preferred is pegylated interferon α-2a.

[0284] Preferably, the HBV antiviral agent with a different 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.

[0285] Preferably, the cyclophilin inhibitor is selected from the group consisting of: OCB-030 (NVP-018), SCY-635, SCY-575 and CPI-431-32.

[0286] 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), tenofovir. Preferably, tenofovir is in the form of a salt. Preferably, tenofovir is in the form of a salt selected from: tenofovir fumarate tesoclav (Viread), tenofovir alfentanil fumarate (TAF), tenofovir tipolo orotate (DA-2802), tenofovir diisopropoxyaspartate (CKD-390), AGX-1009 and CMX157.

[0287] Preferably, the dinucleotide is SB9200. Preferably, the SMAC inhibitor is Birinapant. Preferably, the HDV targeting agent is Lonafamib.

[0288] Preferably, the HBV RNA destabilizer or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452.

[0289] Preferably, the at least one additional therapeutic agent is an agent useful for the treatment and prevention of hepatitis B. Preferably, the at least one additional therapeutic agent is an anti-HDV agent, an anti-HCV agent and / or an anti-HIV agent.

[0290] Preferably, at least one additional therapeutic agent is selected from: HBV polymerase inhibitors, interferons, viral entry inhibitors, BAY41-4109, 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, and clevudine; and the TLR agonist is preferably selected from the following group: SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD8848 ([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.

[0291] Any combination of the above-mentioned additional therapeutic agents is contemplated for use in the present invention.

[0292] Preferably, the compounds of the invention are used in combination with one, two or more additional therapeutic agents as defined above.

[0293] Preferably, the pharmaceutical composition of the invention comprises one, two or more additional therapeutic agents as defined above.

[0294] Preferably, the pharmaceutical composition is used to treat and / or prevent HBV infection and / or conditions associated with HBV infection, and the conditions associated with HBV infection are preferably selected from chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection. Even more preferably, the pharmaceutical composition is used to treat, eradicate, reduce, slow down or inhibit HBV infection in an individual in need thereof, and / or to reduce the viral load associated with HBV infection in an individual in need thereof, and / or to reduce the recurrence of HBV infection in an individual in need thereof, and / or to induce remission of liver damage caused by HBV infection in an individual in need thereof, and / or to preventively treat HBV infection in an individual with latent HBV infection.

[0295] Preferably, in the pharmaceutical composition for use as defined above, the HBV infection and / or the condition associated with HBV infection is caused by any genotype of HBV (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.

[0296] 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 a mammal and / or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

[0297] Another object of the present invention is a method for synthesizing a compound of formula (I), (IA), (IB), (II-A), (II-B), (III-A) or (III-B) according to the synthesis schemes included in the description of the present invention. In particular, the present invention provides a method for synthesizing a compound of formula I as defined above, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein A is C-R3, Y' and Y" are both methylenediyl, 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, the method comprising at least one of the following steps:

[0298]

[0299] - reacting a compound of formula (5a) (wherein each of m and n is independently 1 or 2) with a compound of formula (8a) or with a compound of formula (8b);

[0300]

[0301] - reacting a compound of formula (6) wherein each of m and n is independently 1 or 2 with an amine of formula NHR7R8;

[0302]

[0303] - reacting a compound of formula (7) wherein each of m and n is independently 1 or 2 with an amine of formula NHR7R8;

[0304] The method optionally further comprises at least one of the following steps:

[0305] - reacting the compound of formula (5a) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (6);

[0306] - hydrolyzing the compound of formula (6) in the presence of a base to obtain a compound of formula (7);

[0307]

[0308] - reacting a compound of formula (9) (wherein each of m and n is independently 1 or 2 and R3 = H) with sulfuryl chloride in a solvent such as dichloromethane to obtain a compound of formula (9) (wherein R3 = Cl);

[0309] - reacting a compound of formula (9) wherein each of m and n is independently 1 or 2 and R3 = H with N-bromosuccinimide in a solvent such as chloroform to obtain a compound of formula (9) wherein R3 = Br.

[0310] Then, the present invention also provides a compound of formula (9), a compound of formula (9') or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein all substituents are as defined above:

[0311]

[0312] In a preferred embodiment, the synthesis method of the compound of the present invention comprises at least one of the following steps:

[0313] - reacting a compound of formula (5b) (wherein Ra is selected from Cl, F, CHF2, CF3 and CH3) with (R)-methyl 2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate in the presence of an amine such as 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine and react in the presence of a solvent such as ethanol to obtain a compound of formula (9a):

[0314]

[0315] - reacting a compound of formula (9a) wherein R3 is H and Ra is selected from Cl, F, CHF2, CF3 and CH3 with sulfuryl chloride in a solvent such as dichloromethane to obtain a compound of formula (9b):

[0316]

[0317] Another object of the invention is a pharmaceutical composition comprising an effective amount of one or more compounds as defined above or pharmaceutically acceptable prodrugs thereof, alone or in combination with other active compounds, and at least one pharmaceutically acceptable excipient.

[0318] In a preferred embodiment, the invention relates to compounds of formula (I), wherein Cy is phenyl. Also preferably, the invention relates to compounds of formula (I), wherein X is O or S.

[0319] The present invention includes within its scope prodrugs of compounds of formula (I), (IA), (IB), (II-A) or (II-B) above. In general, such prodrugs will be functional derivatives of compounds of formula (I), (IA), (IB), (II-A) or (II-B) that are easily converted into the desired compound of formula (I), (IA), (IB), (II-A) or (II-B) in vivo. Conventional procedures for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0320] Prodrugs can be pharmacologically inert derivatives of biologically active substances ("parent drugs" or "parent molecules") that require conversion in vivo to release active drugs and have improved delivery properties compared to the parent drug molecule. The in vivo conversion can be, for example, the result of certain metabolic processes, such as chemical or enzymatic hydrolysis of carboxylic acids, phosphoric acids or sulfates, or reduction or oxidation of sensible energy groups.

[0321] The present invention also includes all suitable isotopic variations of the compounds of the present disclosure. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 31 P, 32 P, 35 S, 18 F and 36 Certain isotopic variants of the present disclosure, such as those incorporating radioactive isotopes such as 3 H or 14 C, can be used for drug and / or substrate tissue distribution studies. In addition, the use of isotopes (such as deuterium 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability. Isotopic variations of the disclosed compounds can generally be prepared by conventional techniques, for example, using isotopic variations of appropriate reagents by the preparations described in the illustrative methods or examples.

[0322] The present invention includes within its scope solvates, such as hydrates, alcoholates, and the like, of compounds of Formula (I), Formula (IA), Formula (IB), Formula (II-A), or Formula (II-B) or related salts.

[0323] Additionally, the compounds disclosed herein may exist as tautomers, and all tautomeric forms are intended to be encompassed by the scope of the invention, even if only one tautomeric structure is depicted.

[0324] Compounds may exist in different isomeric forms, all of which are encompassed by the present invention. For example, a particular compound of the present invention may exist in cis and trans geometric isomeric forms, all of which are encompassed by the present invention.

[0325] The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (as described in: EL Eliel and SH Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and exist in the form of racemates, racemic mixtures and individual diastereomers, all possible isomers and mixtures thereof, including optical isomers, all of which stereoisomers are included in the present invention.

[0326] Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by applying methods known in the art and are intended to be encompassed by the scope of the present invention. In particular, "pure stereoisomeric forms" or "stereoisomerically pure" refers to compounds with an excess of at least 80%, preferably at least 85%, of stereoisomers. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts or by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of suitable starting materials, provided that the reaction occurs stereospecifically. The term "enantiomerically pure" should be interpreted in a similar manner, taking into account the enantiomeric ratio.

[0327] When any variable (e.g., R1 and R2, etc.) occurs multiple times in any constituent, its definition at each occurrence is independent of every other occurrence. Furthermore, combinations of substituents and variables are permitted only if they result in stable compounds. Lines leading from substituents into the ring system indicate that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that the bond is attached only to any suitable carbon atom on the proximal ring.

[0328] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those of ordinary skill in the art to provide chemically stable and easily synthesized compounds from readily available starting materials by techniques known in the art and those methods described below. If the substituent itself is substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure can be formed. The phrase "optionally substituted" should be considered equivalent to the phrase "not substituted or substituted with one or more substituents", in which case preferred embodiments will have zero to three substituents. More particularly, there are 0-2 substituents.

[0329] The expressions "one or more substituents" and "1, 2 or more substituents" particularly refer to 1, 2, 3, 4 or more substituents, particularly to 1, 2, 3 or 4 substituents, more particularly to 1, 2 or 3 substituents.

[0330] As used herein, "Y is a single bond" means that in the general formula (I), formula (IA) and formula (IB), X is directly connected to the carbon atom bearing R2 through a single bond; "Y' is a single bond" means that the carbon atom bearing R5 in the general formula (I) is directly connected to N through a single bond; "Y" is a single bond" means that in the general formula (I), N is directly connected to the carbon atom bearing R2 through a single bond; "Y"' is a single bond" means that the carbon atom bearing R5 in the general formula (I) is directly connected to the carbon atom bearing R2 through a single bond. As used herein, "X is a single bond" means that in the general formula (I), Y is directly connected to pyrrole or pyrazole through a single bond.

[0331] 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, "C1-12 alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in a straight or branched chain arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, and the like. In another example, "C1-12 alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in a straight or branched chain arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, and the like. 1-6 "Alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6 carbon atoms in a straight or branched chain, and especially includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc. Preferably, "C 1-12 Alkyl" and "C 1-6 "Alkyl" refers 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 carbon atoms in a straight or branched chain arrangement. For example, "C 1-4 "Alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. "C 1-3 "Alkyl" is defined to include groups having 1, 2, or 3 carbon atoms in a straight or branched chain. For example, "C 1-3 The "alkyl group" specifically includes methyl, ethyl, n-propyl, isopropyl and the like. Preferred alkyl groups are methyl, ethyl, isopropyl, tert-butyl or isobutyl.

[0332] As used herein, "alkoxy" refers to an alkyl group with the indicated number of carbon atoms attached through an oxygen bridge. Thus, "alkoxy" encompasses the above definition of alkyl. 1-6 The alkoxy group is preferably a linear or branched C 1-4 Alkoxy, more preferably C 1-3 Alkoxy, more preferably C 1-2 Alkoxy. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. Preferred alkoxy groups include methoxy, ethoxy and tert-butoxy.

[0333] As used herein, the term "halogenated C 1-6 Alkyl" and "halogenated C 1-6 "Alkoxy" refers to a C group in which one or more (especially 1 to 3) hydrogen atoms have been replaced by halogen atoms (especially fluorine or chlorine atoms). 1-6 Alkyl or C 1-6 Alkoxy. Halogenated C 1-6 The alkoxy group is preferably a linear or branched halogenated C 1-4 Alkoxy, more preferably halogenated C 1-3Alkoxy, more preferably halogenated C 1-2 Alkoxy, for example OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, most particularly OCF3 or OCHF2. 1-6 The alkyl group is preferably a linear or branched halogenated C 1-3 Alkyl, more preferably halogenated C 1-2 Alkyl, for example CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 or CH(CH3)CF3, and more particularly CF3, CHF2 or CH(CH3)CF3.

[0334] As used herein, the term "hydroxy C 1-6 "Alkyl" refers to a C-group in which one or more (especially 1 to 3) hydrogen atoms are replaced by hydroxyl groups. 1-6 Similarly, the term "hydroxyl C 1-4 "Alkyl" refers to a C-group in which one or more (especially 1-2) hydrogen atoms are replaced by hydroxyl groups. 1-4 Alkyl. Illustrative examples include, but are not limited to, CH2OH, CH2CH2OH, CH(CH3)OH, and CHOHCH2OH.

[0335] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic ring comprising carbon atoms and hydrogen atoms. If indicated, such aromatic rings may contain one or more heteroatoms, also referred to as "heteroaryl", preferably 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, preferably nitrogen. As known to those skilled in the art, heteroaryl rings have less aromatic properties than their full carbon para-positioned moieties. Therefore, for purposes of the present invention, heteroaryl only needs to have a certain degree of aromatic properties. An illustrative example of an aryl is an optionally substituted phenyl. An illustrative example of a heteroaryl according to the present invention includes optionally substituted thiophene, oxazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine and pyridine. Thus, examples of monocyclic aromatic groups optionally containing one or more heteroatoms, such as one or two heteroatoms, are 5- or 6-membered aromatic or heteroaromatic groups such as, but not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxadiazolyl and oxazolyl. The polycyclic aromatic rings optionally containing one or more heteroatoms, for example one or two heteroatoms, are exemplified by: 8-10 yuan aryl or heteroaryl, for example, but not limited to, benzimidazolyl, benzofuran diacyl, benzofuranyl, benzofurazyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolinyl (benzoxazolonyl), benzothiazolyl, benzothiadiazolyl, benzodioxazolyl, benzoxadiazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indolizinyl, isoindolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, quinazolinyl, quinolyl, quinoxalinyl, quinolizinyl, naphthyl, naphthyridinyl and phthalazinyl. The preferred aryl according to the present invention is phenyl. The preferred heteroaryl according to the present invention is pyridinyl.

[0336] A heterocycle, heterocyclic compound or ring structure or heterocycloalkyl is a cyclic compound having atoms of at least two different elements as its ring members.

[0337] The substituents on the saturated, partially saturated or unsaturated heterocyclic ring may be attached at any substitutable position.

[0338] As used herein, the term “C 1-6 "Alkanediyl" as a group or part of a group defines a divalent straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. 1-6 Alkanediyl, preferably C 1-4 Alkanediyl, C 1-3 Alkane or more preferably C 1-2Examples include, but are not limited to, methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, and hexanediyl. Methanediyl, ethanediyl, and propanediyl are preferred.

[0339] As used herein, the term “C 2-7 "Alkanediyl" as a group or part of a group defines a divalent straight chain or branched (carbon number limitation is allowed) unsaturated hydrocarbon group having 2 to 7 carbon atoms. 2-7 Non-limiting examples of alkenediyl are: -C=CH-, -CH=C(CH3)CH2-, -CH=CH-CH2-.

[0340] As used herein, the term “C 3-8 The term "cycloalkyl" or "3-8 membered saturated ring" refers to 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 size of the ring, it may also be a bicyclic structure, such as bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, octahydropentadiene, etc. In a specific embodiment of the present invention, "3-8 membered saturated ring" is limited to "3-7 membered saturated ring". The saturated ring optionally contains one or more heteroatoms (also called heterocyclyl, heterocycle or heterocycloalkyl), so that at least one carbon atom is replaced by a heteroatom selected from N, O and S, especially N and O. In a specific embodiment, the term "C 3-8 "Heterocycloalkyl" is a saturated or partially saturated non-aromatic monocyclic or bicyclic ring system having 3 to 8 members, which contains 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 system. Saturated cyclic hydrocarbons having 3 or 4 or 5 carbon atoms and 1 oxygen or 1 nitrogen atom are preferred. Examples include oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, piperidinyl or pyrrolidinyl. Preferred 3-7 membered saturated rings are oxetanyl, cyclopropyl and cyclobutyl.

[0341] As used herein, the expression "3-8 membered partially saturated ring" means a ring containing 3 to 8 carbon atoms and at least one double bond. Depending on the size of the ring, it can be a cyclic or bicyclic structure. In a specific embodiment of the present invention, "3-8 membered partially saturated ring" is limited to "5-7 membered partially saturated ring". Each of the above rings may optionally contain one or more heteroatoms such that at least one carbon is substituted by a heteroatom selected from N, O and S, in particular selected from N and O. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclohexa-1,4-dienyl, cycloheptenyl, cycloheptyl-1,4-dienyl, dihydrofuranyl, dihydropyrrole, dihydropyranyl, hexahydro-1H-cyclopenta[c]furanyl, etc.

[0342] It should be noted that in the definitions used throughout the specification, different isomers of various heterocycles may exist. For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

[0343] It should also be noted that the radical position on any molecular moiety used in the definitions can be anywhere on that moiety as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, 4-pyridyl.

[0344] As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0345] The term "heteroatom" refers to an atom other than carbon or hydrogen in a ring structure or saturated backbone as defined herein. Typical heteroatoms include N(H), O, S.

[0346] As used herein, the term “C 1-6 "Alkylaryl" means a group attached to C 1-6 As used herein, the term "C 1-6 "Alkylheteroaryl" means a group attached to a C 1-6 As used herein, the term "C 1-6 Alkyl-C 3-8 "Cycloalkyl" means a cycloalkyl group attached to a C 1-6 One or more C 3-8 Cycloalkyl.

[0347] The term "spiro-C 3-8 Cycloalkyl" or "spiro-C 3-8 "Heterocycloalkyl" means such a C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, which forms a bicyclic organic compound with rings connected by only one atom. These rings can be different or identical in nature. The connecting atom is also called a spiro atom, the most common of which is a quaternary carbon ("spiro carbon").

[0348] The present invention includes free bases of compounds of formula (I), (IA), (IB), (II-A) or (II-B), and pharmaceutically acceptable salts and stereoisomers thereof. Certain specific compounds exemplified herein are protonated salts of amine compounds. Compounds of formula (I), (IA), (IB), (II-A) or (II-B) containing one or more N atoms may be protonated at any one, some or all of the N atoms. The term "free base" refers to an amine compound in non-salt form. Pharmaceutically acceptable salts encompassed include not only the salts exemplified for the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of compounds of formula (I), (IA), (IB), (II-A) or (II-B). The free form of the specific salt compound may be isolated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous alkaline solution, such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free forms may differ from their respective salt forms in certain physical properties (such as solubility in polar solvents), but otherwise the acid and base salts are pharmaceutically equivalent to their respective free forms for the purposes of the present invention.

[0349] The pharmaceutically acceptable salt of the compounds of this invention can be synthesized by the compounds of this invention containing alkaline or acidic parts by conventional chemical methods. Usually, the salt of the basic compound is prepared by ion exchange chromatography or by reacting the free alkali with a stoichiometric amount or with an excessive amount of the desired salt of the inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salt of the acidic compound is formed by reacting with a suitable inorganic or organic base. In a preferred embodiment, the compound of the present invention has at least one acidic proton, and the corresponding sodium salt or potassium salt can be formed, for example, by reacting with a suitable base.

[0350] Therefore, the 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 an alkaline instant compound with an inorganic or organic acid or an acidic compound with an inorganic or organic base. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; salts 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-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Conventional non-toxic salts also include those derived from inorganic bases, such as potassium hydroxide, sodium hydroxide, magnesium hydroxide or calcium hydroxide, and salts prepared from organic bases such as ethylenediamine, lysine, trimethylamine, meglumine, etc. Preferably, the pharmaceutically acceptable salt of the present invention comprises one equivalent of a compound of formula (I), (IA), (IB), (II-A) or (II-B) and 1, 2 or 3 equivalents of an inorganic or organic acid or base. More particularly, the pharmaceutically acceptable salt of the present invention is a tartrate, trifluoroacetate or chloride salt.

[0351] 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 aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N 1 -Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrazinephenyldiamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0352] The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66: 1-19.

[0353] It should also be noted that the compounds of the present invention are potentially internal salts or zwitterions because under physiological conditions, the deprotonated acidic moieties in the compounds, such as carboxyl groups, can be anionic and this charge can be internally balanced by the cationic charge of the protonated or alkylated basic moieties (such as quaternary nitrogen atoms).

[0354] The compounds of the present invention are useful in a variety of applications in human and animal health.The compounds of the present invention are inhibitors of the hepatitis B virus (HBV).

[0355] In the context of the present invention, HBV may be any known isolate, genotype, strain, etc. of HBV.

[0356] In particular, hepatitis B virus has been classified into eight major genotypes (termed AH), and two additional genotypes (I and J) have been tentatively proposed. HBV genotypes have been further divided into several subgenotypes, which differ by 4.0% to 7.5% in the overall nucleotide sequence. HBV genotypes differ greatly in many virological and possibly some clinical parameters; however, the precise role of HBV genotypes in the evolution of infection remains controversial. Due to geographical distribution, only two or three HBV genotypes co-circulate in most parts of the world, limiting genotypic comparisons.

[0357] The compounds of the present invention are hepatitis B virus (HBV) inhibitors useful for treating and / or preventing HBV infection. In particular, the compounds of the present invention are inhibitors of hepatitis B virus (HBV) core (HBc) protein useful for treating and / or preventing HBV infection.

[0358] It is particularly believed that the compounds, compositions and methods provided herein can be used to treat, ameliorate or prevent HBV infection and related conditions, including chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation caused by hepatitis B virus infection, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage.

[0359] In the present invention, the expression "HBV infection" includes any and all conditions derived from HBV infection, including but not limited to hepatitis B, preferably chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection.

[0360] HBV infection leads to a wide range of liver complications, all of which are conditions associated with HBV infection. As used herein, "conditions associated with 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 caused by hepatitis B virus infection, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage.

[0361] Expressions such as "treat, eradicate, reduce, slow or inhibit HBV infection" are used to indicate that a therapeutic agent (i.e., a compound of the invention) is administered or administered to a patient, alone or in combination with another agent, or to an isolated tissue or cell line from a patient (e.g., for diagnostic or ex vivo applications), who has HBV infection, symptoms of HBV infection, or is likely to develop HBV infection, with the intent to cure, heal, alleviate, mitigate, alter, remedy, improve, ameliorate or affect HBV infection, symptoms of HBV infection, or the likelihood of developing HBV infection. Such treatments can be specifically tailored or modified based on knowledge gained from the field of pharmacogenomics.

[0362] Quantification of viral load or other evidence of infection can be used to determine the effectiveness of treatment, such as by measuring HBeAg, HBsAg, HBV DNA levels, ALT activity levels, serum HBV levels, etc., so that the treatment dose, frequency and length of treatment can be adjusted.

[0363] HBeAg stands for hepatitis B e antigen. This antigen is a protein from the hepatitis B virus that circulates in infected blood when the virus is actively replicating.

[0364] ALT stands for alanine aminotransferase, an enzyme that transfers an amino group from the amino acid alanine to alpha-ketoglutarate to produce glutamate and pyruvate. ALT is primarily located in the liver and kidneys, with lesser amounts in the heart and skeletal muscle. ALT is often measured clinically as part of a liver function test.

[0365] The compounds of the invention can reduce viral load in individuals with HBV infection. In a non-limiting embodiment, the compounds of the invention cause a reduction in viral load during treatment in an individual in need thereof, ranging from a minimum of one or two log reduction to a maximum of about eight log reduction.

[0366] As used herein, the expression alleviating "liver damage caused by HBV infection" means that chronic necroinflammatory liver disease is stopped due to the fact that viral antigens have disappeared from the organ (and the immune system no longer attacks liver cells).

[0367] As used herein, the term "prophylactic treatment" refers to the absence of development of a disease or condition (if it has not occurred), or the absence of further development of a disease or condition (if there has already been development of a disease or condition). The ability to prevent some or all of the symptoms associated with a disease or condition is also contemplated. An example of a prophylactic treatment might 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 the risk of infection of a newborn (in the case of a chronically infected mother through viral transmission during childbirth).

[0368] As used herein, "reducing the recurrence of HBV infection" means that after several years of quiescence, patients may have reactivation of HBV replication and exacerbation of conditions associated with HBV infection, such as hepatitis. These patients may still be at risk of developing conditions associated with HBV infection (e.g., development of hepatocellular carcinoma). Antiviral therapy is also recommended as a preventive measure for HBsAg-positive patients and HBsAg-negative and hepatitis B core antibody-positive patients (who need to be treated with immunosuppressive therapy and have a moderate to high risk of HBV reactivation).

[0369] According to standard pharmaceutical practice, 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. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0370] 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 comprising the active ingredient can be in a form suitable for oral use, such as a tablet, lozenge, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, syrup or elixir. Compositions for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacturing, and the composition can include one or more agents selected from: sweeteners, flavoring agents, coloring agents and preservatives to provide pharmaceutically sophisticated and palatable preparations. Tablets contain a mixture of active ingredients and a pharmaceutically acceptable non-toxic excipient, and the pharmaceutically acceptable non-toxic excipient is suitable for preparing tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques to mask the bad taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, water-soluble taste-masking materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or time-delay materials such as ethylcellulose, cellulose acetate butyrate can be used.

[0371] Preparations for oral use can also be prepared 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).

[0372] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide 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 (for example, ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (for example, sucrose, saccharin or aspartame).

[0373] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil such as liquid paraffin. Oily suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (e.g., those as described above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0374] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient, which is mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents are listed by those mentioned above. Other excipients, such as sweeteners, flavorings and coloring agents, may also be present. These compositions may be preserved by adding antioxidants such as ascorbic acid.

[0375] Pharmaceutical composition of the present invention can also be in the form of water-in-oil emulsion. The oil phase can be a vegetable oil (such as olive oil or groundnut oil), or a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also include sweeteners, flavoring agents, preservatives and antioxidants.

[0376] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents and an antioxidant.

[0377] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.

[0378] The sterile injection preparation can also be a sterile injection oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion.

[0379] The injectable solution or microemulsion may be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention. In order to maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS TM Model 5400 IV Pump.

[0380] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions formulated in nontoxic parenteral acceptable diluents or solvents, such as solutions formulated in 1,3-butanediol. In addition, sterile non-volatile oils are often used as solvents or suspension media. For this purpose, various low-irritation non-volatile oils can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are also used in the preparation of injections.

[0381] The compounds of the present invention can also be given in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature and therefore melt and release the drug in the rectum. These materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0382] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. (For the purpose of this application, topical application should include mouthwashes and gargles.) The compounds of the present invention can be administered in intranasal form by topical use of suitable intranasal carriers and delivery devices, or by transdermal routes using transdermal skin patches of those forms known to those of ordinary skill in the art. In order to be administered in the form of a transdermal delivery system, the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen. The compounds of the present invention can also be delivered in suppository form using a matrix (e.g., cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol).

[0383] The compounds of the present invention can be present in the form of liposomes or other microparticles or other nanoparticles, which are designed to target the compounds. Acceptable liposomes can be neutral, negatively charged or positively charged, and their 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.

[0384] When the compounds of the invention are administered to human subjects, the daily dosage will generally be determined by the prescribing physician and will generally vary according to the age, weight, sex and response of the individual patient and the severity of the patient's symptoms.

[0385] In an exemplary application, a suitable amount of the compound is administered to a mammal undergoing anti-HBV treatment. The amount administered is generally about 0.01 mg / kg body weight to about 100 mg / kg body weight per day, preferably about 0.01 mg / kg body weight to about 60 mg / kg body weight per day, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight per day, preferably about 0.5 mg / kg body weight to about 40 mg / kg body weight per day.

[0386] The compounds of the present invention may also be combined with known therapeutic agents for simultaneous, separate or sequential administration.

[0387] In one embodiment, the compounds of the present invention may be used in combination with at least one or more other therapeutic agents, particularly anti-HBV agents.

[0388] Indications that the compounds of the present invention are useful for treating and / or preventing HBV infection indicate that the compounds are effective for treating, eradicating, reducing, slowing down or inhibiting HBV infection.

[0389] Therapeutic agents are any agents commonly used to treat and / or prevent and / or ameliorate HBV infection or a condition associated with HBV infection. Therapeutic agents are known in the art.

[0390] The term "anti-HBV agent" or more simply "(one or more) HBV antiviral agents" also includes compounds of therapeutic nucleic acids, antibodies or proteins in their native form or chemically modified and / or stabilized. Hepatitis B virus (HBV) strains that are resistant to at least one anti-HBV drug are defined as resistant. The term therapeutic nucleic acid includes, but is not limited to, nucleotides and nucleosides, oligonucleotides, polynucleotides, non-limiting examples of which are antisense oligonucleotides, miRNA, siRNA, shRNA, therapeutic vectors and DNA / RNA editing components.

[0391] The term anti-HBV agent also includes compounds that can treat HBV infection by immunomodulation, i.e., immunomodulators or immunomodulatory compounds. Examples of immunomodulators are interferon-α (IFN-α), pegylated interferon-α or stimulators of the innate immune system, such as Toll-like receptor 7 and / or 8 agonists and therapeutic or prophylactic vaccines. One embodiment of the present invention relates to a compound of formula (I), (IA), (IB), (II-A) or (II-B) as specified herein, or any subgroup thereof, in combination with an immunomodulatory compound, more specifically a Toll-like receptor 7 and / or 8 agonist.

[0392] Other HBV antiviral agents can be selected from, for example, therapeutic vaccines; RNA interference therapeutics / antisense oligonucleotides (e.g., siRNA, ddRNA, shRNA); immunomodulators (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 preventive vaccines, and immune checkpoint regulators; HBV entry inhibitors; cccDNA modulators (e.g., direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, cccDNA transcription inhibitors); HBV protein expression inhibitors; targeted HBV RNA-targeting agents; capsid assembly inhibitors / modulators; core or X protein targeting agents; nucleotide analogs; nucleoside analogs; interferons or modified interferons; HBV antiviral agents with different or unknown mechanisms; cyclophilin inhibitors; sAg release inhibitors; HBV polymerase inhibitors; dinucleotides; SMAC inhibitors; HDV targeting agents; viral maturation inhibitors; reverse transcriptase inhibitors and HBV RNA stabilizers, as well as other small molecule inhibitors of HBV protein expression.

[0393] Specifically, previously known anti-HBV agents, such as interferon-α (IFN-α), pegylated interferon-α, 3TC, tenofovir, lamivudine, entecavir, telbivudine and adefovir or a combination thereof, and a combination of formula (I), (IA), (IB), (II-A) or (II-B) or any subgroup thereof can be used as a drug in combination therapy. Other examples of other therapeutic agents that can be combined with the compounds of the present invention include: zidovudine, didanosine, zalcitabine, stavudine, abacavir, ddA emtricitabine, aprecitabine, aviperine, ribavirin, acyclovir, valacyclovir, famciclovir, ganciclovir, valganciclovir, cidofovir, efavirenz, nevirapine, delavirdine and etravirine.

[0394] Specific examples of such HBV antiviral agents include, but are not limited to:

[0395] - RNA interference (RNAi) therapeutics: 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;

[0396] -HBV entry inhibitors: MyRcludex B, IVIG-TonRol, GC-1102;

[0397] - HBV capsid inhibitors / modulators, core or X protein targeting agents, direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, or cccDNA epigenetic modifiers: BAY41-4109, NVR3-778, 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.

[0398] -HBV polymerase inhibitors: entecavir (Boludin, Entavir), lamivudine (3TC, Gananeng, Heputin, Yipingwei and Yipingwei-HBV), telbivudine (Tizeka, Subivo), cleviidine, besifovir, adefovir (Hevitra), tenofovir (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);

[0399] - HBV RNA destabilizers and other small molecule inhibitors of HBV protein expression: RG7834, AB-452;

[0400] - Cyclophilin inhibitors: OCB-030 (also known as NVP-018), SCY-635, SCY-575, and CPI-431-32;

[0401] -Dinucleotide: SB9200;

[0402] - Compounds with different or unknown mechanisms, such as, but not limited to: 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;

[0403] -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 ([3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate); ARB1598;

[0404] - RIG-I modulator: SB-9200;

[0405] -SMAC inhibitor: birenapam;

[0406] -Immune checkpoint inhibitors: BMS-936558 (Opdivo (nivolumab)), (pembrolizumab);

[0407] - Therapeutic vaccines: HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX110 (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-102-00557HBV MVA, PepTcell;

[0408] -IL agonists and immune activating proteins: INO-9112; recombinant IL12;

[0409] - Interferon: Interferon alpha (IFN-α), Interferon alpha-2a, Recombinant interferon alpha-2a, Pegylated interferon alpha-2a (PEGYMIN), Interferon alpha-2b (Intron A), Recombinant interferon alpha-2b, Interferon alpha-2b XL, Pegylated interferon alpha-2b, Glycosylated interferon alpha-2b, Interferon alpha-2c, Recombinant interferon alpha-2c, Interferon beta, Interferon beta-1a, Pegylated interferon beta-1a, Interferon delta, Interferon lambda (IFN-λ), Pegylated interferon lambda-1, Interferon omega, Interferon tau, Interferon gamma (IFN-γ), Interferon Alfacon-1, Interferon alpha-n1, Interferon alpha-n3, Alb interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-interferon, Belerofon, INTEFEN-IFN, albumin / interferon α2a fusion protein, rHSA-IFNα2a, rHSA-IFNα2b, PEG-IFN-SA, interferon α biomodifier; specifically, pegylated interferon α-2a, pegylated interferon α-2b, glycosylated interferon α-2b, pegylated interferon β-1a and pegylated interferon λ-1; more specifically, pegylated interferon α-2a;

[0410] -HDV targeted agent: lonafarnib.

[0411] Referring to the compounds of the invention, the term "administration" and variations thereof (e.g., "administering" a compound) refers to introducing the compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and variations thereof are understood to include the simultaneous or sequential introduction of the compound or its prodrug and the other agent.

[0412] In some embodiments, pulse administration is more effective than continuous treatment because the total pulse dose is generally lower than the dose expected for continuous administration of the same composition. Each pulse dose can be reduced and the total amount of drug administered during treatment can be minimized. Single pulses can be delivered to the patient continuously over a period of several 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).

[0413] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as a product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0414] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0415] The invention will be described by the following non-limiting examples and biological data will be provided.

[0416] Materials and methods

[0417] Chemical

[0418] Overview

[0419] Unless otherwise noted, commercial reagents and solvents (HPLC grade) were used without further purification.

[0420] Specifically, the following abbreviations may be used in the description of experimental methods:

[0421] 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 (second); h: hour; mg: milligram; g: gram; mL: milliliter; mmol: millimole; nm: nanometer μM: micromolar; M: molar concentration or molar concentration; Rt: retention time (minute); 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; DI PEA: 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-pyrrolidinyl-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-tetramethylammonium tetrafluoroborate.

[0422] Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius) or K (Kelvin).

[0423] 1H-NMR spectra were obtained using an Avance II 300 MHz Bruker spectrometer. Chemical shifts are expressed in parts per million (ppm, delta units). Coupling constants are expressed in Hertz (Hz), and fragmentation patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).

[0424] LC-MS analysis was performed on a UPLC Acquity Waters system (equipped with a SQD spectrometer, a single quadrupole mass detector, and a TUV detector) using Column 1: ACQUITY UPLC BEH SHIELD, RP 18 (2.1x50mm, id=1.7μm); Column 2: ACQUITY UPLC HSS T3, RP 18 (2.1x50mm, id=1.8μm) and column 3: ACQUITY UPLC BEH SHIELD, RP 18 (2.1x100mm, id=1.7μm). Column temperature 40°C. Sample temperature 25°C. Phase A contained water (HiPerSolv ChromanormWater VWR, for HPLC-MS) + 0,05% trifluoroacetic acid; Phase B contained CH3CN (HiPerSolv ChromanormAcetonitrile SuperGradient VWR; for UPLC / UHPLC instruments) + 0,05% trifluoroacetic acid; Flow rate: 0,5mL / min; UV detection (DIODE array) 200nm; ESI+ and ESI- detection in the range of 100-1000 m / z.

[0425] Method 1: Column 1, Run time: 3 min, Run gradient: 5% B to 100% B in 2.80 min + 100% B in 0.2 min, Equilibration time: 0,8 min, Ionization mode: ESI+.

[0426] Method 2: Column 2, Run time: 4 min, Run gradient: 0% B to 45% B in 3.5 min + 45% B to 100% B in 0.05 min + 100% B for 0.45 min, Equilibration time: 0,8 min, Ionization mode: ESI + .

[0427] Method 3: Column 3, run time: 6 min, run gradient: 5% B to 100% B in 5 min + 100% B for 1 min, equilibration time: 2 min.

[0428] Method 4: Column 3, Run time: 6 min, Run gradient: 5% B to 50% B in 5 min + 50% B to 100% B in 0.2 min + 100% B for 0.8 min, Equilibration time: 2 min, Ionization mode: ESI + .

[0429] Method 5: Column 1, run time: 3 min, run gradient: 5% B to 100% B in 2.80 min + 100% B for 0.2 min, equilibration time: 0,8 min, ionization mode: ESI+.

[0430] 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 + .

[0431] Method 7: Column 3, Run time: 6 min, Run gradient: 5% B to 100% B in 5 min + 100% B for 1 min, Equilibration time: 2 min, Ionization mode: ESI + .

[0432] Method 8: Column 3, Run time: 6 min, Run gradient: 5% B to 50% B in 5 min + 50% B to 100% B in 0.2 min + 100% B for 0.8 min, Equilibration time: 2 min, Ionization mode: ESI + .

[0433] Method 9: Column 1, Run time: 4 min, Column 1, Run time: 4 min, Run gradient: 5% B to 100% B in 3.00 min + 100% B for 1 min, Equilibration time: 0,8 min, Ionization mode: ESI + .

[0434] Method 10: Column 1. Run time: 4 min, Run gradient: 5% B to 100% B in 3.00 min + 100% B in 1 min, Equilibration time: 0,8 min, Ionization mode: ESI － .

[0435] Method 11: Column 1, Run time: 3 min, Run gradient: 40% B to 100% B in 2.80 min + 100% B for 0.2, Equilibration time: 0.8 min. Ionization mode: ESI + .

[0436] Method 12: Column 3, Run time: 6 min, Run gradient: 25% B to 70% B in 5 min + 100% B for 1 min, Equilibration time: 2 min, Flow: 0,5 mL / min, Ionization mode: ESI + .

[0437] Method 13: Column 2, Run time: 4 min, Run gradient: 0% B to 60% B in 3.5 min + 60% B to 100% B in 0.05 min + 100% B for 0.45 min, Equilibration time: 0,8 min, Ionization mode: ESI + .

[0438] Method 14: Column 2, Run time: 4 min, Run gradient: 0% B to 30% B in 3.5 min + 30% B to 100% B in 0.05 min + 100% B for 0.45 min, Equilibration time: 0,8 min, Ionization mode: ESI + .

[0439] Method 15: Column 3, Run time: 10 min, Run gradient: 5% B to 100% B + 100% B in 9 min for 1 min, Equilibration time: 2 min, Ionization mode: ESI + .

[0440] synthesis

[0441] According to another aspect of the present invention, a method for preparing a compound of formula (I), formula (IA), formula (IB), formula (II-A), formula (II-B), formula (III-A), formula (III-B) or a salt thereof is provided. The following scheme is an example of a synthetic scheme that can be used to synthesize the compounds of the present invention. In the following scheme, reactive groups and deprotection can be protected with protecting groups according to recognized techniques. In the following scheme, unless otherwise indicated, R1, R2, R3, R5, R7, R8, X, Y, Y', Y", Y'", Cy, Ra, Rb, Rc, Rd are as defined above in each formula (I), formula (IA), formula (IB), formula (II-A), formula (II-B), formula (III-A), formula (III-B).

[0442] Those skilled in the art will appreciate that certain compounds of the invention can be converted to other compounds of the invention according to standard chemical methods.

[0443] The compounds of the present invention can be prepared according to the general route shown in Scheme 1 below:

[0444]

[0445] Ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate, represented in Scheme 1 as compound (1), wherein R1=CH3 and R3=H, is prepared according to the procedure described in WO2017 / 001655. According to Scheme 1, a primary amine derivative (2) bearing a nucleophilic -XH substituent is reacted with compound (1) in the presence of an appropriate base to give the corresponding sulfonamide product (3). Reaction of (3) with an aromatic or heteroaromatic amine in the presence of a strong non-nucleophilic base (such as LiHMDS) in a solvent (such as tetrahydrofuran) converts the ethyl carboxylate into an aromatic amide derivative (4). The subsequent cyclization step affords the tricyclic core of compound (5) by intramolecular nucleophilic attack of fluorine by XH. Depending on the specific protecting group (PG, as shown in Scheme 1) in compound (5), the product can be further elaborated by deprotection and / or further functionalization steps. In particular, when the nitrogen is as an N-Boc derivative, the Boc can be removed by acid treatment and the resulting NH can be further converted to, for example, a carbamate, urea, sulfonamide, sulfonylurea derivative or can be alkylated by, for example, reductive amination chemistry. In a specific embodiment of the invention, in the compound of formula (5), the protected nitrogen is N-COOEt or N-PMB, where the protecting group can be removed by standard chemical methods, such as trimethylsilyl iodide for ethyl carbamate and hydrogenation for p-methoxybenzyl (PMB). In another embodiment of the invention, the nucleophilic group -XH in the compound of formula (2), (3) or (4) can be further elaborated by protection and displacement with different nucleophiles. It is still worth noting that the specific order of steps indicated in Scheme 1 can be changed to optimize the efficiency of the synthetic strategy.

[0446] After deprotection of compound (5) as shown in Scheme 1, a higher intermediate of general structure (5a) is obtained and further reacted as shown in Scheme 2 to obtain the compounds of the present invention.

[0447]

[0448] In a preferred embodiment, in compounds 5a, 6, 7 and 9, m and n are each independently 1 or 2. The compound of formula (9) wherein R3 is H can be further reacted under halogenation conditions to obtain the compound of formula (9) wherein R3 is halogen. For example, the reaction of the compound of formula (9) wherein R3 is H with dichloromethane gives the corresponding chlorinated derivative (i.e. R3 is Cl).

[0449] Certain amine derivatives (2) of Scheme 1 were prepared according to the synthetic strategies outlined in Schemes 3, 4 and 5. The procedures in the Schemes can be used to synthesize the compounds shown below, and can also be used to synthesize the compounds as single diastereomers and / or enantiomers by selecting starting materials with appropriate stereochemical configurations.

[0450]

[0451] Unless otherwise indicated, starting materials and / or intermediates are available from commercial sources or can be obtained by synthetic procedures known in the chemical literature. Indications of the commercial sources of certain compounds in the description of experimental procedures, if provided, are intended only for the convenience of reference of skilled chemists and should not be construed as an indication to use only that particular commercial compound.

[0452] In the following paragraphs, descriptions 1-53 illustrate the preparation of intermediates for preparing compounds of the present invention and their salts. The examples illustrate the preparation of compounds of the present invention and their salts. When compounds have more than one chiral center, it should be understood that they may exist in the form of a mixture of diastereomers or a single isomer. Racemic and chiral compounds are within the scope of the present invention. The procedures provided for indication are only to provide assistance to skilled chemical researchers. The starting materials do not necessarily have to be prepared by the described instructions or examples.

[0453] Description D1: Ethyl (3aR, 6aR)-1-((R)-hydroxy-1-phenylethyl)tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5(3H)-carboxylate (D1)

[0454]

[0455] The preparation was carried out starting from ethyl allyl(2-oxoethyl)carbamate (prepared as reported in US2018 / 0222918) and (R)-2-(hydroxyamino)-2-phenylethan-1-ol (prepared as reported in WO2010 / 016005) according to the process reported in J.Org.Chem.2003,68,8739-8741. 1 H NMR (300 MHz, CDCl3) δ ppm 1.15 (t, J = 7.11 Hz, 3H) 2.87 (dd, J = 8.89, 4.40 Hz, 1H) 3.06-3.56 (m, 5H) 3.57-3.75 (m, 3H) 3.75-3.83 (m, 1H) 3.94-4.11 (m, 3H) 4.27 (br t, J = 8.12 Hz, 1H) 7.22-7.36 (m, 5H). Method 3; Rt = 2.18 min. m / z = 307.32 (M+H) + .

[0456] Description D2: Ethyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate hydrochloride (D2)

[0457]

[0458] 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 room temperature for 16 hours at 1 atm. Acetic acid (15.16 mL, 265.05 mmol) was added and the reaction was stirred for 15 minutes, then filtered through paper and washed with methanol (about 70 mL). The solution was evaporated (30 ° C), and the residue was treated with 1M HCl (20 mL) and then further evaporated. The residue was dissolved in water (10 mL), the pH was adjusted with 1M HCl (3 mL), washed with DCM, and the aqueous layer was further evaporated and co-evaporated with toluene to remove traces of acetic acid to obtain the title compound D2 (1.6 g, 7.12 mmol) as an off-white powder (yield = 75%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.18 (t, J = 7.06 Hz, 3H), 2.54-2.66 (m, 1H), 3.17-3.66 (m, 6H), 3.72-3.88 (m, 1H), 3.93-4.14 (m, 2H), 8.10 (br s, 3H). Method 13; Rt = 1.02 min; m / z = 189.15 (M+H) + .

[0459] Description D3: (2,2-dimethoxyethyl)(2-methylallyl)carbamate (D3)

[0460]

[0461] Procedure 1:

[0462] 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. A 1 M NaHMDS solution in THF (13.45 mL, 13.45 mmol) was added in one portion. The reaction 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 in one portion, the reaction was stirred at room temperature for 30-40 minutes, then heated at 60 ° C for 30 minutes by microwave irradiation, and then heated at 70 ° C for 4 hours in the presence of DMF (2 mL, 0.026 mol). The reaction was diluted with water (10 mL) and extracted with ether (10 mL×3). The combined organic layers were evaporated and purified by direct flash chromatography (eluent petroleum ether / EtOAc) to afford D3 (0.5 g, 2.16 mmol, 22% yield) as a colorless oil.

[0463] Procedure 2:

[0464] 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-diethylethylamine 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 give 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 at room temperature overnight, then filtered through paper, diluted with EtOAc, washed with brine and concentrated. The residue (0.25 g) was purified by direct flash chromatography (eluent petroleum ether / EtOAc) to give D3 (0.64 g, 2.9 mmol, 80% yield) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.18 (br d, J = 6.42 Hz, 3H), 1.62 (s, 3H), 3.15-3.23 (m, 2H), 3.25-3.31 (m, 6H), 3.74-3.91 (m, 2H), 4.05 (br d, J = 6.60 Hz, 2H), 4.40-4.54 (m, 1H), 4.63-4.78 (m, 1H), 4.79-4.91 (m, 1H). Method 9; Rt: 1.79-1.82 min. m / z: 254.22 (M+Na) + .

[0465] Description D4: Synthesis of ethyl (2-methylallyl)(2-oxoethyl)carbamate (D4)

[0466]

[0467] A solution of D3 (0.25 g, 1.08 mmol) in acetone (2 mL) and water (1.5 mL) was heated to 80 ° C by microwave irradiation in the presence of 1 M pyridine 4-methylbenzenesulfonate in water (25 uL, 0.025 mmol). After 1 hour, a further solution of 1 M pyridine 4-methylbenzenesulfonate in water (100 uL, 0.1 mmol) was added and the reaction was heated at 100 ° C for 15 minutes (× 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 purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.28 (m, 3H), 1.54-1.71 (m, 3H), 3.81 (s, 2H), 3.91-4.17 (m, 4H), 4.63-4.80 (m, 1H), 4.85 (s, 1H), 9.48 (d, J = 4.77 Hz, 1H). Method 1; Rt: 1.04-1.54 min. m / z: 186.24 (M+H) + .

[0468] Description D5: cis-1-benzyl-3a-methyltetrahydro-1H-pyrrolo[3,4-c]isoxazole-5(3H)-carboxylic acid ethyl ester (D5)

[0469]

[0470] A solution of D4 (0.5 g, 2.7 mmol) and N-benzylhydroxylamine (0.366 g, 2.97 mmol) in toluene (5 mL) was heated at 50 °C for 30 min under microwave irradiation and then at 100 °C for another 1 h. The reaction was poured into a separatory funnel and washed with 5% citric acid in water (3 mL) and brine (5 mL). The solvent was removed and the residue was purified by direct flash chromatography (eluent petroleum ether / EtOAc). The pure fractions were combined to give D5 (0.2 g, 0.689 mmol, 25% yield) as a pale yellow oil. Method 9; Rt: 1.78. m / z: 291.31 (M+H) + .

[0471] Description D6: Synthesis of cis-4-amino-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylic acid ethyl ester (D6)

[0472]

[0473] Procedure 1:

[0474] A solution of D5 (0.4 g, 1.38 mmol) in methanol (24 mL) was placed in a 40 mL tube, and ammonium formate (0.434 g, 6.89 mmol) was added followed by 10% Pd / C (146.6 mg). The tube was sealed and the black reaction suspension was heated at 70 °C for 1.5 hours. The reactant 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 purification.

[0475] Procedure 2:

[0476] A solution of D5 (0.176 g, 0.61 mmol) in ethanol (11.4 mL) and water (1.2 mL) was passed through an H-CUBE apparatus equipped with a 10% Pd / C mini cartridge (THS01111, ThalesNano). Hydrogenation was performed using the following conditions: pressure H2: 10 bar; flux: 1 mL / min, T = 80°C. Removal of the solvent gave 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) + .

[0477] Description D7: N-(4-methoxybenzyl)prop-2-en-1-amine (D7)

[0478]

[0479] 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 (reaction was carried out neat). p-Benzoyl chloride (2.6 mL, 19.18 mmol) (270245, Sigma Adrich, CAS: 824-94-2) was added over 50 min and the reaction mixture was stirred at room temperature overnight. The 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 give 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) + .

[0480] Description D8: 1-(Allyl(4-methoxybenzyl)amino)propan-2-one (D8)

[0481]

[0482] A mixture of D7 (2.27 g, 16.21 mmol) was suspended in MeCN (1 mL) and treated once with chloroacetone (0.87 mL, 10.81 mmol). The mixture was heated in a sealed vial for 4 hours by conventional heating at 70 ° C. The solvent was removed by evaporation. The residue was distributed between water (15 mL) and EtOAc (15 mL); the organic layer was evaporated and the residue was purified by direct flash chromatography (petroleum ether / EtOAc) to obtain D8 (1.5 g, 6.43 mmol, yield: 59%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 3.11-3.24 (m, 4H), 3.61 (s, 2H), 3.82 (s, 3H), 5.16-5.27 (m, 2H), 5.90 (ddt, J = 17.02, 10.30, 6.42, 6.42 Hz, 1H), 6.88 (d, J = 8.53 Hz, 2H), 7.21-7.32 (m, 3H). Method 9; Rt: 0.96 min; m / z: 234.14 (M+H) + .

[0483] Description D9: 1-(Allyl(4-methoxybenzyl)amino)propan-2-one oxime (D9)

[0484]

[0485] D8 (1.5 g, 6.43 mmol) was dissolved in ethanol (50 mL) and added to a mixture of hydroxylamine chloride (0.89 g, 12.86 mmol) and sodium acetate (1.07 g, 12.86 mmol). The resulting white suspension was stirred at room temperature overnight for 3 hours. The solvent was removed, the residue was dissolved in water (15 mL) and extracted with EtOAc (10 mL × 2), dried over Na2SO4 (anhydrous), filtered and evaporated. The organic layer was evaporated and the residue was purified by direct flash chromatography (petroleum ether / EtOAc) to obtain D9 (1.6 g, 6.43 mmol, quantitative yield). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.68-1.98 (m, 2H), 2.13-2.40 (m, 4H), 4.05 (br d, J = 7.52 Hz, 2H), 4.46 (br dd, J = 13.02, 2.57 Hz, 3H), 4.82 (br d, J = 14.12 Hz, 3H), 6.95 (dd, J = 11.88, 0.87 Hz, 1H), 7.28 (s, 1H), 7.50 (d, J = 8.53 Hz, 1H), 7.69-7.83 (m, 2H), 10.95 (br s, 1H), 11.91 (br s, 1H). Method 9; Rt: 1.01 min. m / z: 249.21 (M+H) + .

[0486] Description D10: cis-5-(4-methoxybenzyl)-6a-methylhexahydro-1H-pyrrolo[3,4-c]isoxazole (D10)

[0487]

[0488] 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 by direct flash chromatography (eluent EtOAc / MeOH) to give impure title product (700 mg), which was further purified by a second direct flash chromatography (eluent DCM / MeOH) to give D10 (0.55 mg, 34% yield). Method 9; Rt: 0.81 min. m / z: 249.27 (M+H) + .

[0489] Description D11: cis-(4-amino-1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl)methanol (D11)

[0490]

[0491] 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 and 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 alkalized 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 light yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (s, 3H), 1.47-2.19 (m, 3H), 2.26-2.38 (m, 2H), 2.44 (d, J = 8.80 Hz, 1H), 2.66 (t, J = 8.94 Hz, 1H), 3.39-3.48 (m, 1H), 3.48-3.63 (m, 3H), 3.79 (s, 3H), 3.94-5.32 (m, 1H), 6.92 (d, J = 8.62 Hz, 2H), 7.26 (d, J = 8.44 Hz, 2H). Method 2; Rt: 1.40 min; m / z: 251.25 (M+H) + .

[0492] Description D12: cis-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-3-amine (D12)

[0493]

[0494] 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 with a dry ice / acetone bath, and a solution of tert-butylchlorodimethylsilane (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, then filtered, and finally evaporated to give a residue (200 mg). Purification by direct flash chromatography (eluent EtOAc / MeOH) afforded D12 (0.127 mg, 51% yield) as a light yellow oil. 1 H NMR(300MHz,DMSO-d6)δppm 0.08-0.04(m,6H),0.76-0.88(m,9H),1.07-1.24(m,3H),1.52(br s, 2H), 1.78-1.91 (m, 1H), 2.14-2.22 (m, 1H), 2.23-2.30 (m, 1H), 2.34-2.39 (m, 1H), 2.56-2.65 (m, 1H), 3.35-3.48 (m, 2H), 3.49-3.58 (m, 1H), 3.63-3.69 (m, 1H), 3.69-3.73 (m, 3H), 6.84 (d, J = 8.53 Hz, 2H), 7.17 (d, J = 8.44 Hz, 2H). Method 2; Rt: 1.56 min; m / z: 365.26 (M+H) + .

[0495] Description D13: (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid ethyl ester (D13)

[0496] The compounds were prepared according to the following scheme:

[0497]

[0498] Step 1:

[0499] To a solution of D2 (1351.61 mg, 7.18 mmol) in anhydrous MeCN (24 mL) was added DIPEA (2.5 mL, 14.36 mmol); 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 over 10 minutes. The reaction was stirred at room temperature for 90 minutes and then concentrated under reduced pressure; diluted with EtOAc (130 mL) and washed with 5% citric acid solution (40 ml) and brine (20 ml), dried over Na2SO4 (anhydrous), filtered and the solvent removed under reduced pressure. The crude product was purified by direct flash chromatography (eluent DCM / AcOEt) to give 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) + .

[0500] Step 2:

[0501] 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) prepared in step 1 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 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown foam D13 which was used without further purification. Method 1: Rt = 1.81 min; m / z = 501.16 (M+H) + .

[0502] Description D14: (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid ethyl ester (D14)

[0503]

[0504] To a solution of D13 (623 mg, 1.24 mmol) in anhydrous DCM (27 mL) were added triethylamine (0.35 mL, 2.49 mmol) and DMAP (15.2 mg, 0.12 mmol) in sequence. 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 obtain the crude product D14 (721 mg) in an almost quantitative yield, which was used in the next step without further purification. Method 1; Rt = 1.98 min; m / z = 579.14 (M+H) + .

[0505] Description D15: (3R,4R)-3-((thioacetyl)methyl)-4-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)pyrrolidine-1-carboxylic acid ethyl ester (D15)

[0506]

[0507] Potassium thioacetate (634 mg, 5.55 mmol) was added to a solution of D14 (257 mg, 0.44 mmol) in anhydrous DMF (7.6 ml). The dark red reaction mixture was stirred at room temperature overnight, then diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent petroleum ether / EtOAc) to give D15 (170 mg, y=68.5%) as off-white foam. 1 H NMR (300MHz, DMSO-d6) δppm1.09-1.21(m,4H),2.23(s,3H),2.30(s,3H),2.33-2.43( m,1H),2.90(m,J=7.50Hz,2H),3.03-3.16(m,1H),3.16-3.26(m,1H),3.35-3.48(m,2H ), 3.81 (s, 4H), 3.93-4.05 (m, 2H), 7.11 (t, J = 9.35 Hz, 1H), 7.41-7.53 (m, 2H), 7.54-7.65 (m, 1H), 8.04-8.30 (m, 1H), 9.84-10.17 (m, 1H). Method 1; Rt = 2.12 minutes; m / z = 559.18 (M+H) + .

[0508] Description D16: (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(mercaptomethyl)pyrrolidine-1-carboxylic acid ethyl ester (D16)

[0509]

[0510] To a solution of D15 (443 mg, 0.79 mmol) in methanol (3.7 mL) was added 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 with 1N HCl until pH = 3 (white solid precipitated), and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain 396 mg of light yellow foam (containing the desired product and SS 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 celite pad, washed with DCM and concentrated under vacuum to obtain a white foamy crude product D16 (431 mg), which was used in the next step without further purification. Method 1; Rt = 2.09 minutes; m / z = 517.17 (M+H) +

[0511] Description D17: Synthesis of cis-4-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylic acid ethyl ester (D17)

[0512] The compounds were prepared according to the following scheme:

[0513]

[0514] Step 1:

[0515] D6 (110 mg, 0.54 mmol) was dissolved in MeCN (2 mL), cooled to 0 ° C, treated with 4- (chlorosulfonyl) -3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (146.7 mg, 0.54 mmol), and then treated with DIPEA (0.21 mL, 1.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was distributed between DCM and saturated NaHCO3 solution; the organic layer was evaporated and the residue was purified by direct flash chromatography (direct phase, eluent petroleum ether / EtOAc) to obtain cis-4- (N- (1- (ethoxycarbonyl) -4- (hydroxymethyl) -4- methylpyrrolidin-3-yl) sulfamoyl) -3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (100 mg, 0.23 mmol) as a white solid. Method 1; Rt: 1.64; m / z: 436.19 (M+H) + .

[0516] Step 2:

[0517] A solution of cis-4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)-4-methylpyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg, 0.23 mmol) and 4-fluoro-3-methylaniline (30.2 mg, 0.24 mmol) prepared in step 1 in anhydrous THF (50 mL) was treated with a single portion of 1 M lithium bis(trimethylsilyl)amide in THF (1.16 mL, 1.16 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. 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). Step 2 provided D17 (100 mg, 0.194 mmol). 1HNMR(300MHz,DMSO-d6)δppm 0.83-0.91(m,3H),1.05-1.12(m,3H),2.16(d,J=1.28Hz,3H),2.49-2.70(m,1H),2.82(br t,J=10.22Hz,1H),3.05(br s,1H),3.27-3.54(m,4H),3.67-3.80(m,3H),3.84-4.05(m,2H),4.55-4.78(m,1H),7.05(t,J=9.22Hz,1H),7.42(br d,J=4.40Hz,2H),7.53(br d,J=6.69Hz,1H),7.77(br d, J = 8.62 Hz, 1H), 9.96 (s, 1H). Method 9; Rt: 1.91; m / z: 515.21 (M+H) +.

[0518] Description D18: cis-4-((4-fluoro-1-methyl-5-((3,4,5-trifluorophenyl)carbamoyl)-1H-pyrrole)-3-sulfonamido)-3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylic acid ethyl ester (D18) The compound was prepared according to the following scheme:

[0519]

[0520] Step 1:

[0521] D6 (110 mg, 0.54 mmol) was dissolved in MeCN (2 mL), cooled to 0 ° C, treated with 4- (chlorosulfonyl) -3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (146.7 mg, 0.54 mmol), and then treated with DIPEA (0.21 mL, 1.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was distributed between DCM and NaHCO3; the organic layer was evaporated and the residue was purified by direct flash chromatography (direct phase, eluent petroleum ether / EtOAc) to give cis-4- (N- (1- (ethoxycarbonyl) -4- (hydroxymethyl) -4- methylpyrrolidin-3-yl) sulfamoyl) -3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (100 mg, 0.23 mmol) as a white solid. Method 1; Rt: 1.64; m / z: 436.19 (M+H) + .

[0522] Step 2:

[0523] A mixture of the intermediate compound 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 at room temperature with a single portion of 1 M lithium bis(trimethylsilyl)amide in THF (0.632 mL, 0.632 mmol). The resulting brown mixture was stirred at room temperature for 15 minutes. The solvent was removed in vacuo and 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) + .

[0524] Description 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)

[0525] The compounds were prepared according to the following scheme:

[0526]

[0527] Step 1:

[0528] Under nitrogen atmosphere, sodium hydride (60% weight in mineral oil, 3.7 g, 92.5 mmol) was added to a solution of 3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (12.5 g, 79.6 mmol) (231254, Fluorochem, CAS: 168102-05-4) in anhydrous DMF (125 mL) cooled to 0 ° C in batches within 30 minutes. The reaction mixture was further stirred for 20 minutes, and then iodomethane (5.8 mL, 93.2 mmol) was added dropwise within 30 minutes. The mixture was further stirred for 30 minutes at the same temperature, 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 vigorously stirred 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 light yellow oil after evaporation of the solvent and was used without further purification. 1H NMR (300MHz, DMSO-d6) δppm 1.27 (t, J = 7.11Hz, 3H), 3.78 (s, 3H), 4.23 (q, J = 7.06Hz, 2H), 5.99 (d, J = 3.03Hz, 1H), 7.00 (dd, J = 5.27, 3.07Hz, 1H).

[0529] Step 2:

[0530] 3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (13.6g, 79.5mmol) and 4- fluoro-3- methylaniline (10.3g, 82.3mmol) prepared in step 1 are dissolved in anhydrous toluene (50mL).LiHMDS (140mL, 1M in toluene, 140mmol) was added dropwise in 30 minutes, and the reaction mixture was stirred at room temperature for another 30 minutes.The reaction mixture was cooled to 0 ℃ and slowly quenched with 2N HCl (200mL), diluted with water (200mL) and toluene (200mL) and stirred at room temperature for 20 minutes.Separate two phases, organic phase saturated NaHCO (200mL) and salt solution (200mL) washing, through Na SO (anhydrous) drying and filtering. 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 was used without further purification. 1 H NMR(300MHz,DMSO-d6)δppm 2.22(s,3H),3.76(s,3H),6.01(d,J=3.03Hz,1H),6.91(dd,J=5.27,3.07Hz,1H), 7.08(t,J=9.22Hz,1H),7.35-7.53(m,1H),7.59(dd,J=7.06,2.20Hz,1H),9.50(br s,1H).

[0531] Step 3:

[0532] Under nitrogen atmosphere, chlorosulfonic acid (5.7 mL, 85.6 mmol) dissolved in anhydrous DCM (120 mL) was added dropwise over 90 minutes to 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. The reaction mixture was further stirred for 30 minutes at the same temperature; the precipitate formed was then filtered and washed several times with Et2O. The resulting light grey solid 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (23.1 g, 88% three-step yield) was dried under vacuum overnight and used without further purification. 1 H NMR(300MHz,DMSO-d6)δppm 2.22(s,3H),3.70(s,3H),6.93(d,J=5.04Hz,1H),7.07(t,J=9.22Hz,1H),7.44-7.52(m,1H),7.60(dd,J=7.06,2.20Hz,1H),9.64(s,1H).

[0533] Step 4:

[0534] Anhydrous DMF (0.35mL, 4.51mmol) is added to a suspension of 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (14.9g, 45.1mmol) prepared in step 3 in thionyl chloride (112mL). The reaction mixture is heated to 75°C and stirred at the same temperature for 45 minutes. The brown solution is cooled to room temperature, diluted with toluene (200mL) and slowly poured into a mixture of toluene (200mL) and ice (500mL) under vigorous stirring. The two-phase system is stirred for 20 minutes, the two phases are separated, and the organic phase is washed with ice water (200ml) and brine (200ml), dried over Na2SO4(anhydrous), filtered and concentrated under reduced pressure. The residue was purified on 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 (300MHz, CDCl3) δppm 2.31 (s, 3H), 4.06 (s, 3H), 7.03 (t, J = 8.89Hz, 1H), 7.26-7.36 (m, 2H), 7.39-7.46 (m, 1H), 7.72 (br d, J = 8.16Hz, 1H).

[0535] Step 5:

[0536] 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 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 at room temperature overnight. 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 at room temperature for 1 hour 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 NaHCO (saturated solution, 10 mL), dried over NaSO (anhydrous), filtered and finally evaporated to give a residue (0.2 g). Purification by direct flash chromatography (eluent 5% MeOH / EtOAc) gave D19 (0.075 g, 0.133 mmol, 49% yield). 1 H NMR(300MHz,DMSO-d6)δppm 1.36(s,3H),1.84-2.06(m,1H),2.23(s,3H),2.27(br dd,J=4.22,2.29Hz,1H),2.54-2.59(m,1H),2.62-2.69(m,1H),2.70-2.80(m,1 H),3.35-3.54(m,3H),3.56-3.67(m,1H),3.71(s,3H),3.78(s,3H),4.94-5.05 (m, 1H), 6.76-6.91 (m, 2H), 7.05-7.21 (m, 3H), 7.28-7.38 (m, 1H), 7.40-7.54 (m, 2H), 7.54-7.66 (m, 1H), 9.86-10.07 (m, 1H). Method 9; Rt: 1.64 min; m / z: 563.30 (M+H) + .

[0537] Description D20: (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)-carboxylic acid ethyl ester 5,5-dioxide (D20)

[0538]

[0539] Cesium carbonate (646mg, 1.98mmol) is added to the solution of crude product D16 (0.793mmol) in DMF (14.5mL), and the reaction mixture is stirred for 1 hour at 135 ℃.The reaction is diluted with EtOAc, and washed with water (× 3).The organic layer is dried over Na2SO4 (anhydrous), filtered and concentrated under vacuum.The gained crude product is purified by flash chromatography on silica gel (eluent DCM / MeOH), then by preparative HPLC-MS (H2O / CH3CN+0.1%HCOOH) D20 (280mg, yield=71%) is obtained after freeze-drying as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (q, J = 6.82 Hz, 3H), 2.23 (s, 3H), 2.31-2.44 (m, 1H), 2.56-2.71 (m, 1H), 2.87-3.09 (m, 1H), 3.16-3.44 (m, 3H), 3.54-3.83 (m, 4H), 3.88-4.13 (m, 2H), 4.59-4.85 (m, 1H), 7.10 (t, J = 9.35 Hz, 1H), 7.42-7.60 (m, 2H), 7.61-7.74 (m, 1H), 8.01-8.25 (m, 1H), 10.32 (s, 1H). Method 3; Rt = 3.47 min; m / z = 497.24 (M+H) + .

[0540] Description D21: (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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D21)

[0541]

[0542] 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, and the residue was absorbed by EtOAc and washed with water (× 3). The organic layer was dried over Na2SO4 (anhydrous), filtered and the solvent was removed under reduced pressure. Then, the obtained light brown foam was treated with Et2O to remove the residual solvent and obtain a light brown solid D21 (2.8 g, yield = 93%), which can be used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.27 (m, 3H), 2.24 (d, J = 1.47 Hz, 3H), 2.92-3.16 (m, 2H), 3.41 (br d, J = 10.91 Hz, 2H), 3.64-4.10 (m, 7H), 4.32-4.69 (m, 2H), 7.11 (t, J = 9.22 Hz, 1H), 7.39-7.67 (m, 3H), 7.96 (s, 1H), 9.34 (s, 1H). Method 1: Rt = 2.00 min; m / z = 481.24 (M+H) + .

[0543] Description D22: (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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D22)

[0544] This compound was prepared according to the following scheme:

[0545]

[0546] Step 1 and step 2 were performed according to the procedure described in 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 performed as described for compound D21. Method 1: Rt = 2.09 min; m / z = 501.30, 503.39 (M+H) + .

[0547] Description D23: (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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D23)

[0548] This compound was prepared according to the following scheme:

[0549]

[0550] Step 1 and step 2 were carried out according to the procedure described in the synthesis of compound D78, 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 obtain D23. Method 1: Rt = 2.08 min; m / z = 503.19 (M+H)+ .

[0551] Description D24: (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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D24)

[0552] This compound was prepared according to the following scheme:

[0553]

[0554] Step 1 and step 2 were carried out according to the procedure described in the synthesis of compound D13, using 3-cyano-4-fluoroaniline (013105, Fluorochem, CAS: 53312-81-5) in step 2 instead of 4-fluoro-3-methylaniline. Step 3 was carried out as described for compound D21 to obtain D24. Method 1: Rt = 1.92 min. m / z = 492.45 (M+H) + .

[0555] Description D25: cis-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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D25)

[0556]

[0557] 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 by microwave radiation for 5 hours. The reaction 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 product was purified by Fraction-Lynx (H2O / CH3CN+1‰TFA) to give D25 (10 mg, 0.019 mmol, 32% yield). 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.12-1.23 (m, 3H), 1.27 (s, 3H), 3.06 (d, J = 10.55 Hz, 1H), 3.16-3.28 (m, 1H), 3.28-3.44 (m, 1H), 3.72-3.84 (m, 3H), 3.84-4.14 (m, 5H), 4.30 (br t, J = 10.82 Hz, 1H), 7.49 (s, 1H), 7.54-7.71 (m, 2H), 8.38-8.54 (m, 1H), 9.67 (br s, 1H). Method 3: Rt = 3.71 min; m / z = 517.37 (M+H) + .

[0558] Description D26: cis-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]oxathiazepine-2(3H)-carboxylic acid ethyl ester 5,5-dioxide (D26)

[0559]

[0560] Prepared following the same procedure as described for the synthesis of D21, starting from D17, D26 was obtained. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.25 (m, 3H) 1.27 (s, 3H) 2.24 (d, J = 1.47 Hz, 3H) 3.07 (d, J = 10.73 Hz, 1H) 3.16-3.28 (m, 1H) 3.36 (s, 1H) 3.72-3.84 (m, 3H) 3.84-4.16 (m, 5H) 4.31 (s, 1H) 7.12 (t, J = 9.22 Hz, 1H) 7.36-7.52 (m, 2H) 7.52-7.67 (m, 1H) 8.31-8.57 (m, 1H) 9.24-9.45 (m, 1H). Method 3: Rt = 3.56 min. m / z = 495.35 (M+H) + .

[0561] Description 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]oxathiazepine-8-carboxamide 5,5-dioxide (D27)

[0562]

[0563] 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 x 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 purification. Method 1; Rt: 1.55 min; m / z: 543.37 (M+H) + .

[0564] 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)

[0565]

[0566] 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 hours. The mixture was quenched by adding methanol at 0 ° C and then evaporated under reduced pressure. The residue was triturated with Et2O to obtain 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) + .

[0567] 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]oxathiazepine-8-carboxamide 5,5-dioxide hydroiodide (D29)

[0568] The compounds were prepared according to the following scheme:

[0569]

[0570] Step 1:

[0571] To a suspension of ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (70 mg, 0.260 mmol) and 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 hours, 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 ethyl 4-(N-(1-(ethoxycarbonyl)-4-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate as a light yellow solid (162 mg). The compound is a cis racemate on the pyrrolidine ring (3S, 4S and 3R, 4R racemates). 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) + .

[0572] Step 2:

[0573] To a solution of the compound from step 1 and 4-fluoro-3-methylaniline in anhydrous THF (2 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (5 equiv) at room temperature. After completion of the reaction and standard work-up, the intermediate product cis-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid ethyl ester was obtained and further reacted. Method 1: Rt = 1.83 min, m / z = 501 (M+H) + .

[0574] For the synthesis of compound D21, step 3 was performed. Step 4 was performed as described for the synthesis of D28 to obtain D29. Method 1: Rt = 1.36 min; m / z = 409.17 (M+H) + .

[0575] 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]oxathiazepin-2-ium iodide 5,5-dioxide (D30)

[0576]

[0577] Procedure 1:

[0578] Prepared analogously to compound D28 starting from D21 to afford D30. Method 1: Rt = 1.36 min; m / z = 409.37 (M+H) + .

[0579] Procedure 2:

[0580] This compound was prepared according to the following scheme:

[0581]

[0582] Steps 1-6 were carried out following the procedure reported in J. Med. Chem 2007, 50, 5493-5508 starting from 2,2-dimethoxyethane-1-amine (094452, Fluorochem, CAS: 22483-09-6) and benzyl chloroformate to obtain (±)3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.55-2.68 (m, 1H) 3.27-3.38 (m, 1H) 3.43-3.67 (m, 5H) 3.84 (br s, 1H) 5.04-5.13 (m, 2H) 7.29-7.41 (m, 5H) 7.90-8.02 (br s, 2H). Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) + .

[0583] Step 7:

[0584] 2-Methoxypropylene (8.81 mL, 92.02 mmol) (174645, Sigma Aldrich, CAS: 116-11-0) was added to a solution of compound (±) 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (11.52 g, 46.02 mmol) from step 6 in acetone (16 mL). 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 placed 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 and washed three times with 60 mL of anhydrous acetone, cooled to -5°C to give (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylic acid benzyl ester [(S)-mandelate] as a white solid (6.2 g, y = 30%).

[0585] Step 8:

[0586] (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylic acid benzyl ester [(S)-mandelate] (500 mg, 1.13 mmol) from step 7 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). (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (245 mg, y=87%) was used in the next step without any further purification. Method 2; Rt=1.81 min. m / z=251.25 (M+H) +

[0587] Step 9:

[0588] To a solution of the compound from step 8, (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (217 mg, 0.870 mmol), N-ethyl-N-isopropylpropan-2-amine (0.6 mL, 3.47 mmol) and 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (302.36 mg, 0.870 mmol) in 5 ml of dry MeCN were added sequentially. The resulting mixture was further 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 crude product was purified by flash chromatography on silica gel (direct phase, eluent DCM / EtOAc) to give benzyl (3R,4R)-3-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (420 mg, y=86%) as a white foam. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.22 (s, 3H) 2.30-2.43 (m, 1H) 3.19-3.29 (m, 1H) 3.29-3.51 (m, 4H) 3.53-3.64 (m, 1H) 3.70-3.92 (m, 4H) 5.04 (d, J = 4.22 Hz, 2H) 7.10 (t, J = 9.26 Hz, 1H) 7.21-7.41 (m, 5H) 7.43-7.54 (m, 2H) 7.59 (br d, J = 7.00 Hz, 1H) 7.97 (d, J = 6.88 Hz, 1H) 9.99 (s, 1H). Method 4; Rt = 2.04 min. m / z = 563 (M+H) + .

[0589] The enantiomeric ratio (ee>99%) of the title compound was determined by chiral HPLC (HPLC conditions: DIACELCHIRALPACK IG column; eluent: phase A: H2O ultrapure 0.05% TFA, MeCN ultrapure 0.05% TFA; flow rate, 1.0 ml / min, UV, 270 nM); retention time of (S, S), 30 minutes; retention time of (R, R) was 45 minutes.

[0590] Step 10:

[0591] To a solution of the compound from step 9 (415 mg, 0.740 mmol) in anhydrous DMF (2 ml) in a sealed vial was added cesium carbonate (604.58 mg, 1.84 mmol); 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 stirred vigorously for 5 minutes, the organic phase was collected, washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated. The obtained crude (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]oxathiazepine-2(3H)-carboxylic acid benzyl ester 5,5-dioxide (397 mg, pure off-white solid) was used without further purification. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3H) 2.87-3.22 (m, 2H) 3.37-3.57 (m, 2H) 3.66-3.86 (m, 4H) 3.86-4.02 (m, 1H) 4.36-4.52 (m, 1H) 4.52-4.66 (m, 1H) 4.98-5.20 (m, 2H) 7.11 (t, J = 9.45 Hz, 1H) 7.29-7.42 (m, 5H) 7.43-7.54 (m, 2H) 7.54-7.66 (m, 1H) 8.41 (br s, 1H) 9.33 (s, 1H). Method 4; Rt = 2.22 min. m / z = 543.24 (M+H) + .

[0592] Step 11:

[0593] The compound 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 min. The mixture was then treated at 0 °C by the addition of methanol (1.2 mL), stirred at the same temperature for 10 min, and then evaporated under reduced pressure. The residue was taken up with Et2O / DCM 5:1 mixture (17 mL), then filtered and the solid washed several times with Et2O to give crude D30 (833 mg, y=87.8%) as a light yellow solid, which was used in the next step without further purification. Method 4; Rt=1.35 min. m / z=409.24.25 (M+H) + .

[0594] Description 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]oxathiazepin-2-ium iodide 5,5-dioxide (D31)

[0595]

[0596] Prepared analogously to compound D28 starting from D22 to afford D31. Method 1: Rt = 1.44 min; m / z = 429.30, 431.39 (M+H) + .

[0597] Procedure 2:

[0598] This compound was prepared according to the following scheme:

[0599]

[0600] Step 1:

[0601] (±)benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate was prepared following the procedure reported in J. Med. Chem 2007, 50, 5493-5508 starting from 2,2-dimethoxyethane-1-amine (094452, Flurochem, CAS: 22483-09-6). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.55-2.68 (m, 1H) 3.27-3.38 (m, 1H) 3.43-3.67 (m, 5H) 3.84 (br s, 1H) 5.04-5.13 (m, 2H) 7.29-7.41 (m, 5H) 7.90-8.02 (br s, 2H). Method 2; Rt = 1.81 min. m / z = 251.25 (M+H) + .

[0602] The compound (11.52 g, 46.02 mmol) in acetone (16 mL) was treated with 2-methoxypropylene (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 placed 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 and washed three times with 60 mL of anhydrous acetone, cooled to -5°C to give (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylic acid benzyl ester [(S)-mandelate] as a white solid (6.2 g, y = 30%).

[0603] Step 2:

[0604] (4aR,7aR)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylic acid benzyl ester [(S)-mandelate] (500 mg, 1.13 mmol) from step 1 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). (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (245 mg, y=87%) was used in the next step without any further purification. Method 2; Rt=1.81 min. m / z=251.25 (M+H) +

[0605] Step 3:

[0606] 4-(Chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.05g, 11.3mmol) was added in batches to a suspension of (3R, 4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (2.83g, 11.3mmol) and DIPEA (4mL, 22.96mmol) in MeCN (40ml). The yellow solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, then diluted with EtOAc (100mL), washed with 5% citric acid aqueous solution (×2) and NaHCO saturated solution. The organic layer was dried over Na SO , filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (eluent gradient from DCM / AcOEt: 5:5 to 100% EtoAc) to afford 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 foam. 1 HNMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.27 (q, J = 6.60 Hz, 3H) 2.31-2.43 (m, 1H) 3.12-3.27 (m, 1H) 3.27-3.48 (m, 4H) 3.49-3.60 (m, 1H) 3.67-3.94 (m, 4H) 4.13-4.38 (m, 2H) 4.92-5.16 (m, 2H) 7.28-7.44 (m, 5H) 7.56 (d, J = 4.58 Hz, 1H) 7.99 (br d, J = 7.90 Hz, 1H). Method 1; Rt = 1.80 min. m / z = 484.4 (M+H) + .

[0607] Step 4:

[0608] 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 1 N lithium bis(trimethylsilyl)amide in toluene (1.15 mL, 1.15 mmol) at room temperature over 1 hour. UPLC-MS analysis indicated complete conversion. The reaction was diluted with toluene, cooled at 0°C and quenched with 2M aqueous HCl, 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 removed under reduced pressure. The resulting crude product was used in the next step without further purification. Method 1; Rt = 2.11 min. m / z = 583.29 (M+H) + .

[0609] Step 5:

[0610] To a solution of the crude (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) from step 4 in anhydrous DMF (4 mL) was added cesium carbonate (199.68 mg, 0.610 mmol); the vial was sealed and the mixture was heated to 135°C and stirred at the same temperature for 4 hours. EtOAc and water were added; the organic phase was washed again with water (×2), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (eluent gradient from 100% DCM to DCM / EtOAc 70 / 30) to give the desired compound. Method 1; Rt=2.30 min. m / z=563.30 (M+H) + .

[0611] Step 6:

[0612] (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]oxathiazepine-2(3H)-carboxylic acid benzyl ester 5,5-dioxide (100 mg, 0.180 mmol) from step 5 was dissolved in anhydrous MeCN (2.5 mL, 0.048 mol). Trimethylsilyl iodide (80 mL, 0.370 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was quenched by the addition of methanol (1 mL) at 0 °C, 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) + .

[0613] 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]oxathiazepin-2-ium iodide 5,5-dioxide (D32)

[0614]

[0615] Prepared analogously to compound D28 starting from D23 to afford D32. Method 1: Rt = 1.46 min; m / z = 431.39 (M+H) + .

[0616] 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]oxathiazepin-2-ium iodide 5,5-dioxide (D33)

[0617]

[0618] Prepared analogously to compound D28 starting from D24 to afford D33. Method 1: Rt = 1.31 min; m / z = 420.38 (M+H) + .

[0619] 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]oxathiazepine-8-carboxamide 5,5-dioxide hydroiodide (D34)

[0620]

[0621] Prepared analogously as described for compound D28 starting from D26 gave D34. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.29 (s, 3H), 2.23 (s, 3H), 2.97-3.27 (m, 3H), 3.81 (s, 3H), 3.99 (s, 2H), 4.17-4.28 (m, 1H), 4.34 (d, J = 11.65 Hz, 1H), 7.12 (t, J = 9.22 Hz, 1H), 7.40-7.48 (m, 1H), 7.49 (s, 1H), 7.53-7.65 (m, 1H), 8.42 (d, J = 9.72 Hz, 1H), 9.15 (br s, 2H), 9.37 (s, 1H). Method 1: Rt = 1.41 min; m / z = 422.14 (M+H) + .

[0622] Description 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]oxathiazepine-8-carboxamide 5,5-dioxide hydrochloride (D35)

[0623]

[0624] D27 (0.062 mg, 0.11 mmol) was dissolved in MeOH (15 mL) and precipitated using an H-CUBE instrument equipped with a 10% Pd / C mini-cartridge (THS01111, ThalesNano). Hydrogenation with H2 pressure: 10 bar, flux: 0.8 mL / min at 25 °C. Wash the cartridge thoroughly with MeOH and 0.5 N HCl in MeOH. Remove the solvent by evaporation and treat the residue with 3 N HCl in MeOH (3 mL). After evaporation, D35 (0.052 g, 0.113 mmol, quantitative yield). Method 1; Rt: 1.27 min; m / z: 423.22 (M+H) + .

[0625] Description D36: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxido-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepin-2(3H)-yl)-2-oxoacetate methyl ester (D36)

[0626]

[0627] 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 2-chloro-2-oxoacetic acid methyl ester (0.930 mmol, 0.344 mL) (151440, Sigma Aldrich, CAS: 5781-53-3) pre-dissolved in anhydrous MeCN (1 mL) was added dropwise. The reaction was stirred at the same temperature for 15 minutes, then quenched by adding 5% citric acid (1 mL), diluted with DCM and water. The organic phase was additionally washed with 1N HCl and brine. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow oil. The crude product was stripped with DCM and finally stripped with 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) + .

[0628] Description D37: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxido-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepin-2(3H)-yl)-2-oxoacetic acid (D37)

[0629]

[0630] To a solution of D36 (337 mg, 0.680 mmol) in anhydrous THF (1 mL, 0.012 mol) was added a previously prepared solution of sodium hydroxide (81.78 mg, 2.04 mmol) in water (1 mL, 0.056 mol) dropwise at room temperature. The reaction was monitored by UPLC / MS after 5 minutes and complete conversion was observed. The solution was cooled to 0 °C and quenched by the addition of HCl 4M to form a white precipitate. The reaction 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) + .

[0631] Description D38: 2-((3-methyloxetane-3-yl)amino)-2-oxoacetate methyl ester (D38)

[0632]

[0633] To a solution of 3-methyl-3-oxetaneamine (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 was stirred at the same temperature for 30 minutes and then quenched with ice. The organic phase was separated with 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 light yellow solid, which was used as is in the next synthetic step. Method 2: Rt = 1.21 min, m / z = 174.14 (M+H) + .

[0634] Description D39: Sodium 2-((3-methyloxetane-3-yl)amino)-2-oxoacetate (D39)

[0635]

[0636] To a solution of D38 (507 mg, 2.93 mmol) in THF (2 mL, 0.025 mol) at room temperature was added sodium hydroxide (117.11 mg, 2.93 mmol) dissolved in water (1 mL). The reaction was stirred at room temperature for 1.5 hours to form a white precipitate. The reaction mixture was diluted with ether, the precipitate was filtered and washed with ether. The product was dried under vacuum pump for 1 hour to obtain D39 as a white powder. UPLC / MS analysis of the mother liquor indicated the presence of the title product. The mother liquor was evaporated, treated with ether and filtered to obtain a second batch of crude D39 (300 mg, 1.66 mmol, yield = 56.6%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.41-1.55 (m, 3H), 4.26 (d, J = 6.51 Hz, 2H), 4.63 (d, J = 6.24 Hz, 2H), 8.65 (br s, 1H). Method 14: Rt = 0.87 min; m / z = 160.06 (M+H) + .

[0637] Description D40: (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetic acid methyl ester (D40)

[0638]

[0639] To a solution of (2R)-1,1,1-trifluoro-2-propylamine 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) was added methyl 2-chloro-2-oxoacetate (0.31 mL, 3.34 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction 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 is in the next synthetic step. Method 1: Rt = 1.12 min, m / z = 200.15 (M+H) + .

[0640] Description D41: Sodium (R)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate (D41)

[0641]

[0642] To a solution of D40 (567 mg, 2.85 mmol) in THF (2 mL, 0.025 mol) at room temperature was added a solution of sodium hydroxide (113.89 mg, 2.85 mmol) in water (1 mL). The reaction was stirred at room temperature overnight, diluted with toluene (30 mL) and evaporated under reduced pressure to give a white powder. The product was additionally dried under vacuum pump overnight to give D41 (562 mg, yield = 95%) as a white powder. Method 13: Rt = 1.25 min, m / z = 130.08 (M+H) + .

[0643] Description D42: Methyl 2-(cyclopropylamino)-2-oxoacetate (D42)

[0644]

[0645] To a solution of cyclopropylamine (1.46 mL, 21 mmol) in DCM (15 mL, 0.18 mmol) and N-ethyl-N-isopropylpropane-2-amine (3.05 mL, 17.5 mmol) was added 2-chloro-2-oxoacetic acid methyl ester (1.61 mL, 17.5 mmol) at 0°C under a nitrogen atmosphere. The reaction 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 Na2SO4, filtered and concentrated to give 2-(cyclopropylamino)-2-oxoacetic acid methyl ester as a pale yellow solid. UPLC / MS analysis of the aqueous phase indicated the presence of the title product. In order to recover the product from the aqueous phase, it was concentrated to dryness and extracted with ethyl acetate to give a second batch of 2-(cyclopropylamino)-2-oxoacetic acid methyl ester. The two batches were combined to provide D42 (1.869 g, yield = 73%). 1 H 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) + .

[0646] Description D43: Sodium 2-(cyclopropylamino)-2-oxoacetate (D43)

[0647]

[0648] To a solution of D42 (1.21 g, 8.44 mmol) in THF (4 mL, 0.049 mol) at room temperature was added a solution of sodium hydroxide (337.55 mg, 8.44 mmol) in water (2 mL). The reaction was stirred overnight at the same temperature and then concentrated under reduced pressure. The solid residue was taken up, sonicated and triturated with toluene. The product was dried under 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) + .

[0649] Description D44: cis-2-(8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxido-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepin-2(3H)-yl)-2-oxoacetate methyl ester (D44)

[0650]

[0651] Prepared analogously as described for compound D36 starting from D29. 1 H 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) + .

[0652] Description D45: cis-2-(7-methyl-5,5-dioxido-8-((3,4,5-trifluorophenyl)carbamoyl)-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepin-2(3H)-yl)-2-oxoacetate methyl ester (D45)

[0653] The compounds were prepared according to the following scheme:

[0654]

[0655] Steps 1-4:

[0656] 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]oxathiazepine-8-carboxamide 5,5-dioxide hydroiodide was prepared as described in steps 1 and 4 of 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) + .

[0657] Step 5:

[0658] The crude compound synthesized after step 1-4 (237 mg, 0.420 mmol) 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 was stirred at 0°C for 20 minutes; then quenched by adding 5 ml of 5% citric acid, diluted with water (5 mL) and EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a light yellow solid, which was used without purification. Method 3: Rt = 1.95 min. m / z = 517.10 (M+H) + .

[0659] 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]oxathiazepine-8-carboxamide 5,5-dioxide hydrochloride (D46)

[0660] The compounds were prepared according to the following scheme:

[0661]

[0662] Step 1:

[0663] Under nitrogen atmosphere, in 30 minutes, sodium hydride (60% weight in mineral oil, 3.7g, 92.5mmol) was added in batches to a solution of 3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (12.5g, 79.6mmol) in anhydrous DMF (125mL) cooled to 0°C. The reaction mixture was further stirred for 20 minutes, and then iodomethane (5.8mL, 93.2mmol) was added dropwise in 30 minutes. The mixture was further stirred for 30 minutes at the same temperature, and then quenched with 2N HCl (20mL). The reaction mixture was poured into water (120mL) and toluene (650mL) and the mixture was stirred vigorously for 10 minutes. The two phases were separated, and the organic phase was washed with water (250mL) and brine (250mL), and filtered through Na2SO4 (anhydrous). Ethyl 3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (13.6 g) was obtained as a light yellow oil after evaporation of the solvent and was used without further purification. 1 H NMR (300MHz, DMSO-d6) δppm 1.27 (t, J = 7.11Hz, 3H), 3.78 (s, 3H), 4.23 (q, J = 7.06Hz, 2H), 5.99 (d, J = 3.03Hz, 1H), 7.00 (dd, J = 5.27, 3.07Hz, 1H).

[0664] Step 2:

[0665] 3- fluoro-1-methyl -1H- pyrrole -2- carboxylic acid ethyl ester (13.6g, 79.5mmol) and 4- fluoro-3- methylaniline (10.3g, 82.3mmol) prepared in step 1 are dissolved in anhydrous toluene (50mL).LiHMDS (140mL, 1M in toluene, 140mmol) was added dropwise in 30 minutes, and the reaction mixture was stirred at room temperature for another 30 minutes.The reaction mixture was cooled to 0 ℃ and slowly quenched with 2N HCl (200mL), diluted with water (200mL) and toluene (200mL) and stirred at room temperature for 20 minutes.Separate two phases, organic phase saturated NaHCO (200mL) and salt solution (200mL) washing, through Na SO (anhydrous) drying and filtering. 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 was used without further purification. 1H NMR(300MHz,DMSO-d6)δppm 2.22(s,3H),3.76(s,3H),6.01(d,J=3.03Hz,1H),6.91(dd,J=5.27,3.07Hz,1H), 7.08(t,J=9.22Hz,1H),7.35-7.53(m,1H),7.59(dd,J=7.06,2.20Hz,1H),9.50(br s,1H).

[0666] Step 3:

[0667] Under nitrogen atmosphere, chlorosulfonic acid (5.7 mL, 85.6 mmol) dissolved in anhydrous DCM (120 mL) was added dropwise over 90 minutes to 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. The reaction mixture was further stirred for 30 minutes at the same temperature; the precipitate formed was then 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% three-step yield) was obtained as a light gray solid, dried overnight under vacuum, and used without further purification. 1 H NMR(300MHz,DMSO-d6)δppm 2.22(s,3H),3.70(s,3H),6.93(d,J=5.04Hz,1H),7.07(t,J=9.22Hz,1H),7.44-7.52(m,1H),7.60(dd,J=7.06,2.20Hz,1H),9.64(s,1H).

[0668] Step 4:

[0669] Anhydrous DMF (0.35mL, 4.51mmol) is added to a suspension of 4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonic acid (14.9g, 45.1mmol) prepared in step 3 in thionyl chloride (112mL). The reaction mixture is heated to 75°C and stirred at the same temperature for 45 minutes. The brown solution is cooled to room temperature, diluted with toluene (200mL) and slowly poured into a mixture of toluene (200mL) and ice (500mL) under vigorous stirring. The two-phase system is stirred for 20 minutes, the two phases are separated, and the organic phase is washed with ice water (200ml) and brine (200ml), dried over Na2SO4(anhydrous), filtered and concentrated under reduced pressure. The residue was purified on 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 (300MHz, CDCl3) δppm 2.31 (s, 3H), 4.06 (s, 3H), 7.03 (t, J = 8.89Hz, 1H), 7.26-7.36 (m, 2H), 7.39-7.46 (m, 1H), 7.72 (br d, J = 8.16Hz, 1H).

[0670] Step 5:

[0671] 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-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole-3-sulfonyl chloride (270 mg, 0.77 mmol) prepared in step 4. The reaction was stirred at room temperature overnight. 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 afford trans-1-(tert-butyl) 3-ethyl 4-((4-fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-1-methyl-1H-pyrrole)-3-sulfonamido)pyrrolidine-1,3-dicarboxylate (450 mg, 0.789 mmol) as a white solid which was used in the next step without any purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.23 (m, 3H), 1.38 (br s, 9H), 2.18-2.27 (m, 3H), 2.92-3.18 (m, 2H), 3.19-3.42 (m, 1H), 3.43-3.65 (m, 2H), 3.80 (s, 3H), 3.88-4.11 (m, 3H), 7.11 (t, J = 9.17 Hz, 1H), 7.42-7.54 (m, 2H), 7.54-7.66 (m, 1H), 8.26 (br d, J = 7.24 Hz, 1H), 10.02 (s, 1H). Method 1; Rt: 2.26 min; m / z: 571.13 (M+H) + .

[0672] Step 6:

[0673] The intermediate (370mg, 0.7mmol) from step 5 is dissolved in THF (5mL) and treated with 1M LiAlH4THF solution (946uL, 0.946mmol), added in 5 minutes with about 200uL of aliquots. After 15 minutes, the reaction was terminated by slowly adding water (2mL) and stirred for 10 minutes. Saturated Rochelle salt solution (tetrahydrate potassium sodium tartrate) (10mL) is added, then EtOAc (20mL) is added, and the reaction mixture is stirred for 20 minutes. The gained mixture is poured into a separating funnel, and the water layer is 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 as a white solid. Method 1; Rt: 2.26 min; m / z: 529.19 (M+H) + .

[0674] Step 7:

[0675] The intermediate (0.13g, 0.25mmol) obtained in step 6 was dissolved in DMF (2.46mL), treated with a single portion of cesium carbonate (0.24g, 0.74mmol), and heated by microwave radiation at 130°C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried with anhydrous Na2SO4, filtered, and finally evaporated. The residue was purified by flash chromatography (eluent DCM / EtOAc) and ground in DEE / DCM to obtain trans-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)-carboxylic acid tert-butyl ester 5,5-dioxide (55mg, 0.106mmol) as a white solid. 1 H NMR(300MHz,DMSO-d6)δppm 1.38(s,9H),2.23(s,3H),2.55-2.66(m,1H),2.81-2.93(m,1H),2.94-3.1 0(m,1H),3.35-3.48(m,1H),3.73-3.90(m,4H),3.93-4.14(m,2H),4.22(br dd,J=11.14,4.45Hz,1H),6.88-6.89(m,1H),7.11(t,J=9.26Hz,1H),7.42-7.55(m,2H),7.56-7.70(m,2H),9.51(br s, 1H). Method 3: Rt = 3.74 min; m / z = 509.28.

[0676] Step 8:

[0677] A solution of the intermediate prepared in step 7 (44 mg, 0.08 mmol) in DCM (1 mL) was treated with a single portion of 3M HCl in MeOH (0.45 mL, 1.35 mmol) and the resulting yellow solution was stirred at room temperature for 2 hours. The solvent was then removed to give D46 (37 mg, 0.083 mmol) in quantitative yield. 1H NMR (300MHz, DMSO-d6+TFA) δppm 2.23 (d, J=1.01Hz, 3H) 2.57-2.70 (m, 1H) 2.79-3.03 (m, 2H) 3.19-3.32 (m, 1H) 3.55-3.77 (m, 1H) 3.82 (s, 3H) 4.07 (br d, J = 9.17 Hz, 2H) 4.12-4.33 (m, 1H) 7.11 (t, J = 9.22 Hz, 1H) 7.43-7.57 (m, 3H) 7.62 (dd, J = 7.06, 2.20 Hz, 1H) 8.85-9.11 (m, 2H) 9.68 (s, 1H) Method 1; Rt: 1.32 min. m / z: 409.24 (M+H) +

[0678] Description D47: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxido-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-c:3',4'-g][1,6,2]dithiazocin-2(3H)-yl)-2-oxoacetate methyl ester (D47)

[0679]

[0680] 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 was stirred at the same temperature for 30 minutes, then quenched by adding 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 min. m / z = 511.23 (M+H) + .

[0681] Description D48: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-7-methyl-5,5-dioxido-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)

[0682]

[0683] To a solution of D47 (158 mg, 0.31 mmol) in THF (3 mL) was added 1 N NaOH solution (0.77 mL, 0.77 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water, acidified with 1 N HCl solution until pH = 3, and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 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) + .

[0684] Description D49: ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D49)

[0685]

[0686] 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) was added acetoacetyl chloride (0.08 mL, 0.70 mmol) dropwise at 0°C under a nitrogen atmosphere. The reaction 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 give D49 (113 mg) as a light orange solid, which was used as is in the next synthetic step. Method 2; Rt = 2.40. m / z = 194.12 (M+H) + .

[0687] Description D50: (S)-ethyl 2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate (D40)

[0688]

[0689] Prepared similarly to compound D49, substituting (2S)-1,1,1-trifluoro-2-propylamine hydrochloride for 3,3-difluoroazetidine hydrochloride, D50 (S)-ethyl 2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate was obtained as a colorless oil. Method 2; Rt = 2.84 min. m / z = 214.34 (M+H)

[0690] Description 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]oxathiazepin-2-ium iodide 5,5-dioxide (D51)

[0691]

[0692] Prepared similarly as described for compound D31 (Procedure 2), substituting 3,4-difluoroaniline for 3-chloro-4-fluoroaniline, D51 was obtained 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) + .

[0693] Description 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]oxathiazepin-2-ium iodide 5,5-dioxide (D52)

[0694]

[0695] Prepared similarly as described for compound D31 (Procedure 2), substituting 3-(difluoromethyl)-4-fluoroaniline for 3-chloro-4-fluoroaniline, D52 was obtained 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) + .

[0696] Description 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]oxathiazepin-2-ium iodide 5,5-dioxide (D53)

[0697]

[0698] Prepared similarly as described for compound D31 (Procedure 2), substituting 4-fluoro-3-(trifluoromethyl)aniline for 3-chloro-4-fluoroaniline, D53 was obtained 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) + .

[0699] Description D54: 2-((3aR,10aR)-8-((4-fluoro-3-methylphenyl)carbamoyl)-6,7-dimethyl-5,5-dioxido-3a,4,10,10a-tetrahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepin-2(3H)-yl)-ethyl 2-oxoacetate (D54)

[0700]

[0701] Step 1:

[0702] Tert-Butyl dicarbonate (270.mg, 1.24mmol) dissolved in 5ml DCM is added to the suspension of D30 (509.mg, 0.950mmol) and triethylamine (0.32mL, 2.28mmol) in DCM (5ml). Pale yellow solution was stirred at room temperature for 12 hours (forming white precipitate). Reaction DCM (30ml) is diluted and washed with 0.5M HCl (20ml), water (20ml) and salt solution (20ml). The organic layer was dried over Na2SO4, filtered and concentrated to afford (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]oxathiazepine-2(3H)-carboxylic acid tert-butyl ester 5,5-dioxide as a white foam which was used without further purification. Method 1; Rt = 2.19 min. m / z = 509 (M+H) + .

[0703] Step 2:

[0704] N-Bromosuccinimide (189.0 mg, 1.06 mmol) was added to a solution of the intermediate (450 mg, 0.880 mmol) from step 1 in a mixture of DCM / MeCN 8:1 (18 ml); the orange solution was stirred at room temperature for 4 hours until it became light yellow, then diluted with DCM (20 ml) and saturated NaHCO3 solution (30 ml) and stirred at room temperature for 30 minutes. The two phases were separated, the organic layer was washed with brine, filtered, dried and concentrated over Na2SO4. The resulting crude product was purified by flash chromatography on silica gel with a gradient of DCM / EtOAc 9:1 to 8:2. The pure fractions were combined and concentrated to afford (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]oxathiazepine-2(3H)-carboxylic acid tert-butyl ester 5,5-dioxide as a white foam. Method 1; Rt = 2.28 min. m / z = 587.4 (M+H) + . 1H NMR(300MHz,DMSO-d6)δppm 1.44(s,9H)2.21-2.28(m,3H)2.72-2.99(m,1H)3.06(q,J=9.17Hz,1H)3.34-3.41(m,2H)3.54-3.77(m,1H)3.80(s,3H)3.99(br t,J=10.73Hz,1H)4.27-4.43(m,2H)0.00(t,J=8.99Hz,1H)7.44-7.54(m,1H)7.54-7.66(m,1H)8.55(br s,1H)9.62(br s,1H).

[0705] Step 3:

[0706] The intermediate (100mg, 0.170mmol), tetrakis (triphenylphosphine) palladium (29.5mg, 0.030mmol) and cesium carbonate (195.3mg, 0.600mmol) from step 2 are weighed in a vial and sealed under a nitrogen atmosphere for 5 minutes. Then dioxane (3mL), water (0.3mL) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxa triborane (0.1mL, 0.680mmol) are added and the mixture is stirred at 130 ° C for 3 hours. The reaction is diluted with toluene (30ml) and saturated NaHCO solution (20ml) and stirred for 30 minutes. Separate the two phases, the organic layer is filtered and dried on NaSO and concentrated. The crude product is purified by flash chromatography on silica gel, and the eluent is from DCM / EtOAc 9:1 to 6:4. The pure fractions were combined and concentrated to afford (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]oxathiazepine-2(3H)-carboxylic acid tert-butyl ester 5,5-dioxide as a colorless oil. Method 1; Rt = 2.22 min. m / z = 523.31 (M+H) + .

[0707] Step 4:

[0708] 3N HCl in MeOH (0.8 mL, 2.42 mmol) was slowly added to a solution of the intermediate of step 3 (63.35 mg, 0.120 mmol) in DCM (3 mL) at room temperature. The pale yellow solution was stirred at room temperature for 3 hours until less than 4% SM was detected; the solution was then concentrated under reduced pressure to afford D54 as a pale yellow solid. Method 1; Rt = 1.38 min. m / z = 423 (M+H) + .

[0709] Description D55: Sodium 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D55)

[0710]

[0711] Prepared analogously to compound D43 starting from D49. Method 6; Rt = 0.92 min.

[0712] Description D56: Sodium (S)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate (D56)

[0713]

[0714] Prepared analogously to compound D43 starting from D50. Method 6; Rt = 1.34 min.

[0715] Description D57: ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D57)

[0716]

[0717] Prepared similarly as described for compound D42, using 2,2,2-trifluoroethylamine hydrochloride instead of cyclopropylamine, ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate D57 was obtained as a white solid which was used as such in the next synthetic step. 1 HNMR (300 MHz, DMSO-d6) δ ppm 1.29 (t, J = 7.11 Hz, 3H) 3.83-4.08 (m, 2H) 4.27 (q, J = 7.12 Hz, 2H) 9.35-9.70 (m, 1H). Method 6; Rt = 2.32 min. m / z = 200.2 (M+H) + .

[0718] Description D58: Sodium 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D58)

[0719]

[0720] Prepared analogously to compound D43 starting from D57. Method 6; Rt = 1.22 min. m / z = 172.1 (M+H) + .

[0721] Description D59: ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D59)

[0722]

[0723] Prepared similarly as described for compound D42, using 2,2,2-trifluoro-1,1-dimethylethylamine hydrochloride instead of cyclopropylamine, ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate D57 was obtained as a colorless solid which was used as such in the next synthetic step. Method 6; Rt = 3.54 min. m / z = 228.13 (M+H) + .

[0724] Description D60: Sodium 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D60)

[0725]

[0726] Prepared analogously to compound D43 starting from D59. Method 6; Rt = 1.07 min. m / z = 200.15 (M+H) + .

[0727] Description D61: (3R, 4R)-1-benzyl-4-(benzyl((S)-1-phenylethyl)amino)-3-methylpyrrolidine-3-carboxylic acid tert-butyl ester (D61)

[0728]

[0729] A 2-neck round-bottom flask (100 mL) equipped with a magnetic stirrer and a thermometer was evacuated with nitrogen and charged 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. n-Butyl lithium (1.9 mL, 3.04 mmol) was added over 30 minutes, keeping the temperature below -70 ° C. The purple solution was stirred at -78 ° C for 1 hour and 15 minutes. A preformed 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, keeping the internal temperature below -73 ° C. The resulting orange solution was stirred at this temperature for 3 hours. A solution of iodomethane (187.24 uL, 3.01 mmol) in THF (1 mL) was added over 15 minutes, with the internal temperature below -70 ° C. The cooling bath was removed after 10 minutes, the reaction was warmed to -30 ° C in about 20 minutes, and then the reaction was terminated with NH4Cl (saturated solution), dried over anhydrous Na2SO4, filtered and evaporated to give 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 min. m / z = 485.19 (M+H) +

[0730] Description D62: (3R, 4R)-4-amino-3-methylpyrrolidine-1,3-dicarboxylic acid di-tert-butyl ester (D62)

[0731]

[0732] A mixture of (3R,4R)-tert-butyl 3-methyl-4-[[(1S)-1-phenylethyl]-(benzyl)amino]-1-(benzyl)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 H-CUBE apparatus (cartridge small tip 10% Pd / C, 5 bar, throughput 0.7 mL / min, T=25°C). Working at 10 atm, complete deprotection was very slow. The solvent was removed and the instrument was washed with ethanol. The substrate was dissolved in 9 / 1 EtOH / H2O (40 mL) and further hydrogenated at 50°C at 10 atm until completion by UPLC (about 3 runs) to provide compound D62 (200 mg, 0.67 mmol). 1H NMR (300 MHz, DMSO-d 6+TFA )δppm 1.19(s,3H)1.27(s,9H)1.31(s,9H)2.85-3.11(m,1H)3.30(br s,1H)3.41-3.73(m,3H)8.12(br s,2H)11.28(br s,3H)

[0733] Description 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]oxathiazepine-8-carboxamide 5,5-dioxide hydrochloride (D63)

[0734]

[0735] Obtained as reported for intermediate D46, using intermediate D62 instead of trans-1-tert-butyl-3-ethyl-4-aminopyrrolidine-1,3-dicarboxylate in step 5. Method 10; Rt = 1.35 min. m / z = 423.42 (M+H) +

[0736] Description D64: (3S,4S)-1-benzyl-4-(benzyl((S)-1-phenylethyl)amino)-3-fluoropyrrolidine-3-carboxylic acid tert-butyl ester (D64)

[0737]

[0738] D61 was synthesized as reported, 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 iodomethane to give D64 (250 mg, 0.512 mmol). 1H NMR(300MHz,CHLOROFORM-d)δppm 1.29(d,J=6.97Hz,3H)1.50(s,9H)2.32(t,J=9.54Hz,1H)2.72(br t,J=7.70Hz,1H)2.80-3.15(m,2H)3.21-3.54(m,3H)3.77(ddd,J=25.03,10.18 ,6.51Hz,1H)3.92(d,J=15.31Hz,1H)4.19(q,J=6.82Hz,1H)7.08-7.36(m,15H). 19 F NMR (300 MHz, CHLOROFORM-d) δ ppm-142 (s, 1F). Method 1; Rt = 2.07 min. m / z = 489.61 (M+H) +.

[0739] Description D65: (3S,4S)-4-amino-3-fluoropyrrolidine-1,3-dicarboxylic acid di-tert-butyl ester (D65)

[0740]

[0741] D62 was synthesized as reported starting from D64 (480 mg, 0.982 mmol) to give D65 (140 mg, 0.460 mmol). Method 1; Rt = 1.33 min. m / z = 305.28 (M+H) + .

[0742] 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]oxathiazepine-8-carboxamide 5,5-dioxide hydrochloride (D63)

[0743]

[0744] Synthesized as reported for D46, using D65 (179 mg, 0.29 mmol) instead of trans-1-tert-butyl-3-ethyl-4-aminopyrrolidine-1,3-dicarboxylate in step 5. The reaction afforded D66 (17.5 mg, 0.038 mmol). Method 1; Rt = 1.32 min. m / z = 447.33 (M+Na) +

[0745] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E1)

[0746]

[0747] 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]oxathiazecin-8-carboxamide 5,5-dioxide hydroiodide (25 mg, 0.054 mmol), N,N-dimethyloxalic 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 was stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure to give a brown solid, which was purified by 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, 6H), 2.99-3.25 (m, 2H), 3.33-3.55 (m, 2H), 3.76-4.00 (m, 5H), 4.45-4.69 (m, 2H), 7.50 (s, 1H), 7.59-7.76 (m, 2H), 8.47-8.59 (m, 1H), 9.63-9.69 (m, 1H). Method 3: Rt = 3.09 min; m / z = 530.47 (M+H) + .

[0748] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E2)

[0749]

[0750] 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-tetramethylisourea hexafluorophosphate (V) (20.56 mg, 0.050 mmol) and D39 (14.69 mg, 0.080 mmol) in DMF (1.5 mL, 0.019 mol) was added dropwise N-ethyl-N-isopropylpropan-2-amine (0.03 mL, 0.160 mmol) at room temperature and nitrogen atmosphere. The reaction was stirred at the same temperature for 1 hour. It was then 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 give E2 (2.03 mg, 0.004 mmol). 1 H NMR(300MHz,DMSO-d6)δ1.52(d,J=6.14Hz,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=9.26Hz,1H),7.45-7.54(m,2H),7.56-7.64(m,1H),8.41(br s,1H),9.23(br d,J=8.07Hz,1H),9.35(br d, J = 5.23 Hz, 1H). Method 3: Rt = 3.03 min; m / z = 550.40 (M+H) + .

[0751] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E3)

[0752]

[0753] Prepared similarly as described for compound E2 starting from D30 and D39. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E3 (92.16 mg). 1H NMR (300MHz, DMSO-d6) δppm 1.52 (d, J=6.24Hz, 3H), 2.24 (s, 3H), 2.89-3.13 (m, 1H), 3.20 (br t,J=11.10Hz,1H),3.42-3.66(m,2H),3.74-4.14(m,6H),4.25-4.36(m,2H),4.41-4.55(m,1 H),4.57-4.68(m,3H),7.11(t,J=9.17Hz,1H),7.46-7.55(m,2H),7.55-7.62(m,1H),8.41(br s, 1H), 9.22 (d, J = 8.34 Hz, 1H), 9.35 (d, J = 5.04 Hz, 1H). Method 3: Rt = 3.03 minutes; m / z = 550.40 (M+H) + .

[0754] Example E4: (3aR, 10aR)-7-methyl-2-(2-((3-methyloxetane-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]oxathiazepine-8-carboxamide 5,5-dioxide (E4)

[0755]

[0756] Prepared similarly as described for compound E2 starting from D32 and D39. The crude was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to give E4 (22 mg) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J = 6.33 Hz, 3H), 2.88-3.13 (m, 1H), 3.14-3.68 (m, 2H), 3.81 (s, 3H), 3.83-4.15 (m, 3H), 4.22-4.37 (m, 2H), 4.41-4.55 (m, 1H), 4.56-4.74 (m, 3H), 7.52 (s, 1H), 7.60-7.83 (m, 2H), 8.34-8.53 (m, 1H), 9.23 (d, J = 7.70 Hz, 1H), 9.67 (d, J = 3.58 Hz, 1H). Method 3; Rt = 3.20 min; m / z = 572.35 (M+H) + .

[0757] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E5)

[0758]

[0759] Prepared similarly as described for compound E2 starting from D31 and D39. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to give E5 as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δppm 1.52(d,J=6.42Hz,3H),2.84-3.13(m,1H),3.41-3.68(m,2H),3.72-4.19(m,6H ),4.24-4.37(m,2H),4.41-4.55(m,1H),4.56-4.71(m,3H),7.36-7.46(m,1H),7 .49 (s, 1H), 7.56-7.77 (m, 1H), 7.89-8.06 (m, 1H), 8.29-8.64 (m, 1H), 9.23 (d, J = 7.24 Hz, 1H), 9.57 (d, J = 4.77 Hz, 1H). Method 3: Rt = 3.17 minutes; m / z = 570.39; 572.35 (M+H) + .

[0760] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E6)

[0761]

[0762] Prepared similarly as described for compound E2 starting from D33 and D39. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to give E6 as an off-white solid. 1H NMR (300MHz, DMSO-d6) δppm 1.52 (d, J=6.42Hz, 3H), 2.86-3.13 (m, 1H), 3.15-3.69 (m, 1H), 3.48 (br s, 2H), 3.72-4.18 (m, 7H), 4.23-4.38 (m, 2H), 4.41-4.56 (m, 1H), 4.56-4.74 (m, 3H), 7.46-7.63 (m, 2H), 7.95-8.11 (m, 1H), 8.19 (ddd, J = 5.64, 4.54, 2.75 Hz, 1H), 8.27-8.59 (m, 1H), 9.23 (d, J = 7.06 Hz, 1H), 9.68 (d, J = 4.13 Hz, 1H). Method 3: Rt = 2.88 min; m / z = 561.34 (M+H) + .

[0763] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E7)

[0764]

[0765] Tert-butylamine (0.02 mL, 0.190 mmol) was added to a solution of D37 (30 mg, 0.060 mmol), benzotriazole-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (30.38 mg, 0.070 mmol) and DIPEA (25 uL, 0.140 mmol) in anhydrous DMF (2.5 mL, 0.032 mol) at room temperature, and the reaction mixture was stirred for 4 hours under the same conditions. 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 give E7 as an off-white solid. 1H NMR(300MHz,DMSO-d6)δppm 1.31(d,J=7.70Hz,9H),2.24(s,3H),2.91-3.09(m,1H),3.12-3.65(m,2H),3.71-4.08(m,6H),4.43 -4.56(m,1H),4.61(brdd,J=11.10,3.85Hz,1H),7.11(t,J=9.20Hz,1H),7.42-7.55(m,2H),7.59(br s, 1H), 7.97 (d, J = 14.12 Hz, 1H), 8.37-8.49 (m, 1H), 9.34 (d, J = 5.41 Hz, 1H). Method 3: Rt = 3.44 minutes; m / z = 536.42 (M+H) + .

[0766] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E8)

[0767]

[0768] Prepared similarly as described for compound E7 using cyclopropylamine instead of tert-butylamine to afford E8. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford 15.69 mg of an off-white solid. 1 H NMR(300MHz,DMSO-d6)δppm 0.51-0.70(m,4H),2.21-2.27(m,3H),2.66-2.83(m,1H),2.91-3.11(m,1H),3.14-3 .64(m,2H),3.73-4.13(m,6H),4.41-4.55(m,1H),4.55-4.67(m,1H),7.11(t,J=9.1 7 Hz, 1H), 7.45-7.54 (m, 2H), 7.56-7.62 (m, 1H), 8.41 (dd, J = 9.90, 2.66 Hz, 1H), 8.70 (dd, J = 9.90, 4.95 Hz, 1H), 9.34 (d, J = 3.94 Hz, 1H). Method 3: Rt = 3.12 min; m / z = 520.26 (M+H) + .

[0769] Example E9: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E9)

[0770]

[0771] Prepared similarly to compound E7 using (2R)-1,1,1-trifluoro-2-propylamine hydrochloride (Fluorochem, catalog number 093835) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to give E9. 1 HNMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 6.88 Hz, 3H), 2.24 (s, 3H), 2.92-3.13 (m, 1H), 3.15-3.68 (m, 2H), 3.78-4.09 (m, 6H), 4.43-4.56 (m, 1H), 4.55-4.73 (m, 2H), 7.11 (t, J = 9.17 Hz, 1H), 7.43-7.55 (m, 2H), 7.54-7.64 (m, 1H), 8.37-8.53 (m, 1H), 9.21-9.31 (m, 1H), 9.31-9.39 (m, 1H). Method 3: Rt = 3.48 min; m / z = 576.33 (M+H) + .

[0772] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E10)

[0773]

[0774] 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. 1HNMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3H), 2.57-2.75 (m, 3H), 2.91-3.08 (m, 1H), 3.20-3.65 (m, 2H), 3.75-4.11 (m, 6H), 4.42-4.53 (m, 1H), 4.54-4.68 (m, 1H), 7.11 (t, J = 9.20 Hz, 1H), 7.43-7.52 (m, 2H), 7.56-7.63 (m, 1H), 8.41 (s, 1H), 8.61 (br s, 1H), 9.34 (d, J = 3.40 Hz, 1H). Method 3: Rt = 2.94 min; m / z = 494.21 (M+H) + .

[0775] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E11)

[0776]

[0777] Prepared similarly to compound E10 using NH3 (7N solution in MeOH) instead of methylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E11. 1 H NMR(300MHz,DMSO-d6)δppm 2.24(s,3H)2.92-3.10(m,1H)3.19-3.63(m,2H)3.76-4.11(m,6H)4.42-4.54(m,1H) 4.55-4.66(m,1H)7.11(t,J=9.17Hz,1H)7.45-7.55(m,2H)7.55-7.62(m,1H)7.69(br d,J=11.00Hz,1H)7.97(br d,J=5.14Hz,1H)8.42(br s, 1H) 9.34 (d, J = 3.58 Hz, 1H). Method 3: Rt = 2.81 min. m / z = 480.29 (M+H) +.

[0778] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E12)

[0779]

[0780] Prepared analogously to the description for compound E10 starting from D45 and using methylamine 2M in THF. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E12. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.65 (dd, J = 7.11, 4.91 Hz, 3H), 2.92-3.10 (m, 1H), 3.19-3.67 (m, 2H), 3.79-4.08 (m, 6H), 4.41-4.54 (m, 1H), 4.56-4.68 (m, 1H), 7.51 (s, 1H), 7.64-7.74 (m, 2H), 8.42 (br s, 1H), 8.61 (brt, J = 5.55 Hz, 1H), 9.64-9.69 (m, 1H). Method 3: Rt = 3.14 min; m / z = 516.09 (M+H) + .

[0781] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E13)

[0782]

[0783] Prepared analogously to the description of compound E10 starting from D45 and using NH3 (7N solution in MeOH). The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to give E13. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.94-3.07 (m, 1H), 3.18-3.61 (m, 2H), 3.79-4.11 (m, 6H), 4.49 (m, 1H), 4.55-4.67 (m, 1H), 7.51 (s, 1H), 7.63-7.75 (m, 3H), 7.97 (br d, J = 5.14 Hz, 1H), 8.44 (br s, 1H), 9.67 (s, 1H). Method 3: Rt = 3.01 min; m / z = 502.18 (M+H) + .

[0784] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E14)

[0785]

[0786] Prepared similarly to compound E7 using 3,3-difluorocyclobutylamine hydrochloride (Fluorochem, catalog number 091836) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E14. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.22-2.28 (m, 3H), 2.63-3.12 (m, 6H), 3.15-3.70 (m, 2H), 3.73-4.21 (m, 6H), 4.40-4.70 (m, 2H), 7.11 (t, J = 9.22 Hz, 1H), 7.43-7.55 (m, 2H), 7.59 (dt, J = 6.74, 3.32 Hz, 1H), 8.40 (m, 1H), 9.23 (t, J = 6.65 Hz, 1H), 9.35 (d, J = 4.77 Hz, 1H). Method 3: Rt = 3.41 min; m / z = 570.25 (M+H) + .

[0787] Example E15: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E15)

[0788]

[0789] Prepared similarly to compound E7 using (2S)-1,1,1-trifluoro-2-propylamine hydrochloride (Fluorochem, catalog number 093836) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to give E15. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 5.59 Hz, 3H), 2.24 (s, 3H), 2.95-3.13 (m, 1H), 3.16-3.68 (m, 2H), 3.78-4.13 (m, 6H), 4.62 (m, 3H), 7.11 (t, J = 9.12 Hz, 1H), 7.45-7.54 (m, 2H), 7.56-7.62 (m, 1H), 8.44 (br s, 1H), 9.21-9.32 (m, 1H), 9.32-9.38 (m, 1H). Method 3: Rt = 3.51 min; m / z = 576.13 (M+H) + .

[0790] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E16)

[0791]

[0792] Prepared similarly 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 afford E16. 1H NMR (300MHz, DMSO-d6) δppm 0.84 (t, J=6.56Hz, 6H), 1.77 (dd, J=13.75, 6.88Hz, 1H), 2.24 (s, 3H), 2.95 (br d,J=7.89Hz,3H),3.20-3.67(m,2H),3.76-3.83(m,3H),3.83-4.13(m,3H),4.49(br s, 1H), 4.56-4.70 (m, 1H), 7.11 (t, J = 9.22 Hz, 1H), 7.43-7.55 (m, 2H), 7.59 (dt, J = 6.79, 3.39 Hz, 1H), 8.32-8.55 (m, 1H), 8.64 (dt, J = 9.40, 6.17 Hz, 1H), 9.34 (d, J = 7.15 Hz, 1H). Method 3: Rt = 3.45 minutes; m / z = 536.21 (M+H) + .

[0793] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E17)

[0794]

[0795] Prepared similarly to compound E7 using 2,2,2-trifluoroethane-1-amine hydrochloride (180386, Sigma Aldrich, CAS: 373-88-6) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E17. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.18-2.27 (m, 3H), 2.90-3.15 (m, 1H), 3.20-3.65 (m, 2H), 3.81 (s, 3H), 3.83-4.16 (m, 5H), 4.36-4.78 (m, 2H), 7.11 (t, J = 9.17 Hz, 1H), 7.43-7.55 (m, 2H), 7.55-7.64 (m, 1H), 8.43 (br s, 1H), 9.13-9.50 (m, 2H). Method 3: Rt = 3.41 min. m / z = 562.15 (M+H)+.

[0796] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E18)

[0797]

[0798] Prepared similarly to compound E7 using 1-methylcyclopropylamine hydrochloride (092116, Sigma Aldrich, CAS: 88887-87-0) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E18. 1 H NMR(300MHz,DMSO-d6)δppm 0.52-0.73(m,4H),1.29(d,J=7.06Hz,3H),2.24(s,3H),2.89-3.09(m,1H),3.16–3.60(m,2H),3.74-4.09(m,6H ),4.42-4.55(m,1H),4.57-4.66(m,1H),7.11(t,J=9.22Hz,1H),7.45-7.53(m,2H),7.54-7.62(m,1H),8.40(br s, 1H), 8.80 (d, J = 14.86 Hz, 1H), 9.34 (d, J = 4.68 Hz, 1H). Method 3; Rt = 3.25 minutes; m / z = 534.26 (M+H) + .

[0799] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E19)

[0800]

[0801] Prepared similarly to compound E7 using 1-trifluoromethyl-cyclopropylamine hydrochloride (093841, Sigma Aldrich, CAS: 112738-67-7) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E19.1 H NMR(300MHz,DMSO-d6)δppm 0.94-1.19(m,2H),1.19-1.34(m,2H),2.24(s,3H),2.86-3.10(m,1H),3.11-3.65 (m,2H),3.81(s,3H),3.83-4.13(m,3H),4.40-4.55(m,1H),4.56-4.74(m,1H),7. 11 (t, J = 9.26 Hz, 1H), 7.42-7.55 (m, 2H), 7.55-7.65 (m, 1H), 8.31-8.49 (m, 1H), 9.34 (d, J = 7.34 Hz, 1H), 9.47 (d, J = 13.57 Hz, 1H). Method 3: Rt = 3.51 min; m / z = 588.19 (M+H) + .

[0802] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E20)

[0803]

[0804] Prepared similarly to compound E7 using cyclopropanemethylamine (Sigma Aldrich, catalog number 08460) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E20. 1H NMR (300MHz, DMSO-d6) δppm 0.18 (br t, J=4.81Hz, 2H), 0.39 (br t,J=6.05Hz,2H),0.89-1.05(m,1H),2.23(s,3H),2.99(q,J=6.85Hz,3H),3.12-3.66(m,2H),3.76-4.16(m,6H),4.48(br d,J=5.32Hz,1H),4.61(dt,J=11.55,5.59Hz,1H),7.10(t,J=9.17Hz,1H),7.43-7.54(m,2H),7.55-7.62(m,1H),8.41(br d, J = 6.05 Hz, 1H), 8.67-8.77 (m, 1H), 9.34 (d, J = 5.69 Hz, 1H). Method 3: Rt = 3.34 minutes; m / z = 534.26 (M+H) + .

[0805] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E21)

[0806]

[0807] Prepared similarly to compound E7 using isopropylamine (Sigma Aldrich, catalog number 471291) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E21. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J = 6.65 Hz, 6H), 2.24 (s, 3H), 2.91-3.10 (m, 1H), 3.18-3.63 (m, 2H), 3.78-4.09 (m, 7H), 4.49 (m, 1H), 4.54-4.66 (m, 1H), 7.11 (t, J = 9.22 Hz, 1H), 7.46-7.54 (m, 2H), 7.54-7.62 (m, 1H), 8.38-8.51 (m, 2H), 9.34 (d, J = 5.69 Hz, 1H). Method 3: Rt = 3.25 min; m / z = 522.23 (M+H) + .

[0808] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E22)

[0809]

[0810] Prepared similarly to compound E7 using cyclobutylamine hydrochloride (Sigma Aldrich, catalog number 59271) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E22. 1 H NMR(300MHz,DMSO-d6)δppm 1.55-1.70(m,2H),1.99-2.19(m,4H),2.20-2.28(m,3H),2.89-3.11(m,1H),3.19-3.75(m,2H),3.77-4.08(m,6H),4.23(dt,J=1 6.99,8.42Hz,1H),4.42-4.53(m,1H),4.53-4.66(m,1H),7.11(t,J=9.22Hz,1H),7.45-7.54(m,1H),7.55-7.63(m,1H),8.41(br s, 1H), 8.89 (t, J = 8.30 Hz, 1H), 9.34 (d, J = 5.50 Hz, 1H). Method 3: Rt = 3.37 minutes; m / z = 534.26 (M+H) + .

[0811] 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]dithiazocin-8-carboxamide 5,5-dioxide (E23)

[0812]

[0813] Prepared analogously as described for compound E2 starting from D28 and D43. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to afford E23 as a white solid. 1H NMR(300MHz,DMSO-d6+TFA)δppm 0.46-0.59(m,2H),0.59-0.70(m,2H),2.23(s,3H),2.30-2.43(m,1H),2.57-2.81(m,2H),2.95-3.61(m,3 H),3.72(s,3H),3.75-4.09(m,2H),4.68-4.88(m,1H),7.11(t,J=9.22Hz,1H),7.44-7.60(m,2H),7.66(br d, J = 6.42 Hz, 1H), 8.08-8.24 (m, 1H), 8.67 (dd, J = 15.50, 4.95 Hz, 1H), 10.33 (d, J = 2.38 Hz, 1H).. Method 3; Rt = 3.17 min; m / z = 536.18 (M+H) + .

[0814] Example E24: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-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 (E24)

[0815]

[0816] Prepared analogously as described for compound E2 starting from D28 and D41. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰ HCOOH) to afford E24 as a white solid. 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.30(t,J=6.74Hz,3H),2.23(s,3H),2.29-2.44(m,1H),2.60-2.79(m,1H),3.02-3.44(m,2H),3.46-3.65(m,1H),3.7 2(s,3H),3.75-4.09(m,2H),4.47-4.71(m,1H),4.71-4.87(m,1H),7.11(t,J=9.12Hz,1H),7.46-7.61(m,2H),7.66(br d, J = 6.79 Hz, 1H), 8.11-8.30 (m, 1H), 9.24 (t, J = 9.81 Hz, 1H), 10.33 (d, J = 4.49 Hz, 1H). Method 3; Rt = 3.59 minutes; m / z = 592.13 (M+H)+ .

[0817] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E25)

[0818]

[0819] Prepared similarly as described for compound E2 starting from D34 and D43. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E25. 1 H NMR (300MHz, DMSO-d6+TFA) δppm 0.48-0.74(m,4H),1.27(d,J=4.95Hz,3H),2.24(s,3H),2.65-2.84(m,1H),3.27(br d, J = 7.52 Hz, 1H), 3.49-4.30 (m, 8H), 4.36 (d, J = 11.37 Hz, 1H), 7.11 (t, J = 9.22 Hz, 1H), 7.36-7.50 (m, 2H), 7.52-7.65 (m, 1H), 8.46 (dd, J = 9.49, 3.71 Hz, 1H), 8.71 (t, J = 4.40 Hz, 1H), 9.33 (d, J = 4.86 Hz, 1H). Method 3; Rt = 3.30 min; m / z = 534.23 (M+H) + .

[0820] Example E26: cis-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E26)

[0821]

[0822] Prepared similarly as described for compound E2 starting from D34 and D41. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E26. 1H 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) + .

[0823] Example E27: cis-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E27)

[0824]

[0825] Prepared similarly as described for compound E2 starting from D35 and D41. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E27. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.09-1.34 (m, 4H), 1.35-1.58 (m, 3H), 2.24 (s, 3H), 3.17-3.74 (m, 3H), 3.75-4.00 (m, 4H), 4.16-4.75 (m, 3H), 7.10 (t, J = 9.08 Hz, 1H), 7.41-7.67 (m, 3H), 8.03-8.21 (m, 1H), 9.17-9.28 (m, 1H), 9.28-9.41 (m, 1H). Method 3: Rt = 3.58 min; m / z = 590.19 (M+H) + .

[0826] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E28)

[0827]

[0828] Prepared similarly as described for compound E2 starting from D35 and D43. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E28. 1 H NMR(300MHz,DMSO-d6)δppm 0.43-0.71(m,4H),1.08-1.30(m,1H),1.33-1.49(m,3H),2.17-2.26(m,3H),2.63-2.71( m,1H),3.17-3.51(m,1H),3.54-3.78(m,2H),3.78-3.87(m,3H),3.87-4.00(m,1H),4.13 -4.65 (m, 2H), 7.09 (t, J = 9.22 Hz, 1H), 7.44-7.54 (m, 2H), 7.54-7.65 (m, 1H), 8.10 (d, J = 2.48 Hz, 1H), 8.65 (t, J = 4.36 Hz, 1H), 9.31 (d, J = 4.86 Hz, 1H). Method 3; Rt = 3.18 min; m / z = 534.23.

[0829] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E29)

[0830]

[0831] Prepared similarly to that described for compound E29 using 3,3-difluoroazetidine hydrochloride (Fluorochem, cat. no. 013896) instead of tert-butylamine. 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 2.23 (s, 3H), 2.91-3.10 (m, 1H), 3.13-3.64 (m, 2H), 3.74-4.08 (m, 6H), 4.36-4.54 (m, 3H), 4.56-4.80 (m, 3H), 7.08 (t, J = 9.12 Hz, 1H), 7.44-7.53 (m, 2H), 7.57 (br d, J = 6.60 Hz, 1H), 8.37 (br d, J = 9.54 Hz, 1H), 9.32 (s, 1H). Method 3; Rt = 3.31 min; m / z = 556.20 (M+H) + .

[0832] Example E30: trans-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E30)

[0833]

[0834] 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 a single portion of N-ethyl-N-isopropylpropan-2-amine (25.25 uL, 0.14 mmol) to give a brown solution. PyBop (37.72 mg, 0.07 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 1.5 hours. 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). 1H NMR(300MHz,DMSO-d6+TFA)δppm 1.09-1.42(m,4H)2.23(s,3H)2.57-2.71(m,1H)2.98-3.30(m,1H)3.33-3.70(m,1H)3.74-3.92(m,3H)3.94-4 .39(m,4H)4.41-4.77(m,1H)7.01-7.16(m,1H)7.43-7.55(m,2H)7.55-7.65(m,1H)7.66-7.82(m,1H)9.25(br dd,J=9.03,2.80Hz,1H)9.51(br d, J = 9.63 Hz, 1H). Method 3; Rt: 3.46 min. m / z: 576.33 (M+H) +.

[0835] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E31)

[0836]

[0837] A mixture of D46 (21.5 mg, 0.050 mmol) and D43 (10.95 mg, 0.070 mmol) in DMF (1 mL, 0.013 mL) was treated with a single portion of N-ethyl-N-isopropylpropan-2-amine (25.25 uL, 0.140 mmol) to give a brown solution. PyBop (37.72 mg, 0.070 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 1.5 hours. 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). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.77 (m, 4H) 2.24 (d, J = 0.92 Hz, 3H) 2.63-2.77 (m, 1H) 2.97-3.67 (m, 3H) 3.83 (s, 3H) 3.88-4.40 (m, 5H) 7.11 (t, J = 9.22 Hz, 1H) 7.44-7.55 (m, 2H) 7.56-7.78 (m, 2H) 8.68 (dd, J = 7.06, 5.14 Hz, 1H) 9.51 (d, J = 8.53 Hz, 1H). Method 3; Rt: 3.06 min. m / z: 520.21 (M+H)+.

[0838] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E32)

[0839]

[0840] Prepared similarly to compound E7 using 2,2,2-trifluoro-1,1-dimethyl-ethylamine hydrochloride (Fluorochem, catalog number 033026) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to give E32 as a white powder. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.53 (br d, J = 6.14 Hz, 6H) 2.22 (s, 3H) 2.89-3.65 (m, 3H) 3.69-4.12 (m, 6H) 4.41-4.73 (m, 2H) 7.08 (br t, J = 9.40 Hz, 1H) 7.38-7.68 (m, 3H) 8.35-8.54 (m, 2H) 9.32 (br d, J = 8.25 Hz, 1H). Method 3; Rt = 3.67 min. m / z = 590.31 (M+H) + .

[0841] 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]oxathiazepine-8-carboxamide 5,5-dioxide (E33)

[0842]

[0843] Prepared similarly to compound E7 using 1-trifluoromethyl-cyclobutylamine (Fluorochem, catalog number 075973) instead of tert-butylamine. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to give E33 as a white powder. 1 HNMR(300MHz,DMSO-d6+TFA)δppm 1.77-1.99(m,2H)2.20(s,3H)2.34-2.51(m,4H)2.89-3.12(m,1H)3.13-3.67(m,2H)3.7 3-4.10(m,6H)4.41-4.69(m,2H)6.97-7.08(m,1H)7.40(s,1H)7.42-7.58(m,2H)8.41(br t,J=10.18Hz,1H)9.22(br d,J=12.29Hz,1H)9.35(br d, J = 8.16 Hz, 1H). Method 3; Rt = 3.67 min. m / z = 602.20 (M+H) +.

[0844] 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]dithiazocin-8-carboxamide 5,5-dioxide (E34)

[0845]

[0846] 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 hour. The solvent was removed under reduced pressure and the resulting crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E34 (15 mg) as a white solid after lyophilization. 1H NMR(300MHz,DMSO-d6+TFA)δppm 2.23 (s, 3H) 2.30-2.44 (m, 1H) 2.56-2.71 (m, 1H) 2.98-3.41 (m, 2H) 3.42-3.60 (m, 1H) 3.72 (s, 3H) 3.74-4.09 (m, 2H) 4.68-4.88 (m, 1H) 7.10 (t, J = 9.08 Hz, 1H) 7.45-7.60 (m, 2H) 7.60-7.76 (m, 2H) 7.95 (d, J = 11.92 Hz, 1H) 8.19 (q, J = 4.77 Hz, 1H) 10.21-10.45 (m, 1H). Method 3; Rt = 2.88 min. m / z = 496.30 (M+H) + .

[0847] 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]dithiazocin-8-carboxamide 5,5-dioxide (E35)

[0848]

[0849] The preparation method was similar to that described for E34, starting from D47, using 2M NH2CH3 in THF instead of 7N NH3 in MeOH. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E35 (13 mg) as a white solid. 1 HNMR(300MHz,DMSO-d6+TFA)δppm 2.23(s,3H)2.29-2.43(m,1H)2.55-2.70(m,4H)2.98-3.61(m,3H)3.71(s,3H)3.73-4.09(m,2H)4.65-4.88(m, 1H)7.10(t,J=9.35Hz,1H)7.43-7.61(m,2H)7.62-7.73(m,1H)8.18(d,J=10.09Hz,1H)8.46-8.72(m,1H)10.21

[0850] -10.45 (m, 1H). Method 3; Rt = 3.00 min. m / z = 510.14 (M+H) + .

[0851] 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]dithiazocin-8-carboxamide 5,5-dioxide (E36)

[0852]

[0853] DBU (0.02mL, 0.13mmol) was added to a suspension of D28 (35mg, 0.06mmol) and D49 (14.8mg, 0.08mmol) in ethanol (1mL), 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 was precipitated. EtOAc was then added and each phase was separated. The water layer was extracted with EtOAc again, and the combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC (H2O / CH3CN+0.1%HCOOH) to give E36 as a white solid after freeze drying. 1 H NMR(300MHz,DMSO-d6+TFA)δppm 2.23(s,3H)2.28-2.46(m,1H)2.58-2.71(m,1H)2.99-3.39(m,2H)3.41-3.57(m,1H)3.72(s,3H)3.74- 4.07(m,2H)4.43(q,J=12.29Hz,2H)4.56-4.87(m,3H)7.11(t,J=9.08Hz,1H)7.44-7.61(m,2H)7.66(br d, J = 6.33 Hz, 1H) 8.05-8.30 (m, 1H) 10.33 (s, 1H). Method 3; Rt = 3.35 minutes. m / z = 572.21 (M+H) + .

[0854] Example E37: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-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 (E37)

[0855]

[0856] Prepared similarly as described for compound E36 using D50 instead of ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E36 (35 mg) as a white solid. 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.21-1.39(m,3H)2.23(s,3H)2.27-2.45(m,1H)2.59-2.82(m,1H)3.04-3.42(m,2H)3.43-3.61(m,1H)3.72( s,3H)3.75-4.08(m,2H)4.46-4.72(m,1H)4.73-4.91(m,1H)7.11(t,J=9.00Hz,1H)7.45-7.61(m,2H)7.66(br d, J = 6.69 Hz, 1H) 8.22 (d, J = 9.10 Hz, 1H) 9.25 (dd, J = 25.40, 8.89 Hz, 1H) 10.33 (br s, 1H). Method 3; Rt = 3.57 min. m / z = 592.27 (M+H) + .

[0857] 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)

[0858]

[0859] To a solution of D48 (30 mg, 0.060 mmol) in anhydrous DMFF (0.8 mL) was added 2,2,2-trifluoroethylamine hydrochloride (12.3 mg, 0.09 mmol), followed by anhydrous DIPEA (0.05 mL, 0.30 mmol) under N2 atmosphere. Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.09 mmol) was added to the stirred solution, and the reaction mixture was stirred at room temperature for 2 hours. Water and EtOAc were added, and the organic layer was then washed with 5% aqueous citric acid solution (×2) and water. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The crude product obtained was E38 (19 mg) as a white solid. 1H NMR(300MHz,DMSO-d6+TFA)δppm 2.23 (s, 3H) 2.30-2.44 (m, 1H) 2.60-2.73 (m, 1H) 3.02-3.41 (m, 2H) 3.42-3.65 (m, 1H) 3.72 (s, 3H) 3.75-4.15 (m, 4H) 4.68-4.90 (m, 1H) 7.10 (t, J = 9.17 Hz, 1H) 7.43-7.61 (m, 2H) 7.62-7.74 (m, 1H) 8.20 (dd, J = 9.63, 6.42 Hz, 1H) 9.11-9.45 (m, 1H) 10.32 (d, J = 4.58 Hz, 1H). Method 3; Rt = 3.47 min. m / z = 578.22 (M+H) + .

[0860] 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]dithiazocin-8-carboxamide 5,5-dioxide (E39)

[0861]

[0862] Prepared similarly as described for compound E38, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E39 (26 mg) as a white solid. 1 H NMR(300MHz,DMSO-d6+TFA)δppm 0.05-0.26(m,2H)0.29-0.46(m,2H)0.82-1.06(m,1H)2.22(s,3H)2.29-2.42(m,1H)2.57-2. 70(m,1H)2.85-3.02(m,2H)3.04-3.39(m,2H)3.41-3.61(m,1H)3.71(s,3H)3.74-4.08(m,2H )4.67-4.92 (m, 1H)7.09 (t, J = 9.17 Hz, 1H)7.40-7.60 (m, 2H)7.60-7.76 (m, 1H)8.18 (dd, J = 9.90, 5.96 Hz, 1H)8.54-8.80 (m, 1H)10.32 (d, J = 3.39 Hz, 1H). Method 3; Rt = 3.39 minutes. m / z = 550.19 (M+H) + .

[0863] 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]dithiazocin-8-carboxamide 5,5-dioxide (E40)

[0864]

[0865] Prepared similarly as described for compound E38, using 1-methylcyclopropylamine hydrochloride instead of 2,2,2-trifluoroethylamine hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E40 (28 mg) as a white solid. 1 HNMR(300MHz,DMSO-d6+TFA)δppm 0.42-0.59(m,2H)0.61-0.76(m,2H)1.28(d,J=7.61Hz,3H)2.23(s,3H)2.30-2.44(m ,1H)2.56-2.71(m,1H)3.20(s,2H)3.39-3.59(m,1H)3.62-4.05(m,5H)4.58-4.89(m, 1H) 7.10 (t, J = 9.35 Hz, 1H) 7.43-7.60 (m, 2H) 7.62-7.74 (m, 1H) 8.17 (t, J = 9.54 Hz, 1H) 8.77 (d, J = 21.37 Hz, 1H) 10.32 (d, J = 3.03 Hz, 1H). Method 3; Rt = 3.31 min. m / z = 550.26 (M+H) + .

[0866] 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]dithiazocin-8-carboxamide 5,5-dioxide (E41)

[0867]

[0868] Prepared similarly as described for compound E38, using 3,3-difluorocyclobutylamine hydrochloride instead of 2,2,2-trifluoroethylamine hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E41 (24 mg) as a white solid. 1H NMR(300MHz,DMSO-d6+TFA)δppm 2.23(s,3H)2.30-2.44(m,1H)2.62-2.98(m,5H)3.02-3.43(m,2H)3.44-3.62(m,1H)3.72( s,3H)3.75-4.22(m,3H)4.62-4.89(m,1H)7.10(t,J=9.12Hz,1H)7.46-7.61(m,2H)7.66(br d, J = 6.42 Hz, 1H) 8.14-8.23 (m, 1H) 9.21 (dd, J = 12.01, 7.34 Hz, 1H) 10.32 (d, J = 2.84 Hz, 1H). Method 3; Rt = 3.46 min. m / z = 586.33 (M+H) + .

[0869] 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]dithiazocin-8-carboxamide 5,5-dioxide (E42)

[0870]

[0871] Prepared similarly as described for compound E38, using 3-methyl-3-oxetanamine instead of 2,2,2-trifluoroethylamine hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E42. Method 1; Rt=1.79 min. m / z=566.13 (M+H) + .

[0872] Example E43: (3aR, 10aR)-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E43)

[0873]

[0874] 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 product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E43. 1 H NMR (300MHz, DMSO-d6) δppm 1.31 (t, J=6.97Hz, 3H) 2.93-3.13 (m, 1H) 3.20 (br t,J=11.46Hz,1H)3.36-3.67(m,2H)3.81-4.09(m,5H)4.44-4.70(m,3H)7.41(t,J=9. 03Hz,1H)7.50(s,1H)7.61-7.69(m,1H)7.99(ddd,J=6.79,4.03,2.66Hz,1H)8.49(br d,J=8.80Hz,1H)9.28(br d, J = 7.43 Hz, 1H) 9.57 (d, J = 10.18 Hz, 1H). Method 3; Rt = 3.67 min. m / z = 596.39 (M+H) + .

[0875] Example E44: (3aR, 10aR)-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E44)

[0876]

[0877] Prepared in a similar manner as described for compound E43 starting from D51 instead of D31. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E44. 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (t, J = 6.97 Hz, 3H) 2.86-3.12 (m, 1H) 3.14-3.68 (m, 2H) 3.81 (s, 3H) 3.82-4.12 (m, 3H) 4.42-4.55 (m, 1H) 4.57-4.72 (m, 2H) 7.30-7.47 (m, 2H) 7.48 (s, 1H) 7.75-7.95 (m, 1H) 8.35-8.56 (m, 1H) 9.16-9.33 (m, 1H) 9.56 (d, J = 9.72 Hz, 1H). Method 3; Rt = 3.51 min. m / z = 580.29 (M+H)+.

[0878] Example E45: (3aR, 10aR)-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E45)

[0879]

[0880] Prepared in a similar manner as described for compound E43 starting from D52 instead of D31. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E45. 1 H NMR(300MHz,DMSO-d6)δppm 1.30(t,J=7.06Hz,3H)2.90-3.13(m,1H)3.15-3.70(m,2H)3.78-4.09(m,6H)4.44-4.68(m,3H)6.97-7.40(m,2H)7.47(s,1H)7.79(br dd, J = 7.70, 3.58 Hz, 1H) 8.02-8.09 (m, 1H) 8.45 (dd, J = 16.87, 9.90 Hz, 1H) 9.18-9.30 (m, 1H) 9.60 (d, J = 9.63 Hz, 1H). Method 3; Rt = 3.51 min. m / z = 612.39 (M+H) +.

[0881] Example E46: (3aR, 10aR)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E46)

[0882]

[0883] Prepared in a similar manner as described for compound E43 starting from D53 instead of D31. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E46. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (t, J = 7.11 Hz, 3H) 2.88-3.14 (m, 1H) 3.14-3.70 (m, 2H) 3.81 (s, 3H) 3.82-4.11 (m, 3H) 4.43-4.55 (m, 1H) 4.56-4.73 (m, 2H) 7.36-7.62 (m, 2H) 7.87-8.00 (m, 1H) 8.14-8.25 (m, 1H) 8.35-8.56 (m, 1H) 9.17-9.32 (m, 1H) 9.71 (d, J = 9.45 Hz, 1H). Method 3; Rt = 3.75 min. m / z = 630.33 (M+H)+.

[0884] Example E47: (3aR, 10aR)-6-chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E47)

[0885]

[0886] A solution of E43 (15 mg, 0.030 mmol) in DCM (2.1 mL) was cooled to 0 ° C, and sulfuryl chloride (2.3 μL, 0.030 mmol) pre-dissolved in DCM (0.4 mL) was added portionwise at 0 ° C within 1 minute. The reaction was left at room temperature and stirred for 3 hours. UPLC / MS showed that the conversion was less than 50%. Additional sulfuryl chloride (2 μL) dissolved in DCM (0.4 mL) was added, and the reaction was stirred for another 2 hours at room temperature. The reaction was quenched with water (0.5 mL), then concentrated under reduced pressure and directly purified by preparative HPLC (H2O / CH3CN+0.1%HCOOH) to give E47. 1 HNMR(300MHz,DMSO-d6)δppm 1.24-1.40(m,3H)2.84-3.06(m,1H)3.17-3.70(m,2H)3.73-4.16(m,6H)4.26-4.50(m,2H)4.52-4.74(m,1H)7.42(s,1H)7 .58-7.74(m,1H)7.88-8.10(m,1H)8.48-8.92(m,1H)9.11-9.54(m,1H)9.71-9.99(m,1H).Method 3; Rt:3.82.m / z:630.63(M+H) + .

[0887] Example E48: (3aR, 10aR)-6-chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E48)

[0888]

[0889] Prepared analogously as described for compound E47 starting from E44. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E48. 1H NMR(300MHz,DMSO-d6)δppm 1.26-1.38(m,3H)2.81-3.05(m,1H)3.33(m,2H)3.71-4.14(m,6H)4.33-4.51(m,2 H)4.52-4.76(m,1H)7.27-7.58(m,2H)7.68-7.96(m,1H)8.32-8.91(m,1H)9.27(br s,1H)9.82(d,J=7.70Hz,1H).Method 3; Rt:3.67.m / z:614.42(M+H) + .

[0890] Example E49: (3aR, 10aR)-6-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E49)

[0891]

[0892] Prepared analogously as described for compound E47 starting from E45. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E49. 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.30(t,J=7.20Hz,3H)2.79-3.08(m,1H)3.14-3.72(m,2H)3.72-4.17(m,6H)4.34-4.51(m,2H)4.51-4.75(m,1H)6.91-7.49(m,2H)7.80(br dd,J=7.93,3.81Hz,1H)8.03(br s,1H)8.67(dd,J=18.75,9.86Hz,1H)9.24(t,J=8.53Hz,1H)9.86(d,J=8.25Hz,1H). Method 3; Rt:3.66.m / z:646.43(M+H) + .

[0893] Example E50: (3aR, 10aR)-6-chloro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E50)

[0894]

[0895] Prepared analogously as described for compound E47 starting from E46. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E50. 1 H NMR(300MHz,DMSO-d6)δppm 1.22-1.40(m,3H)2.85-3.03(m,1H)3.17-3.67(m,2H)3.69-4.13(m,6H)4.34-4.53(m,2H)4.53-4.75(m,1H)7.49-7.57(m,1H )7.89-8.03(m,1H)8.13-8.26(m,1H)8.49-8.88(m,1H)9.19-9.41(m,1H)9.91-10.06(m,1H).Method 3; Rt:3.89.m / z:664.46(M+H) + .

[0896] Example E51: (3aR, 10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E51)

[0897]

[0898] Prepared analogously as described for compound E47 starting from E9. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E51. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36-1.48 (m, 3H) 2.33-2.38 (m, 3H) 2.94-3.15 (m, 1H) 3.29-3.77 (m, 2H) 3.87-4.19 (m, 6H) 4.47-4.62 (m, 2H) 4.64-4.85 (m, 1H) 7.23 (t, J = 9.17 Hz, 1H) 7.57-7.72 (m, 2H) 8.67 (s, 1H) 9.32-9.48 (m, 1H) 9.65-9.77 (m, 1H). Method 3; Rt: 3.69. m / z: 610.44 (M+H) + .

[0899] Example E52: (3aR, 10aR)-6-bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E52)

[0900]

[0901] N-Bromosuccinimide (32.11 mg, 0.180 mmol) was added to a solution of E9 (97 mg, 0.170 mmol) in CHCl (3.2 ml); the colorless solution was stirred at room temperature overnight. The crude product was diluted with DCM (20 ml) and saturated NaHCO solution (20 ml) and stirred at room temperature for 30 minutes. The two phases were separated, the organic layer was washed with brine, filtered and dried over NaSO (anhydrous) and concentrated. The crude product was purified by preparative HPLC (H O / CH CN + 0.1% HCOOH) to give E52. 1H NMR(300MHz,DMSO-d6)δppm 1.31(t,J=7.06Hz,3H)2.24(s,3H)2.90(td,J=9.28,5.09Hz,1H)3.19-3.69(m,2H)3.79-3.91(m,4H)3.96-4.1 2(m,2H)4.30-4.51(m,2H)4.52-4.71(m,1H)7.12(t,J=9.22Hz,1H)7.45-7.54(m,1H)7.54-7.63(m,1H)8.61(br dd,J=18.94,9.40Hz,1H)9.26(br t, J = 8.16 Hz, 1H) 9.61 (d, J = 7.52 Hz, 1H). Method 3; Rt: 3.71. m / z: 656.4 (M+H) + .

[0902] Example E53: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E53)

[0903]

[0904] Prepared in a similar manner as described for compound E43 starting from D54 instead of D31. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E53. 1 H NMR(300MHz,DMSO-d6)δppm 1.31(t,J=7.34Hz,3H)2.24(s,3H)2.43(s,3H)2.84-3.05(m,1H)3.14-3 .63(m,2H)3.67-3.76(m,3H)3.78-4.09(m,3H)4.37-4.54(m,2H)4.63(br s,1H)7.11(t,J=9.17Hz,1H)7.40-7.53(m,1H)7.54-7.65(m,1H)8.36-8.60 (m,1H)9.19-9.36(m,1H)9.36-9.47(m,1H).Method 3; Rt:3.58.m / z:590.4(M+H) + .

[0905] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E54)

[0906]

[0907] (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 37.6 mg, 0.080 mmol) was added to 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]oxathiazepine-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 uL, 0.200 mmol) in anhydrous DMF (0.5 mL). 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 uL), acidified with formic acid (50 uL) and purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH) to afford E54 (21.6 mg, 0.04 mmol). 1 H NMR(300MHz,DMSO-d6)δppm 0.43-0.56(m,2H)0.58-0.72(m,2H)1.40-1.66(m,1H)1.76-2.01(m,2H)2.25(s,3H)2.64-2.79(m,2H)3.04-3.20(m,1H) 3.69-3.82(m,2H)3.82-3.88(m,3H)4.20-4.46(m,3H)7.12(t,J=9.22Hz,1H)7.45-7.52(m,2H)7.54-7.62(m,1H)8.05(br t, J = 8.90 Hz, 1H) 8.76 (d, J = 4.40 Hz, 1H) 9.27 (d, J = 9.63 Hz, 1H). Method 3; Rt: 3.01 min. m / z: 534 (M+H) + .

[0908] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E55)

[0909]

[0910] Prepared similarly to that described for compound E54 using D55 instead of D43. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E55. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.42-1.68 (m, 1H) 1.80-2.03 (m, 2H) 2.25 (s, 3H) 2.63-2.91 (m, 1H) 3.08-3.25 (m, 1H) 3.69-3.96 (m, 5H) 4.20-4.72 (m, 7H) 7.12 (t, J = 9.17 Hz, 1H) 7.42-7.53 (m, 2H) 7.54-7.66 (m, 1H) 8.03 (br s, 1H) 9.20-9.42 (m, 1H). Method 3; Rt: 3.27 min. m / z: 570 (M+H) + .

[0911] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E56)

[0912]

[0913] Prepared similarly to that described for compound E54 using D56 in place of D43. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E56. 1H NMR (300MHz, DMSO-d6) δppm 1.28 (t, J = 6.90Hz, 3H) 1.46-1.68 (m, 1H) 1.79-2.04 (m, 2H) 2.24 (br d,J=6.24Hz,3H)2.72(s,1H)3.11-3.25(m,1H)3.60-3.79(m,2H)3.80-3.87(m,3H)4.18-4.26(m,1H)4.26-4.47(m,2H)4.65(br s,1H)7.06-7.16(m,1H)7.42-7.68(m,3H)8.07(br s, 1H) 9.23-9.31 (m, 1H) 9.36-9.47 (m, 1H). Method 3; Rt: 3.38 min. m / z: 590 (M+H) + .

[0914] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E57)

[0915]

[0916] Prepared similarly to that described for compound E54 using D58 instead of D43. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E57. 1 H NMR(300MHz,DMSO-d6)δppm 1.45-1.70(m,1H)1.78-2.06(m,2H)2.24(br d,J=5.04Hz,3H)2.68-2.89(m,1H)3.17(q,J=12.81Hz,1H)3.66-3.86(m,5H)3.94-4 .09(m,2H)4.19-4.46(m,3H)7.11(td,J=9.10,6.46Hz,1H)7.42-7.66(m,3H)8.07(br s, 1H) 9.27 (d, J = 7.60 Hz, 1H) 9.42-9.55 (m, 1H). Method 3; Rt: 3.28. m / z: 576 (M+H) + .

[0917] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E58)

[0918]

[0919] Prepared similarly to compound E54 using D60 instead of D43. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E58. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49-1.68 (m, 7H) 1.84-2.06 (m, 2H) 2.23 (d, J=7.43 Hz, 3H) 2.63-2.84 (m, 1H) 3.11-3.24 (m, 1H) 3.52-3.66 (m, 1H) 3.70-3.79 (m, 1H) 3.83 (s, 3H) 4.18-4.52 (m, 3H) 7.03-7.18 (m, 1H) 7.44-7.64 (m, 3H) 8.08 (br s, 1H) 8.82-8.92 (m, 1H) 9.24-9.31 (m, 1H). Method 3; Rt: 3.49. m / z: 604 (M+H) + .

[0920] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E59)

[0921]

[0922] Prepared similarly to that described for compound E54 using D41 instead of D43. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E59. 1H NMR(300MHz,DMSO-d6)δppm 1.22-1.34(m,3H)1.46-1.68(m,1H)1.81-2.05(m,2H)2.24(br d,J=6.24Hz,3H)2.66-2.86(m,1H)3.07-3.25(m,1H)3.59-3.79(m,2H)3.83(d,J=2.66Hz,3H)4.22(br s,3H)4.58-4.75(m,1H)7.06-7.16(m,1H)7.42-7.64(m,3H)8.07(br s, 1H) 9.21-9.33 (m, 1H) 9.36-9.49 (m, 1H). Method 3; Rt: 3.38. m / z: 590 (M+H) + .

[0923] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E60)

[0924]

[0925] (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 41.34 mg, 0.09 mmol) was added to 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]oxathiazacin-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 uL, 0.22 mmol) in anhydrous DMF (0.7 mL). 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; the organic layer was washed with 5% citric acid solution (×2) and water. The organic portion was dried over Na2SO4, filtered and 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). 1H NMR(300MHz,DMSO-d6)δppm 1.21-1.39(m,3H)1.39-1.68(m,2H)2.24(s,3H)2.54-2.79(m,1H)2.97-3.16(m,1H )3.43-3.80(m,3H)3.81(s,3H)4.05-4.26(m,1H)4.26-4.56(m,2H)4.57-4.85(m,1 H)7.11(t,J=9.17Hz,1H)7.39-7.47(m,1H)7.47-7.55(m,1H)7.55-7.63(m,1H)7.8 6-8.15(m,1H)8.90-9.26(m,1H)9.27-9.44(m,1H).Method 3; Rt:3.47.m / z:590.4(M+H) + .

[0926] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E61)

[0927]

[0928] Prepared similarly as described for compound E60 using D58 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E61. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.36-1.66 (m, 2H) 2.24 (s, 3H) 2.54-2.72 (m, 1H) 3.01-3.14 (m, 1H) 3.47-3.77 (m, 2H) 3.81 (s, 3H) 3.86-4.27 (m, 4H) 4.27-4.60 (m, 2H) 7.11 (t, J = 9.17 Hz, 1H) 7.39-7.47 (m, 1H) 7.48-7.55 (m, 1H) 7.55-7.63 (m, 1H) 7.90-8.19 (m, 1H) 9.07-9.28 (m, 1H) 9.34 (s, 1H). Method 3; Rt = 3.37 minutes. m / z = 576.4 (M+H) + .

[0929] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E62)

[0930]

[0931] Prepared similarly as described for compound E60 using D60 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E62. 1 H NMR(300MHz,DMSO-d6)δppm 1.24-1.52(m,2H)1.52-1.68(m,6H)2.24(s,3H)2.54-2.79(m,1H)2.99-3.14(m,1H )3.46-3.79(m,3H)3.81(s,3H)4.06-4.24(m,1H)4.25-4.41(m,1H)4.41-4.57(m,1 H) 7.11 (t, J = 9.26 Hz, 1H) 7.45 (d, J = 5.78 Hz, 1H) 7.47-7.55 (m, 1H) 7.55-7.65 (m, 1H) 7.80-8.15 (m, 1H) 8.26-8.68 (m, 1H) 9.34 (s, 1H). Method 3; Rt = 3.57 minutes. m / z = 604.4 (M+H) + .

[0932] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E63)

[0933]

[0934] Prepared similarly as described for compound E60 using D55 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E63. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31-1.65 (m, 2H) 2.24 (s, 3H) 2.63-2.80 (m, 1H) 3.02-3.13 (m, 1H) 3.47-3.73 (m, 2H) 3.75-3.91 (m, 4H) 4.10-4.42 (m, 2H) 4.43-4.59 (m, 3H) 4.60-4.69 (m, 1H) 4.70-4.95 (m, 1H) 7.11 (t, J = 9.26 Hz, 1H) 7.44-7.55 (m, 2H) 7.56-7.63 (m, 1H) 7.86-8.22 (m, 1H) 9.35 (s, 1H). Method 3; Rt = 3.31 min. m / z = 570.45 (M+H) + .

[0935] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E64)

[0936]

[0937] Prepared similarly as described for compound E60 using D43 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E64. 1 H NMR(300MHz,DMSO-d6)δppm 0.45-0.54(m,1H)0.54-0.78(m,3H)1.24-1.66(m,2H)2.24(s,3H)2.55-2.78(m,2H)2.95-3.1 2(m,1H)3.35-3.56(m,1H)3.59-3.73(m,1H)3.74-3.96(m,4H)4.01-4.21(m,1H)4.24-4.43(m, 1H) 4.43-4.58 (m, 1H) 7.11 (t, J = 9.08 Hz, 1H) 7.38-7.47 (m, 1H) 7.47-7.55 (m, 1H) 7.55-7.63 (m, 1H) 7.82-8.14 (m, 1H) 8.23-8.69 (m, 1H) 9.33 (s, 1H). Method 3; Rt = 3.10 minutes. m / z = 534.39 (M+H) + Exact mass: 533.17

[0938] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E65)

[0939]

[0940] Prepared similarly as described for compound E60 using D56 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E65. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.22-1.38(m,3H)1.39-1.70(m,2H)2.24(s,3H)2.55-2.78(m,1H)3.02- 3.18(m,1H)3.38-3.78(m,3H)3.81(s,3H)4.07-4.25(m,1H)4.27-4.55( m,2H)4.56-4.81(m,1H)7.11(t,J=9.22Hz,1H)7.40-7.47(m,1H)7.47-7 .55(m,1H)7.55-7.63(m,1H)7.85-8.27(m,1H)8.92-9.26(m,1H)9.34(br s, 1H). Method 3; Rt = 3.47 min. m / z = 590.38 (M+H) + .

[0941] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E66)

[0942]

[0943] (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 38 mg, 0.086 mmol) was added to 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]oxathiazepine-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). 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; the organic layer was washed with 5% citric acid solution (×2) and water. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (H2O / CH3CN+1‰HCOOH) to give E66. 1 H NMR(300MHz,DMSO-d6)δppm 1.21-1.59(m,4H)1.70-1.87(m,1H)1.99-2.17(m,1H)2.18-2.28(m,3H)2.60-2.7 7(m,1H)2.99-3.19(m,1H)3.38-3.73(m,2H)3.73-3.91(m,3H)4.01-4.16(m,1H)4 .24-4.44 (m, 2H) 4.55-4.76 (m, 1H) 7.09 (t, J = 9.12 Hz, 1H) 7.42-7.52 (m, 2H) 7.52-7.61 (m, 1H) 8.03-8.22 (m, 1H) 9.22-9.44 (m, 2H). Method 3; Rt = 3.41 minutes. m / z = 590.4 (M+H) + .

[0944] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E67)

[0945]

[0946] Prepared similarly to that described for compound E66 using D43 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E67. 1 H NMR(300MHz, DMSO-d6)δppm 0.43-0.58(m,2H)0.59-0.70(m,2H)1.47(br d,J=3.85Hz,1H)1.76(br d,J=11.55Hz,1H)2.06(br d,J=5.78Hz,1H)2.23(s,3H)2.57-2.75(m,2H)2.97-3.11(m,1H)3.45(br t, J = 10.36 Hz, 1H) 3.66-3.88 (m, 4H) 4.01-4.14 (m, 1H) 4.22-4.40 (m, 2H) 7.08 (t, J = 9.17 Hz, 1H) 7.43-7.52 (m, 2H) 7.56 (brd, J = 6.79 Hz, 1H) 8.09-8.20 (m, 1H) 8.73 (dd, J = 7.47, 4.45 Hz, 1H) 9.27 (s, 1H). Method 3; Rt = 3.04 min. m / z = 534.4 (M+H) + .

[0947] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E68)

[0948]

[0949] Prepared similarly to that described for compound E66 using D58 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E68. 1H NMR(300MHz, DMSO-d6)δppm 1.28-1.58(m,1H)1.77(br d,J=10.73Hz,1H)2.07(br d,J=6.14Hz,1H)2.23(s,3H)2.67(br t, J = 11.92 Hz, 1H) 3.08 (brd, J = 12.38 Hz, 1H) 3.40-3.71 (m, 2H) 3.82 (s, 3H) 3.91-4.14 (m, 3H) 4.25-4.41 (m, 2H) 7.09 (t, J = 9.22 Hz, 1H) 7.43-7.59 (m, 3H) 8.06-8.23 (m, 1H) 9.28 (s, 1H) 9.37-9.48 (m, 1H). Method 3; Rt = 3.32 min. m / z = 576.4 (M+H) + .

[0950] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E69)

[0951]

[0952] Prepared similarly to that described for compound E66 using D60 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E69. 1 H NMR (300MHz, DMSO-d6) δppm 1.32-1.61 (m, 7H) 1.75 (br d, J=12.75Hz, 1H) 2.06 (br d, J = 8.44 Hz, 1H) 2.23 (s, 3H) 2.55-2.71 (m, 1H) 3.06 (q, J = 12.23 Hz, 1H) 3.43-3.71 (m, 2H) 3.82 (s, 3H) 4.00-4.11 (m, 1H) 4.21-4.39 (m, 2H) 7.08 (t, J = 9.12 Hz, 1H) 7.43-7.52 (m, 2H) 7.52-7.58 (m, 1H) 8.08-8.20 (m, 1H) 8.77-8.85 (m, 1H) 9.28 (d, J = 3.94 Hz, 1H). Method 3; Rt = 3.54 min. m / z = 604.5 (M+H) + .

[0953] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E70)

[0954]

[0955] Prepared similarly to that described for compound E66 using D55 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E70. 1 H NMR(300MHz,DMSO-d6)δppm 1.19-1.57(m,1H)1.71-1.87(m,1H)1.98-2.16(m,1H)2.22(s,3H)2.60-2 .79(m,1H)2.98-3.20(m,1H)3.34-3.59(m,1H)3.76-3.98(m,4H)4.13(br d,J=5.41Hz,1H)4.20-4.71(m,6H)7.07(t,J=9.17Hz,1H)7.43-7.53(m,2H)7.55(br d,J=6.97Hz,1H)8.18(br d, J = 8.80 Hz, 1H) 9.28 (s, 1H). Method 3; Rt = 3.29 min. m / z = 570.3 (M+H) + .

[0956] Example E71: trans-N-(4-fluoro-3-methylphenyl)-2-methyl-7-(2-oxo-2-(((S)-1,1,1-trifluoropropane-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]oxathiazepine-1-carboxamide 4,4-dioxide (E71)

[0957]

[0958] Prepared similarly to that described for compound E66 using D56 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E71. 1H NMR(300MHz, DMSO-d6)δppm 1.22-1.52(m,4H)1.77(br d,J=11.74Hz,1H)2.06(br d,J=8.07Hz,1H)2.23(s,3H)2.66(br t, J = 11.78 Hz, 1H) 3.00-3.16 (m, 1H) 3.42-3.71 (m, 2H) 3.82 (s, 3H) 4.02-4.15 (m, 1H) 4.25-4.42 (m, 2H) 4.56-4.72 (m, 1H) 7.08 (t, J = 9.17 Hz, 1H) 7.43-7.52 (m, 2H) 7.52-7.59 (m, 1H) 8.05-8.22 (m, 1H) 9.26-9.40 (m, 2H). Method 3; Rt = 3.42 min. m / z = 590.4 (M+H) + .

[0959] Example E72: cis-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropane-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]oxathiazepine-1-carboxamide 4,4-dioxide (E72)

[0960]

[0961] (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (Sigma Aldrich, catalog number 226084; 20.05 mg, 0.050 mmol) was added 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]oxathiazepine-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 uL, 0.10 mmol) in anhydrous DMF (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours, then diluted with water (400uL), acidified with formic acid (50uL) and purified by Fraction-Lynx (H2O / CH3CN+1‰HCOOH). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (H2O / CH3CN+1‰HCOOH) to afford E72. 1H NMR(300MHz,DMSO-d6)δppm 1.15-1.34(m,3H)1.71-2.02(m,2H)2.23(br d,J=3.76Hz,3H)2.35-2.46(m,1H)2.86-3.61(m,3H)3.78-4.07(m,5H)4.15-4.75(m,3H)7.04-7.14(m,1H )7.45-7.60(m,3H)8.28-8.37(m,1H)9.24-9.30(m,1H)9.32-9.42(m,1H). Method 3; Rt:3.41m / z:590.45(M+H) + .

[0962] 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]oxathiazepine-1-carboxamide 4,4-dioxide (E73)

[0963]

[0964] Prepared similarly to that described for compound E72 using D58 instead of D41. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to afford E73. 1 H NMR(300MHz,DMSO-d6)δppm 1.69-2.31(m,4H)2.36-2.51(m,5H)2.82-3.67(m,3H)3.77-4.54(m,6H)7.07(td,J=9.26,5.59Hz,1H)7.42-7.60(m,2H)8.34(br d,J=9.45Hz,1H)9.04-9.38(m,2H)9.38-9.49(m,1H). Method 3; Rt:3.31m / z:576.40(M+H) + .

[0965] Example E74: (3aR, 10aR)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E74)

[0966]

[0967] Prepared similarly to compound E72 using D63 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]oxathiazepine-1-carboxamide 4,4-dioxide hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E74. Method 3: Rt=3.68 min. m / z=590.2 (M+H) + .

[0968] Example E75: (3aS, 10aS)-N-(4-fluoro-3-methylphenyl)-10a-hydroxy-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide (E75)

[0969]

[0970] The preparation method is similar to that of compound E72, using D66 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]oxathiazepine-1-carboxamide 4,4-dioxide hydrochloride. The crude product was purified by preparative HPLC (H2O / CH3CN+0.1% HCOOH) to give E75. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.27-1.38 (m, 3H) 2.24 (d, J = 1.47 Hz, 3H) 3.41-4.06 (m, 9H) 4.18-4.96 (m, 6H) 5.94 (br dd, J = 16.23, 3.76 Hz, 1H) 7.11 (t, J = 9.17 Hz, 1H) 7.41-7.67 (m, 3H) 8.02-8.59 (m, 1H) 9.18 (d, J = 2.20 Hz, 1H) 9.34 (br dd, J = 17.65, 9.03 Hz, 1H). Method 3; Rt = 3.41 min; m / z = 592.34. (M+H) + .

[0971] biology

[0972] test

[0973] Cells and culture conditions

[0974] HepAD38 cell line (Ladner et al., Antimicrob Agents Chemother, 1997, 41, 1715-20) was used for HBV inhibition test. HepAD38 is derived from the hepatoblastoma cell line HepG2 ( No.: HB-8065TM) subclone, which expresses the HBV genome (genotype D subtype ayw) under the transcriptional control of a tetracycline-responsive promoter in the TET-OFF system: Addition of doxycycline, an antibiotic belonging to the tetracycline class, inhibits HBV replication, while its removal turns on a process that allows the release of HBV viral particles in the cell supernatant. The HepAD38 cell line was maintained in DMEM / F12 supplemented with 10% fetal bovine serum, 1% glutamine, 1% penicillin / streptomycin, 0.4mg / ml of G418 and 0.3ug / ml of tetracycline. For the HBV inhibition assay, medium without doxycycline was used to allow virion production.

[0975] HepG2 cell line was used for HBV genotype and core variant inhibition assays. HepG2 cell line was maintained in DMEM supplemented with 10% fetal bovine serum, 1% glutamine and 1% penicillin / streptomycin.

[0976] In vitro anti-HBV activity

[0977] In vitro HBV inhibitory activity was performed in 96-well plates. During the primary (first) screening, compounds were first tested at concentrations of 0.02 μM, 0.1 μM, 0.5 μM, and 1 μM (with three replicates). For selected compounds, an 8-point dose-response curve was obtained using a 1:2 serial dilution (starting at 0.01 μM, 0.1 μM, 0.4 μM, or 5 μM, depending on the degree of inhibition observed in the primary screening). From the dose-response curve, the half-maximal effective concentration (EC 50 ) (see also below).

[0978] In more detail, compounds usually dissolved in DMSO stock solution were diluted in 100 μl of the above medium (without doxycycline) to twice the final desired concentration and plated in triplicate in 96-well plates.

[0979] At the same time, HepAD38 cells—extensively pre-washed in medium without doxycycline to induce HBV production—were cultured at 2 × 10 4 Each cell was suspended in 100 μl of medium without doxycycline and added to each well of the plate to yield a final assay volume of 200 μl.

[0980] DMSO used for stock solutions and compound dilutions was always present in the assay at a final concentration of 0.5%.

[0981] The plates were then incubated at 37°C for 96 h before cell viability assays and extracellular HBV quantification to assess the cytotoxic potential and antiviral activity of the compounds.

[0982] Cytotoxicity was assessed by a commercial fluorometric assay that measures the metabolic activity of cells, which is directly related to cell viability (Cell Titer Blue, Promega). For each compound, cytotoxicity was assessed at the same concentration as that used to assess its anti-HBV activity. Anti-HBV activity was assessed by direct qPCR quantification of extracellular HBV DNA. Specifically, the supernatant was collected and centrifuged to clarify cell debris, and viral DNA was extracted from virions by adding lysis buffer (1 mM 1,4-dithiothreitol, 0.2% sodium dodecyl sulfate) and incubating at 95°C for 10 minutes. The samples were then diluted 1:40 and subjected to real-time PCR amplification using the SYBR Green assay (Power SYBR TM 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)).

[0983] The antiviral activity data for each compound are reported as EC 50 Values ​​(see Table 1 legend). Excel and GraphpadPrism programs were commonly used for data refinement and EC 50 calculate.

[0984] Antiviral effect of HBV AE genotype

[0985] For the antiviral effect of HBV AE genotype, HepG2 cell line and DNA plasmids expressing HBV genomes of different genotypes (from A to E) were used. HepG2 was transiently transfected with plasmid DNA containing 1.1-mer ultralong genome sequences of each HBV genotype A to E isolate, cloned into pcDNA3.1 / Zeo(-) vector as described in J Virol.2010,84,3879-88 (https: / / doi.org / 10.1128 / JVI.02528-09). Each plasmid contained 1.1×HBV genome under the control of CMV promoter. The plasmid list 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 (described as p26, HBV genotype D in the above reference), pcDNA3.1-HBV1.1-E (HBV genotype E). The method of generating plasmids is well known in the art (e.g., 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 suitable methods is not a limitation of the present invention.

[0986] HepG2 cells were cultured at 2×10 4Cells were seeded at a density of 10 cells / well in a poly-lysine-coated 96-well plate and incubated overnight at 37°C. The next day, cells were transfected with HBV plasmids (100 ng / well) using Lipofectamine 3000 reagent (Thermo Fisher Scientific) and following the manufacturer's instructions. Five hours later, the transfection mixture was removed and cells were treated with compounds diluted in 0.5% DMSO in an 8-point dose response series as described previously. After incubation with compounds for 96 hours at 37°C, supernatants were collected, centrifuged to clarify cell debris, and incubated with DNase I Amplification Grade 1 Unit / 50 μl (Sigma) for 1 hour at 37°C to allow digestion of plasmid input. Extracellular HBV DNA was quantified using direct qPCR as described previously. To avoid nonspecific detection of HBV plasmids and confirm plasmid digestion, specific primers designed across the plasmid backbone and HBV sequences 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)). The antiviral activity data for each genotype are reported as EC 50 In addition, the EC 50 The offset value corresponds to the observed EC 50 EC of genotype D used as reference genotype 50 The Excel and Graphpad Prism programs were commonly used for data refinement and EC 50 calculate.

[0987] Antiviral effects against naturally occurring core variants

[0988] The experimental procedure for the antiviral effect against HBV core protein variants was similar to that described previously for the antiviral effect against HBV AE genotypes. Different core point mutations (F23Y, F110I, I105T, L37Q, T33N, T33P, T128I, V124G, Y118F) were selected based on their ability to reduce the potency of CAMs currently under development (literature data) and were introduced into a plasmid containing the HBV genome of genotype D (pcDNA3.1-HBV1.1-D, as described above). The following list of plasmids were generated by site-directed mutagenesis of the parental plasmid pcDNA3.1-HBV1.1-D (p26 in J Virol. 2010, 84, 3879-88): 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 relative to 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 are reported as EC 50 Mean values ​​and EC compared with wild type 50 The Excel and Graphpad Prism programs were commonly used for data refinement and EC 50 calculate.

[0989] result

[0990] Exemplary compounds described herein were tested in the above assays. All compounds showed no significant cytotoxicity at all concentrations in the dose response curve (maximum tested doses were 0.01 μM, 0.1 μM, 0.4 μM or 5 μM, depending on the potency of the compound).

[0991] The results of HBV inhibition are reported in Table 1 below.

[0992] Table 1. HBV inhibition, legend: A = EC 50 Less than 0.5 μM; B = EC50 greater than 0.5 μM.

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005] The data in Table 1 show that the compounds of the present invention are very effective HBV replication inhibitors, and their EC 50 Values ​​are always in the nanomolar range.

[1006] Antiviral effect of HBV AE genotype

[1007] Compound E15 was selected as a representative compound to evaluate the antiviral activity of the compound class of the present invention against HBV AE genotype. The antiviral activity data for each genotype were reported as the mean EC50 value and the EC50 value compared with genotype D. 50 Transient transfection of HepG2 cells with plasmids carrying different HBV genotypes showed that compound E15 behaved as a pan-genotypic (A to E) anti-HBV agent. Minimal variation in anti-HBV activity was observed between genotypes AE, as shown in the EC 50 Values ​​and relative EC of genotype D 50 The offsets are shown in (Table 2).

[1008] Table 2. Antiviral activity data for each genotype reported as EC 50 Mean values ​​and EC compared with genotype D 50 Offset

[1009] HBV genotype <![CDATA[Compound E15 EC 50 ±StD (nM)]]> <![CDATA[Compound E15 EC 50 Offset]]> A 2.14±0.43 2.27 B 1.58±0.70 1.67 C 0.72±0.55 0.76 D 0.94±0.49 -1 E 1.79±1.08 1.90

[1010] Antiviral effects against naturally occurring core variants

[1011] The representative compound E15 was tested against a panel of 9 HBV core protein variants and showed EC 50 Shift ≥ 2 (relative to known CAM) (literature data). The compounds of the invention showed low / mid nanomolar EC for each mutant 50 , including the most resistant variant T33N (associated with a high potency shift with other CAMs). All HBV variants remained sensitive to inhibition by E15, with an average EC 50 The fold changes ranged from 0.7 to 29.5 fold. These data suggest that the compounds of the invention have broad spectrum activity against wild-type HBV and against several variants that may be resistant to other CAMs. Results are shown as EC 50 Values ​​and relative EC relative to wild type 50 offsets, included in Table 3.

[1012] Table 3. Antiviral activity data for each variant reported as EC 50 Mean values ​​and EC compared with wild type 50 Offset

[1013]

Claims

1. A compound of general formula (I): in: 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 C optionally substituted with one or more R4 1-6 Alkanediyl or C 2-7 alkenediyl, or a single bond; R1 is H or C 1-6 alkyl; R2 is selected from H, OH, halogen and C 1-6 alkyl; R3 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl and halogen; R4 is selected from H, OH, C 1-6 Alkyl, C 3-8 Cycloalkyl and halogen, or two pairs of R4 together with the atoms to which they are attached form a spiro-C 3-8 Cycloalkyl or spiro-C 3-8 Heterocycloalkyl; R5 is H or C 1-6 alkyl; Or R2 and R5 together form C 1-6 Alkanediyl bridge; R6 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl and C 1-6 Alkyl-C 3-8 Cycloalkyl, wherein each of the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl or C 1-6 Alkyl-C 3-8 The cycloalkyl group is optionally substituted with each independently selected from OH, halogen, halo 1-6 Alkyl, cyano and NH2 are substituted with one or more substituents; Each of R7 and R8 is independently selected from: -hydrogen; -C 1-12 Alkyl, which is optionally substituted with one or more substituents each independently selected from the group consisting of: OH, halogen, CN, NH2, NH(R9), N(R9)2, halogenated C 1-6 alkyl, aryl, heteroaryl, 3-7 membered saturated ring and 5-7 membered partially saturated ring, each of the saturated or partially saturated ring optionally contains one or more heteroatoms selected from O, N and S, and each of the aryl, heteroaryl, 3-7 membered saturated ring or 5-7 membered partially saturated ring is optionally substituted by one or more each independently selected from OH, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, CN, halogenated C 1-6 Alkoxy and C 1-6 substituted by an alkoxy substituent; - aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of OH, halogen, halogenated C 1-6 Alkyl, CN, halogenated C 1-6 Alkoxy and C 1-6 Alkoxy; and - a 3-8 membered saturated or partially saturated ring or bicyclic ring, which optionally contains one or more heteroatoms each independently selected from O, S and N, and the 3-8 membered saturated or partially saturated ring or bicyclic ring is optionally substituted by 1, 2 or more substituents each independently selected from the following group: OH, halogen, CN, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C(O)OR9, C(O)R9, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and C 1-6 Alkoxy; or R7 and R8 together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of aziridine, azetidine, pyrrolidine, piperidine, azetidine, morpholine, thiomorpholine and piperazine, each of which is optionally substituted by one or more each independently selected from OH, halogen, CN, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy and C 1-6 substituted by an alkoxy substituent; Ra, Rb, Rc and Rd are each independently selected from hydrogen, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 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 independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl and C 1-6 Alkyl-C 3-8 Cycloalkyl; or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: -Cy is aryl; and / or -X is O or S; and / or -Y is methylenediyl, Y' and Y" are methylenediyl or ethylenediyl and Y'" is a single bond.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: R2 is H, C 1-6 Alkyl or OH; and R3 is H, C 1-6 Alkyl or halogen.

4. A compound of formula (IA) as claimed in any one of the preceding claims: or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

5. A compound of formula (IB) as claimed in claim 1 or 2: or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

6. The compound of formula (II-A), formula (III-A) or formula (III-B) according to claim 4: in: 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 R4 together with the atoms to which they are attached form a spiro-C 3-8 Cycloalkyl or spiro-C 3-8 Heterocycloalkyl; and wherein the remaining substituents are as defined in claim 1; or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

7. The compound of formula (II-B) as claimed in claim 4: in: represents a single bond or a double bond; R2 is H or C 1-6 alkyl; R3 is H, C 1-6 Alkyl or halogen; and wherein the remaining substituents are as defined in claim 1; or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

8. A compound according to any preceding claim, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein Cy is phenyl, R1 is CH3, R3 is H, methyl, chloro or bromo, R5 is hydrogen or methyl, and R6 is hydrogen.

9. A compound according to any preceding claim, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: R7 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, and / or R8 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 10. The compound of formula (I) as claimed in claim 1, which is selected from: -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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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-trifluoropropane-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]oxathiazepine-8-carboxamide 5,5-dioxide; -cis-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -cis-N-(4-fluoro-3-methylphenyl)-3a,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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]oxathiazepine-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]oxathiazepine-8-carboxamide 5,5-dioxide; - trans-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]dithiazocin-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]dithiazocin-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]dithiazocin-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((S)-1,1,1-trifluoropropane-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; -(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; -(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]dithiazocin-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-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo -2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-6-chloro-N-(3-chloro-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-6-chloro-N-(3,4-difluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-6-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine -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-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine -8-Carboxamide 5,5-dioxide; -(3aR,10aR)-6-chloro-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-6-bromo-N-(4-fluoro-3-methylphenyl)-7-methyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-6,7-dimethyl-2-(2-oxo-2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-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]oxathiazepine-1-carboxamide 4,4-dioxide; -cis-N-(4-fluoro-3-methylphenyl)-2-methyl-8-(2-oxo-2-(((R)-1,1,1-trifluoropropane-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]oxathiazepine-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]oxathiazepine-1-carboxamide 4,4-dioxide; -(3aR,10aR)-N-(4-fluoro-3-methylphenyl)-7,10a-dimethyl-2-(2-oxo- -2-(((R)-1,1,1-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-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-trifluoropropane-2-yl)amino)acetyl)-2,3,3a,4,10,10a-hexahydro-1H,7H-dipyrrolo[3,4-b:3',4'-f][1,4,5]oxathiazepine-8-carboxamide 5,5-dioxide; or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof.

11. A compound as defined in any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, for use in medicine.

12. A compound for use as defined in claim 11 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein the use is for the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection.

13. The compound for use according to claim 12 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: The HBV infection-related conditions are selected from: chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation caused by hepatitis B virus infection, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection.

14. The compound for use according to any one of claims 10 to 13, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: The use is for treating, eradicating, reducing, slowing down or inhibiting HBV infection in an individual in need thereof, and / or for reducing the viral load associated with HBV infection in an individual in need thereof, and / or for reducing the recurrence of HBV infection in an individual in need thereof, and / or for inducing remission of liver damage caused by HBV infection in an individual in need thereof, and / or for the prophylactic treatment of HBV infection in an individual with latent HBV infection.

15. The compound for use according to any one of claims 12 to 14, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: The HBV infection and / or the disease associated with HBV infection is caused by any genotype of HBV, and / or the HBV infection or disease is caused by a drug-resistant HBV mutant; the genotype includes genotype A, B, C, D or E.

16. A compound for use according to any one of claims 9 to 15, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein the use is in combination with at least one additional therapeutic agent.

17. The compound for use according to claim 16 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: The at least one additional therapeutic agent is selected from: therapeutic vaccines; RNA interference therapeutics / antisense oligonucleotides; immunomodulators; STING agonists; RIG-I modulators; NKT modulators; IL agonists; interleukins or other immune activating proteins; therapeutic and preventive vaccines; immune checkpoint regulators / inhibitors; HBV entry inhibitors; cccDNA regulators; HBV protein expression inhibitors; substances targeting HBV RNA; capsid assembly inhibitors / modulators; core or X protein targeting agents; nucleotide analogs; nucleoside analogs; interferons or modified interferons; HBV antivirals with different or unknown mechanisms; cyclophilin inhibitors; sAg release inhibitors; HBV polymerase inhibitors; dinucleotides; SMAC inhibitors; HDV targeting agents; viral maturation inhibitors; reverse transcriptase inhibitors and HBV RNA destabilizers or other small molecule inhibitors of HBV protein expression; or a combination thereof.

18. The compound for use according to claim 17 or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein: The therapeutic vaccine is selected from: HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX110 (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, HBVMVA and PepTcell; wherein 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; wherein the immunomodulator is a TLR agonist; wherein the RIG-I modulator is SB-9200; wherein the IL agonist or other immune activating protein is INO-9112 or recombinant IL12; wherein the immune checkpoint regulator / inhibitor is BMS-936558 (Opdivo (nivolumab)) or pembrolizumab; wherein the HBV entry inhibitor is MyRcludex B, IVIG-TonRol or GC-1102; wherein the cccDNA regulator is selected from: a direct cccDNA inhibitor, an inhibitor of cccDNA formation or maintenance, a cccDNA epigenetic modifier and a cccDNA transcription inhibitor; wherein the capsid assembly inhibitor / modulator, 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;The interferon or modified interferon is selected from the group consisting of interferon α (IFN-α), pegylated interferon α (PEG-IFN-α), interferon α-2a, recombinant interferon α-2a, pegylated interferon α-2a (Pegasys), interferon α-2b (intron A), recombinant interferon α-2b, interferon α-2b XL, pegylated interferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, pegylated interferon beta-1a, interferon delta, interferon lambda (IFN-λ), pegylated interferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon Alfacon-1, interferon alpha-nl, interferon alpha-n3, alb-interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-stem hydrazine, Belerofon, INTEFEN-IFN, albumin / interferon α2a fusion protein, rHSA-IFNα2a, rHSA-IFNα2b, PEG-IFN-SA and interferon α bio-modifier; wherein the HBV antiviral agent with different or unknown mechanism is selected from: AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl) 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; The cyclophilin inhibitor is selected from the group consisting of OCB-030 (NVP-018), SCY-635, SCY-575 and CPI-431-32; the HBV polymerase inhibitor is selected from the group consisting of entecavir (Boludin, Entavir), lamivudine (3TC, Gan An Neng, Hepudin, Yipingwei and Yipingwei-HBV), telbivudine (Tizeka, Subivo), cleviidine, besifovir, adefovir (Heweili ... 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 birenapam; wherein the HDV targeting agent is lonafarnib; wherein the HBV RNA destabilizer or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452. ; 19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19, wherein the at least one additional therapeutic agent is as defined in claim 17 and / or 18.

21. A pharmaceutical composition according to claim 19 or 20, for use as defined in any one of claims 12 to 15.

22. A method for synthesizing a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, wherein A is C-R3, Y' and Y" are both methylenediyl, 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 in claim 1, the method comprising at least one of the following steps: - reacting a compound of formula (5a) (wherein each of m and n is independently 1 or 2) with a compound of formula (8a) or with a compound of formula (8b); - reacting a compound of formula (6) wherein each of m and n is independently 1 or 2 with an amine of formula NHR7R8; reacting a compound of formula (7) wherein each of m and n is independently 1 or 2 with an amine of formula NHR7R8; The method optionally further comprises at least one of the following steps: - reacting the compound of formula (5a) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (6); - hydrolyzing the compound of formula (6) in the presence of a base to obtain a compound of formula (7); - reacting a compound of formula (9) (wherein each of m and n is independently 1 or 2 and R3 = H) with sulfuryl chloride in a solvent such as dichloromethane to obtain a compound of formula (9) (wherein R3 = Cl); - reacting a compound of formula (9) wherein each of m and n is independently 1 or 2 and R3 = H with N-bromosuccinimide in a solvent such as chloroform to obtain a compound of formula (9) wherein R3 = Br.

Images