Spirocyclic inhibitors of hepatitis B virus

Abstract

The present invention relates to compounds that act as hepatitis B virus (HBV) inhibitors. These compounds can be used alone or in combination with other agents to treat, ameliorate, prevent, or cure HBV infection and related conditions. The present invention also relates to pharmaceutical compositions containing these compounds.

Description

Field of the Invention

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

[0002] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnaviridae family that is transmitted through contact with infected blood and body fluids and causes acute and chronic necrotizing inflammatory liver diseases of varying severity (Guidotti LG, Chisari FV. Annu Rev Pathol. 2006; 1: 23-61). The HBV lipid envelope comprises three in-frame viral envelope proteins (large, medium, and small), each of which harbors the hepatitis B surface antigen (HBsAg) determinant (Seeger C, Mason WS. Virology. 2015 May; 479-480: 672-86). This envelope encloses a protein shell, or capsid, composed of 240 monomers of the core protein, each of which harbors the hepatitis B core antigen (HBcAg or Cp) determinant. The capsid encloses a partially double-stranded, relaxed circular DNA (rcDNA) form of the viral genome and 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 to the nuclear envelope. The rcDNA is then released into the nucleus and repaired by cellular polymerases into an episomal "minichromosome," termed covalently closed circular DNA (cccDNA), which serves as the viral transcription template. The negative strand of the viral DNA encodes mRNA species of 3.5, 2.4, 2.1, and 0.7 kb, which are translated into the viral structural (envelope and core) and nonstructural (polymerase, precore, and X) proteins. After transport to the cytoplasm, one of the 3.5 kb RNAs (termed the pregenomic RNA) is selectively packaged into nascent capsids through interaction 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 (-) strand DNA molecule, which serves as the template for viral polymerase-mediated DNA (+) strand synthesis. The cohesive structure of the linear DNA intermediate converts it into a relaxed circular double-stranded molecule. A portion of these "mature" capsids containing HBV DNA is transported back to the nucleus, where second-chain synthesis is completed and the ends of the two chains are joined, leading to the expansion 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 exits the cell as an infectious virion, beginning a new infection cycle.

[0003] Therefore, the HBV core protein and associated capsid 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 the HBV core protein and associated capsid are widely considered to be attractive antiviral targets (Durantel D, Zoulim F; J Hepatol. 2016 Apr; 64(1 Suppl): S117-S131).

[0004] 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 most of these people have successfully cleared the virus, more than 250 million remain persistently infected, and nearly 900,000 of them die annually from complications of chronic infection (i.e., cirrhosis and / or hepatocellular carcinoma). HBV infection is highly prevalent 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 in the Western world has also been steadily increasing in recent years, largely due to an influx of immigrants from endemic areas. Furthermore, HBV is a helper virus for hepatitis D 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).

[0005] Well-tolerated vaccines that generate neutralizing antibodies to HBsAg are effective in preventing de novo HBV infection but offer no therapeutic potential for the millions of people who already have persistent infection (Zoulim, Durantel D; Cold Spring Harb Perspect Med. 2015 Apr 1;5(4)). Treatment for these individuals 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 a limited duration of treatment and a high HBsAg seroconversion rate, but is associated with significant side effects. Consequently, the number of patients receiving PEG-IFN-α is gradually decreasing.

[0006] Different chemical classes of inhibitors targeting the HBV encapsidation process (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 CAMs 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. JNJ-56136379 (or JNJ-379), a compound developed by Janssen, recently showed potent antiviral activity and is currently in Phase 2 clinical trials.

[0007] WO2017 / 001655A1 published on January 5, 2017, relates to cyclized sulfamoyl arylamide derivatives having the following structure:

[0008]

[0009] The compounds disclosed in WO2017 / 001655A1 include 3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine substituted at the 6-position with N-phenyl-carboxamide. 1,1-dioxide derivatives. Some of the derivatives disclosed herein have spiro-fused oxetane, tetrahydrofuran, or pyrroline rings. WO 2017 / 001655 A1 does not disclose or suggest compounds in which the spiro-fused rings are further functionalized with amide or oxalamide groups.

[0010] Potential problems encountered with HBV direct-acting antivirals include toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility, and / or off-target activity, and to date, no compounds of any of the structural classes identified above have been approved as drugs for the treatment of HBV patients.

[0011] 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.

[0012] The present invention provides a small molecule drug obtained by chemically modifying a known sulfamoyl arylamide derivative. In particular, the compound of the present invention is characterized by a tricyclic core structure comprising a pyrrole ring with an amide or oxamide substituent at a specific position of the fused tricyclic core. The chemical type found in the present invention results in 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 drug candidates (Tu M. et al., Current Topics in Medicinal Chemistry, 2013, 13, 857-866). Summary of the Invention

[0013] The compounds of the present invention are inhibitors of hepatitis B virus (HBV).

[0014] Therefore, one of the objects of the present invention is the compound of general formula (I):

[0015]

[0016] in:

[0017] Cy is an aryl or heteroaryl group;

[0018] m and n are each independently 1 or 2;

[0019] R1 is H, F, Br, Cl or CH3;

[0020] R2 is selected from the group consisting of:

[0021] -5 or 6 membered heteroaromatic ring, which is optionally substituted by one or more substituents, each of which is independently selected from the group consisting of OH, halogen, CN, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy and NH2;

[0022] -Halogenated C 1-4 alkyl; and

[0023] -C(=O)NR3R4;

[0024] R3 and R4 are each independently selected from the following group:

[0025] -hydrogen;

[0026] -C 1-3 alkyl;

[0027] -Halogenated C 1-4 alkyl; and

[0028] -C 3-5 - cycloalkyl, which is optionally substituted by one or more substituents each independently selected from the group consisting of methyl, F, Cl, CHF2 and CF3;

[0029] or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of aziridine, azetidine, pyrrolidine, piperidine, morpholine and thiomorpholine, each of the cyclic amines being optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine, CHF2 and CF3;

[0030] Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, halogen, methyl, CN, CHF2 and CF3;

[0031] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0032] The embodiments disclosed below can be combined with each other in any possible way to produce stable compounds. All such combinations are within the scope of the present invention.

[0033] In a preferred embodiment, R2 is:

[0034] - a 5-membered heteroaromatic ring, which is optionally substituted by one or more substituents, each of which is independently selected from the group consisting of OH, halogen, CN, methyl and trifluoromethyl; or

[0035] -C(=O)NR3R4, wherein R3 is H, and R4 is selected from the group consisting of: C 1-3 Alkyl, halogenated C 1-4 Alkyl and C 3-5 - cycloalkyl, which is optionally substituted by one or more substituents each independently selected from the group consisting of methyl, fluorine and CF3;

[0036] or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of aziridine, azetidine, pyrrolidine and piperidine, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine and CF3.

[0037] In a preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, Cl, F, methyl and CHF2.

[0038] In another preferred embodiment, m is 1 and n is 2; or m is 1 and n is 1; or m is 2 and n is 2. Preferably, m is 1 and n is 2.

[0039] In another preferred embodiment, R1 is H or Cl. Preferably, m is 1, n is 2 and R1 is H or Cl. Preferably, m is 2, n is 2 and R1 is H or Cl. Preferably, m is 1, n is 1 and R1 is H or Cl.

[0040] In another preferred embodiment, Cy is phenyl. Preferably, Cy is phenyl; any two of Ra-Rd are independently F, Cl or CHF2; and the other two of Ra-Rd are H.

[0041] In another preferred embodiment, express

[0042] In another preferred embodiment, R2 is:

[0043]

[0044] Preferably, the compound of the present invention is selected from the group consisting of:

[0045] -N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0046] -N-(3,4-difluorophenyl)-7'-methyl-1-(5-methyl-1,3,4-oxadiazole-2-carbonyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0047] -8'-chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0048] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0049] -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0050] -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0051] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0052] -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0053] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0054] -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0055] -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0056] -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0057] -N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0058] -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0059] -N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0060] -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0061] -N-(3-chloro-4-fluorophenyl)-1-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0062] -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0063] -1-(2-(cyclopropylamino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0064] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0065] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0066] -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0067] -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0068] -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0069] -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0070] -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0071] -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0072] -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0073] -(S)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0074] -(R)-8'-Chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0075] -(R)-8'-chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0076] -(R)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0077] -(R)-8'-chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0078] -(R)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0079] -(R)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide;

[0080] -N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; and

[0081] -8'-chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide

[0082] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0083] The present invention then further provides compounds of formula (IA), (IB) and / or (IC):

[0084]

[0085] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein all substituents are as defined above.

[0086] Preferably, in the compounds of formula (IA), (IB) or (IC), R1 is Cl or H, and / or in the compounds of formula (IA), (IB) or (IC), R2 is -C(=O)NR3R4.

[0087] Preferably, the compounds of the present invention have formula (I-AA), (I-AB) or (I-AC):

[0088]

[0089]

[0090] Wherein, R1 is H or Cl;

[0091] R2 is:

[0092] - a 5- or 6-membered heteroaromatic ring, which is optionally substituted by one or more substituents, each of which is independently selected from the group consisting of OH, halogen, CN, methyl, trifluoromethyl; or

[0093] -C(=O)NR3R4;

[0094] R3 and R4 are each independently selected from the following group:

[0095] -hydrogen;

[0096] -methyl;

[0097] -Halogenated C 1-4 alkyl; and

[0098] -C 3-5 - cycloalkyl, which is optionally substituted by one or more substituents each independently selected from the group consisting of methyl, fluorine and CF3;

[0099] or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic amine selected from the group consisting of aziridine, azetidine, pyrrolidine and piperidine, each of said cyclic amines being optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine and CF3;

[0100] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0101] Further combinations of any of the embodiments are also contemplated to be within the scope of the present invention.

[0102] In a preferred aspect, the compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above is for medical use. Preferably, the compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above is for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection. Preferably, the conditions associated with HBV infection are selected from the group consisting of chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection.

[0103] Even more preferably, the compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above is used for the following purposes: 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.

[0104] Preferred compounds exhibit greater than 50% inhibition of HBV at the concentrations tested (1.0 micromolar to 0.1 micromolar) and / or an EC50 as defined below of less than 0.5 micromolar. 50 HBV inhibition refers to the inhibition of HBV expression and / or replication. The inhibitory activity of the compounds of the present invention can be determined as described below or by any other technique known in the art.

[0105] Preferably, the compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above 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.

[0106] The present invention also relates to pharmaceutical compositions comprising a compound, a pharmaceutically acceptable salt, a solvate or a stereoisomer as defined above, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient.

[0107] Preferably, the at least one additional therapeutic agent is an anti-HBV agent or HBV antiviral agent. More preferably, the at least one additional therapeutic agent, anti-HBV agent or HBV antiviral 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-affecting 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 and HBV RNA destabilizers or other small molecule inhibitors of HBV protein expression; or combinations thereof.

[0108] Preferably, the therapeutic vaccine is selected from the group consisting of: 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-102-00557, HBV MVA and PepTcell.

[0109] Preferably, the RNA interference therapeutic agent is siRNA, ddRNA or shRNA. Preferably, the RNA interference therapeutic agent is selected from: 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.

[0110] 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 (also known as 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]acetate) and ARB-1598.

[0111] 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.

[0112] Preferably, the cccDNA modulator is selected from the group consisting of: direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers and cccDNA transcription inhibitors.

[0113] Preferably, 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 the group consisting of: 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, and RO7049389.

[0114] 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-infergen, 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.

[0115] 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.

[0116] Preferably, the cyclophilin inhibitor is selected from the group consisting of: OCB-030 (also known as NVP-018), SCY-635, SCY-575 and CPI-431-32.

[0117] Preferably, the HBV polymerase inhibitor is selected from the group consisting of: entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevidine, besifovir, adefovir (Hepsera), tenofovir. Preferably, tenofovir is in the form of a salt. Preferably, tenofovir is in the form of a salt selected from the group consisting of tenofovir disoproxil fumarate (Viread), tenofovir alfentanil fumarate (TAF), tenofovir tipoloxetate (also known as DA-2802), tenofovir diisopropoxyaspartate (also known as CKD-390), AGX-1009 and CMX157.

[0118] Preferably, the dinucleotide is SB9200. Preferably, the SMAC inhibitor is Birinapant. Preferably, the HDV targeting agent is Lonafamib.

[0119] Preferably, the HBV RNA destabilizer or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452.

[0120] 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.

[0121] Preferably, the at least one additional therapeutic agent is selected from the group consisting of an HBV polymerase inhibitor, an interferon, a viral entry inhibitor, BAY 41-4109, a reverse transcriptase inhibitor, a TLR agonist, 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, wherein the HBV polymerase inhibitor is preferably lamivudine, entifen, At least one of clavir, tenofovir, adefovir, telbivudine, and clevudine; and wherein the TLR agonist is preferably selected from the group consisting of 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]acetic acid methyl ester), and combinations thereof.

[0122] Preferably, the compounds of the invention are used in combination with one, two or more additional therapeutic agents as defined above.

[0123] Preferably, the pharmaceutical composition of the invention comprises one, two or more additional therapeutic agents as defined above.

[0124] In a preferred embodiment, the pharmaceutical composition is used to treat and / or prevent HBV infection and / or conditions associated with HBV infection, wherein the 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, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation, and liver damage caused by HBV infection. Preferably, the pharmaceutical composition is used to treat, eradicate, reduce, slow, or inhibit HBV infection in a subject in need thereof, and / or to reduce the viral load associated with HBV infection in a subject in need thereof, and / or to reduce the recurrence of HBV infection in a subject in need thereof, and / or to induce remission of liver damage caused by HBV infection in a subject in need thereof, and / or to prophylactically treat HBV infection in a subject with latent HBV infection.

[0125] 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 in a mammal and / or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

[0126] Another object of the present invention is a method for treating, ameliorating or preventing HBV infection and related conditions, including chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection, which method comprises administering to a subject a therapeutically effective amount of a compound as defined above.

[0127] Another object of the present invention is a method for synthesizing a compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above, for example according to the synthesis schemes included in the examples. Specifically, the present invention provides a method for synthesizing a compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above, comprising at least one of the following steps:

[0128]

[0129] - reacting a compound of formula (6) with a reagent selected from the group consisting of a compound of formula (9), an acid of formula R2COOH and an acid chloride of formula R2COCl;

[0130]

[0131] - reacting a compound of formula (7) or (8) with an amine of formula NHR3R4;

[0132] The method optionally further comprises at least one of the following steps:

[0133] - reacting the compound of formula (6) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (7);

[0134] - hydrolyzing the compound of formula (7) in the presence of a base to obtain the compound of formula (8).

[0135] The reaction of compounds of formula (6) with compounds of formula (9) can be carried out under standard conditions, for example in a polar solvent such as DMF or EtOH and / or in the presence of an organic base such as DIPEA or DBU and / or at room temperature (RT).

[0136] The reaction of the compound of formula (6) with the acid of formula R2COOH can be carried out under standard coupling conditions (see, for example, Chem. Soc. Rev., 2009, 38, 606-631).

[0137] The reaction of a compound of formula (6) with an acid chloride of formula R2COCl can be carried out under standard conditions, for example in a polar aprotic solvent such as MeCN and / or in the presence of an organic base such as TEA and / or at a temperature between 0°C and room temperature.

[0138] The reaction of a compound of formula (7) or (8) with an amine of formula NHR3R4 can be carried out under standard conditions, for example under amide coupling conditions or by stirring the reagents in a solvent such as THF at elevated temperature.

[0139] Compounds of formula (6), (7) or (8) can be prepared as described in the synthetic schemes of the Examples.

[0140] Specifically, the reaction of the compound of formula (6) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (7) can be carried out under standard conditions, for example, in a polar aprotic solvent (such as MeCN) and / or in the presence of an organic base (such as DIPEA) and / or at a temperature from 0°C to room temperature.

[0141] Also in particular, the hydrolysis of compounds of formula (7) in the presence of a base to obtain compounds of formula (8) can be carried out under standard conditions, for example by treatment with a base such as sodium hydroxide in a polar aprotic solvent such as THF and / or at a temperature between 0°C and room temperature.

[0142] 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.

[0143] The present invention includes within its scope prodrugs of compounds of Formula (I), Formula (IA), or Formula (I-AA) as described above. Generally, such prodrugs will be functional derivatives of compounds of Formula (I), Formula (IA), or Formula (I-AA) that are readily converted in vivo to the desired compound of Formula (I), Formula (IA), or Formula (I-AA). Conventional procedures for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0144] Prodrugs can be pharmacologically inert derivatives of biologically active substances ("parent drugs" or "parent molecules") that require conversion in vivo to release the active drug 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, phosphates or sulfates, or reduction or oxidation of sensory groups.

[0145] The present invention also includes all suitable isotopic variations of the disclosed compounds. Examples of isotopes that can be incorporated into the disclosed compounds include, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F and 36 Isotopes of Cl. 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, by the preparations described in the illustrative methods or examples using isotopic variations of appropriate reagents.

[0146] The present invention includes within its scope solvates, such as hydrates, alcoholates, and the like, of compounds of Formula (I), Formula (IA), or Formula (I-AA), or related salts.

[0147] 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.

[0148] The compounds of the present invention may possess asymmetric centers, axes of chirality and planes of chirality (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and exist as 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.

[0149] Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by the application of methods known in the art and are intended to be encompassed by the scope of the present invention. In particular, "pure stereoisomeric forms" or "stereomerically pure" refers to compounds having an excess of at least 80%, preferably at least 85%, of a stereoisomer. 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 appropriate 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.

[0150] 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. A line leading from a substituent into a ring system indicates 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.

[0151] 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 compounds that can be easily synthesized by readily available starting materials using techniques known in the art and those 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," and in this case, preferred embodiments will have zero to three substituents. More particularly, there are 0-2 substituents.

[0152] The expression "one or more substituents" particularly refers to 1, 2, 3, 4 or more substituents, in particular to 1, 2, 3 or 4 substituents, more particularly to 1, 2 or 3 substituents.

[0153] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-6 "Alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6 carbon atoms in a straight or branched chain, and particularly includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc. Preferably, "C 1-6 "Alkyl" refers to "C 1-4 Alkyl" or "C 1-3 More preferably, "C 1-6 Alkyl" or "C 1-3 "Alkyl" refers to methyl.

[0154] As used herein, "alkoxy" refers to an alkyl group with the indicated number of carbon atoms connected through an oxygen bridge. Therefore, "alkoxy" encompasses the above definition of alkyl. Preferably, alkoxy refers to a straight or branched C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or 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.

[0155] 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 Alkoxy is preferably a linear or branched halogenated C1-4 Alkoxy, more preferably halo C 1-3 Alkoxy, more preferably halogenated C 1-2 Alkoxy, for example OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, most particularly OCF3 or OCHF2. Halo C 1-6 The alkyl group is preferably a linear or branched halogenated C 1-4 Alkyl, more preferably halogenated C 1-3 Alkyl, more preferably halogenated C 1-2 Alkyl, such as CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 or CH(CH3)CF3. More preferably, halogenated C 1-6 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-3 Any of the alkyl groups refers to: CF3, CHF2, CH(CH3)CF3, CH2CF3 or (CH3)2CF3.

[0156] 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 hydroxy groups. 1-6 Illustrative examples include, but are not limited to, CH2OH, CH2CH2OH, CH(CH3)OH, and CHOHCH2OH.

[0157] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic ring comprising carbon and hydrogen atoms. If indicated, such an aromatic ring may include one or more heteroatoms and is then also referred to as a "heteroaryl". Illustrative examples of heteroaryl groups according to the present invention include 5- or 6-membered heteroaryl groups, such as thiophene, oxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine, and pyridine. Preferred aryl groups according to the present invention are phenyl groups. Preferred heteroaryl groups according to the present invention are pyridyl groups. Further preferred 5-membered heteroaryl rings are oxadiazole and oxazole. The oxadiazole is preferably substituted with one methyl group.

[0158] As used herein, the term "C 3-5 "Cycloalkyl" refers to a saturated cyclic hydrocarbon (cycloalkyl) having 3, 4 or 5 carbon atoms and is a general term for cyclopropyl, cyclobutyl or cyclopentyl. The saturated ring optionally contains one or more heteroatoms (also called "heterocyclyl" or "heterocycle" or "heterocycloalkyl"), whereby at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular N and O. Preferably, the C 3-5 Cycloalkyl is cyclopropyl.

[0159] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred. In particular, for halogen at positions Ra, Rb, Rc or Rd, fluorine and chlorine are preferred. Also in particular, for halogen at position R1, chlorine is preferred. More particularly, for halogen at position C 3-5 - Halogen, fluorine as a substituent of a cycloalkyl group or a cyclic amine is preferred.

[0160] 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, and S.

[0161] The present invention includes free bases of compounds of formula (I), (IA), (I-AA), as well as pharmaceutically acceptable salts and stereoisomers thereof. Certain specific compounds exemplified herein are protonated salts of amine compounds. Compounds of formula (I), (IA), (I-AA) containing one or more N atoms may be protonated at any, some, or all of the N atoms. The term "free base" refers to the non-salt form of the amine compound. 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 forms of compounds of formula (I), (IA), (I-AA). 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 base 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.

[0162] The pharmaceutically acceptable salt of the compounds of this invention can be synthesized by the compounds of this invention containing alkaline or acidic moieties by conventional chemical methods. Usually, the salt of basic compound is prepared by ion exchange chromatography or by reacting free alkali with stoichiometric amount or with excessive inorganic or organic acid of the required salt of formation in suitable solvent or various combinations of solvent. Similarly, the salt of acidic compound is formed by reacting with suitable inorganic or organic base. In a preferred embodiment, compound of the present invention has at least one acidic proton, and corresponding sodium salt or potassium salt can be formed, for example, by reacting with suitable base.

[0163] Thus, 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 a basic compound of the present invention with an inorganic or organic acid or an acidic compound with an inorganic or organic base. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and 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, and the like. 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), formula (IA) or formula (I-AA) 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.

[0164] 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, manganic salts, manganous, potassium, sodium, zinc, and the like. 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, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0165] 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.

[0166] It should also be noted that the compounds of the present invention are potentially inner salts or zwitterions because under physiological conditions, 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 protonated or alkylated basic moieties (such as quaternary nitrogen atoms).

[0167] 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).

[0168] In the context of the present invention, HBV can be any known isolate, genotype, strain, etc. of HBV. In particular, hepatitis B virus has been classified into eight major genotypes (called 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 entire 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 circulate in most parts of the world, limiting genotypic comparisons.

[0169] The compounds of the present invention are hepatitis B virus (HBV) inhibitors useful in 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 in treating and / or preventing HBV infection.

[0170] The compounds, compositions and methods provided herein are particularly contemplated as useful for treating, ameliorating or preventing 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.

[0171] In the present invention, the expression "HBV infection" includes any and all conditions resulting 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.

[0172] 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 hepatitis B, 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.

[0173] 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 present invention (which is administered or administered alone or in combination with another agent), is administered or administered to a patient, 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, relieve, 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.

[0174] 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.

[0175] 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.

[0176] 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 smaller amounts in the heart and skeletal muscle. ALT is often measured clinically as part of liver function tests.

[0177] The compounds of the present invention can reduce viral load in individuals with HBV infection. In one non-limiting embodiment, the compounds of the present invention result in 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.

[0178] As used herein, the expression "reducing 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).

[0179] As used herein, the term "prophylactic treatment" refers to the absence of development of a disease or condition (if it has not already occurred), or the absence of further development of the disease or condition (if the disease or condition has already developed). The ability to prevent some or all of the symptoms associated with the disease or condition is also contemplated. An example of prophylactic treatment might also indicate the need to reduce the risk of infection of the liver graft (in the case of liver transplantation in a chronically infected patient) or the risk of infection of the newborn (in the case of transmission of the virus during childbirth from a chronically infected mother).

[0180] As used herein, "reducing the recurrence of HBV infection" means that after several years of quiescence, patients may have the reactivation of HBV replication and the exacerbation of conditions related to HBV infection, such as hepatitis. These patients may still be at risk of developing conditions related to HBV infection (such as the 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).

[0181] 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 accordance with standard pharmaceutical practice. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0182] The present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions comprising the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and may include one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically superior and palatable formulations. Tablets contain a mixture of the active ingredient and a pharmaceutically acceptable nontoxic excipient suitable for the preparation of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-delay materials such as ethylcellulose or cellulose acetate butyrate may be used.

[0183] 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).

[0184] 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 phospholipids (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 (such as ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (such as sucrose, saccharin or aspartame).

[0185] 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 flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0186] 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 above. Other excipients, such as sweeteners, flavorings, and coloring agents, may also be present. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0187] Pharmaceutical composition of the present invention can also be the form of water-in-oil emulsion.The oil phase can be vegetable oil (such as olive oil or peanut oil), or mineral oil (such as liquid paraffin), or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide, for example soybean lecithin, and ester or partial ester derived from fatty acid and hexitol anhydride, for example sorbitan monooleate, and the condensation product of described partial ester and ethylene oxide, for example polyoxyethylene sorbitan monooleate.Emulsion can also comprise sweetener, flavoring, preservative and antioxidant.

[0188] 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.

[0189] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.

[0190] Sterile injectable formulations can also be sterile injectable oil-in-water microemulsions, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can first be 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.

[0191] The injectable solution or microemulsion can 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. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS TM Model 5400 IV Pump.

[0192] Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. Such suspensions can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents, as described above. Sterile injectable formulations can also be sterile injectable solutions or suspensions formulated in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Sterile, fixed oils are often used as solvents or suspending media. For this purpose, various low-irritation fixed oils can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, are also used in the preparation of injectables.

[0193] 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 that are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. 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.

[0194] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are used. (For the purposes of this application, topical application shall include mouthwashes and gargles.)

[0195] The compound of the present invention can be given with intranasal form by topical use of suitable intranasal carriers and delivery devices, or the transdermal skin patches of those forms known to those of ordinary skill in the art are given by transdermal routes. In order to be administered in the form of a transdermal delivery system, in the entire dosage regimen, dosage administration will certainly be continuous rather than discontinuous. The compound of the present invention can also be delivered in suppository form using matrix (such as theobroma oil, glycerinated gelatin, hydrogenated vegetable oil, a mixture of polyethylene glycol of various molecular weights and the fatty acid ester of polyethylene glycol).

[0196] The compounds of the present invention may be present in the form of liposomes or other microparticles or other nanoparticles designed to target the compound. Acceptable liposomes may be neutral, negatively charged, or positively charged, with their charge being a function of the charge of the liposome components and the pH of the liposome solution. Liposomes are typically prepared using a mixture of phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, and phosphatidylinositol. Polyethylene glycol may be added to improve the blood circulation time of the liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

[0197] 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.

[0198] 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, and preferably about 0.5 mg / kg body weight to about 40 mg / kg body weight per day.

[0199] The compounds of the present invention may also be combined with known therapeutic agents for simultaneous, separate or sequential administration.

[0200] 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.

[0201] 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.

[0202] Therapeutic agents are any agents commonly used to treat and / or prevent and / or ameliorate HBV infection or conditions associated with HBV infection. Therapeutic agents are known in the art.

[0203] 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 may be resistant to at least one anti-HBV agent and are therefore also 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.

[0204] 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), (I-AA), or any subgroup thereof, as specified herein, in combination with an immunomodulatory compound, more particularly a Toll-like receptor 7 and / or 8 agonist.

[0205] 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 regulators (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; interferon or modified interferon; 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 destabilizers, as well as other small molecule inhibitors of HBV protein expression.

[0206] Specifically, previously known anti-HBV agents, such as interferon-α (IFN-α), pegylated interferon-α, 3TC, tenofovir, lamivudine, entecavir, telbivudine and adefovir or combinations thereof, and compounds of formula (I), (IA), (I-AA) or any subgroup thereof can be used as drugs 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.

[0207] With reference to the compounds of the present invention, the term "administration" and variations thereof (e.g., "administering" a compound) means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the present invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and variations thereof are understood to include simultaneous or sequential introduction of the compound or its prodrug and the other agent.

[0208] In some embodiments, pulse administration is more effective than continuous treatment because the total pulse dose is generally lower than the dose expected from continuous administration of the same composition. The dose of each pulse can be reduced, minimizing the total amount of drug administered during treatment. Single pulses can be delivered to the patient continuously over a period of several hours (e.g., approximately 2, 4, 6, 8, 10, 12, 14, or 16 hours) or over several days (e.g., 2, 3, 4, 5, 6, or 7 days).

[0209] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0210] 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 the researcher, veterinarian, medical doctor or other clinician.

[0211] The invention will be described by the following non-limiting examples and biological data.

[0212] Materials and methods

[0213] Chemical

[0214] Overview

[0215] Unless otherwise noted, commercial reagents and solvents (HPLC grade) were used without further purification.

[0216] Specifically, the following abbreviations may be used in the description of experimental methods:

[0217] NMR: nuclear magnetic resonance; 1 H: proton; MHz: megahertz; Hz: hertz; HPLC: high-performance liquid chromatography; LC-MS: liquid chromatography-mass spectrometry; s: second; min: minute; h or hr: hour; mg: milligram; g: gram; Ml: microliter; mL: milliliter; mmol: millimole; nm: nanometer; μM: micromolar; M: molarity or molarity; Rt: retention time in minutes; anh: anhydrous; ss: saturated solution; aq: aqueous; sat.aq.: saturated aqueous solution; MW: microwave; Boc: tert-butyloxycarbonyl protecting group; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DMF: dimethylformamide; DIPEA: N,N-diisopropyl azodicarboxylate Propylethylamine; DMSO: dimethyl sulfoxide; EtOH: ethanol; EtOAc: ethyl acetate; IPA: isopropylamine; LiHMDS: lithium 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; TBDMS: tert-butyldimethylsilyl; TEA: triethylamine; THF: tetrahydrofuran; pTSA: p-toluenesulfonic acid; TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate.

[0218] Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius) or K (Kelvin).

[0219] 1 H-NMR spectra were obtained using an Avance II 300 MHz Bruker spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are expressed in Hertz (Hz), and fragmentation patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), and m (multiplet).

[0220] LC-MS analysis was performed on a UPLC Acquity Waters system (equipped with an 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 (2.1 x 100 mm, ID = 1.7 μm). Column temperature 40°C. Sample temperature 25°C. Phase A consisted of water (HiPerSolv Chromanorm Water VWR, for HPLC-MS) + 0.05% trifluoroacetic acid; Phase B consisted of CH3CN (HiPerSolv Chromanorm Acetonitrile SuperGradient VWR; for UPLC / UHPLC instruments) + 0.05% trifluoroacetic acid; Flow rate: 0.5 mL / min; UV detection (DIODE array) at 200 nm; ESI+ and ESI- detection in the m / z range of 100-1000.

[0221] 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 + .

[0222] 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 + .

[0223] Method 3: Column 3, run time: 6 minutes, run gradient: 5% B to 100% B in 5 minutes + 100% B for 1 minute, equilibration time: 2 minutes.

[0224] Method 4: Column 3, Run time: 6 minutes, Run gradient: 5% B to 50% B in 5 minutes + 50% B to 100% B in 0.2 minutes, 100% B for 0.8 minutes, Equilibration time: 2 minutes, Ionization mode: ESI + .

[0225] 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 + .

[0226] Method 6: 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 + .

[0227] Method 7: Column 3, Run time: 6 minutes, Run gradient: 5% B to 100% B in 5 minutes + 100% B for 1 minute, Equilibration time: 2 minutes, Ionization mode: ESI + .

[0228] Method 8: Column 3, Run time: 6 minutes, Run gradient: 5% B to 50% B in 5 minutes + 50% B to 100% B in 0.2 minutes, 100% B for 0.8 minutes, Equilibration time: 2 minutes, Ionization mode: ESI + .

[0229] 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 in 1 min, Equilibration time: 0.8 min, Ionization mode: ESI + .

[0230] Method 10: 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 - .

[0231] Method 11: Column 1, Run time: 3 min, Run gradient: 40% B to 100% B in 2.80 min + 100% B for 0.2 min, Equilibration time: 0.8 min, Ionization mode: ESI + .

[0232] 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 + .

[0233] 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 + .

[0234] 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 + .

[0235] synthesis

[0236] According to another aspect of the present invention, a method for preparing a compound of formula (I) 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 this invention. In the following scheme, reactive groups and deprotection can be protected with blocking groups according to generally recognized techniques. In the following scheme and paragraphs, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Cy, n and m are defined as above in formula (I).

[0237] Those skilled in the art will appreciate that certain compounds of the present invention can be converted into other compounds of the present invention according to standard chemical methods.

[0238] The compounds of the present invention can be prepared according to the general routes shown in Schemes 1 and 2 below:

[0239]

[0240] Ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate, indicated as compound (1) in Scheme 1, is prepared according to the process described in WO2017 / 001655. According to Scheme 1, a primary amine derivative (2) bearing a nucleophilic –OH 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 provides the tricyclic core of compound (5) via intramolecular nucleophilic attack of the fluorine by the OH group. 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 an N-Boc derivative, the Boc can be removed by acid treatment and the resulting NH can be further converted to, for example, an amide or oxamide derivative or can be alkylated by, for example, reductive amination chemistry. In a particular embodiment of the invention, in the compound of formula (5), the protected nitrogen is N-COOEt or N-PMB, wherein the protecting group can be cleaved by standard chemical methods, such as trimethylsilyl iodide for ethyl carbamate and hydrogenation for p-methoxybenzyl (PMB). Still, it is worth noting that the specific order of steps indicated in Scheme 1 can be modified to optimize the efficiency of the synthetic strategy.

[0241] Deprotection of compound (5) shown in Scheme 1 gives an advanced intermediate having the general structure (6), wherein Z is a counterion as shown in Scheme 1, such as Cl - CF3COO - , p-tolyl SO3 -The compound of formula (6) is reacted with R2-COOH or a derivative thereof such as an acyl chloride or ester under suitable coupling conditions to obtain a compound of formula (I). Specifically, the compound of formula (I) wherein R2 is -(C=O)NR3R4 is obtained as shown in Scheme 2.

[0242]

[0243] Compounds of formula (I) wherein R1 is H can be converted to compounds of formula (I) wherein R1 is halogen by standard halogenation procedures (see, for example, Journal of Organic Chemistry (1981), 46(11), 2221-5).

[0244] 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.

[0245] 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. Indication of the commercial sources of certain compounds in the description of experimental procedures (if provided) is provided solely for the convenience of skilled chemists and should not be construed as an instruction to use only that particular commercial compound.

[0246] In the following paragraphs, descriptions 1-28 illustrate the preparation of intermediates used to prepare the compounds of the present invention and their salts. The examples illustrate the preparation of the compounds of the present invention and their salts. When the compounds have more than one chiral center, it should be understood that they may exist as mixtures of diastereomers or as single isomers. Both racemic and chiral compounds are within the scope of the present invention. The procedures provided are intended solely to assist skilled chemists. The starting materials are not necessarily prepared from the batches mentioned in the description or examples.

[0247] Description D1: Racemic 4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (D1)

[0248] Compound D1 was prepared according to the following scheme:

[0249]

[0250] A solution of ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.37 mmol) and tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (237078, Fluorochem, CAS: 889949-18-2; 80.2 mg, 0.37 mmol) in anhydrous MeCN (2 mL) was treated with TEA (0.15 mL, 1.11 mmol). The reaction was stirred at room temperature for 30 minutes; then concentrated under reduced pressure; diluted with EtOAc and washed with 5% citric acid solution and brine, dried over Na2SO4 (anhydrous), filtered, and the solvent removed under reduced pressure. The crude product D1 (131 mg, 0.29 mmol, yield = 78.6%) was used as is in the next synthetic step. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + .

[0251] Description D2: 6'-((3,4-difluorophenyl)carbamoyl)-7'-methyl-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-1-Chlorine 1',1'-dioxide (D2)

[0252] The compounds were prepared according to the following scheme:

[0253]

[0254] Step 1:

[0255] To a solution of D1 (130 mg, 0.29 mmol) and 3,4-difluoroaniline (001459, Fluorochem, CAS: 63-11-4; 30 μL, 0.304 mmol) in anhydrous THF (3 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF) (1.45 mL) at room temperature. After 60 minutes, the reaction was quenched with water, diluted with DCM and washed with 5% aqueous citric acid solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give foamy tert-butyl 3-((5-((3,4-difluorophenyl)carbamoyl)-4-fluoro-1-methyl-1H-pyrrole)-3 tert-butyl-sulfonylamino)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (154 mg, 0.289 mmol, quantitative yield), which was used without further purification. Method 1: Rt = 1.98 min; m / z = 533.4 (M+H) + .

[0256] Step 2:

[0257] To a solution of the compound (154 mg, 0.289 mmol) from step 1 in DMF (2.9 mL) was added cesium carbonate (282.7 mg, 0.868 mmol) and the reaction mixture was stirred in an oil bath at 135 ° C for 1 hour. The reaction was diluted with EtOAc and washed with water (x3). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated in vacuo to give 6'-((3,4-difluorophenyl)carbamoyl)-7'-methyl-2'H, 4'H, 7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine as a solid. ]-tert-Butyl 1-carboxylate 1',1'-dioxide (148 mg, 0.289 mmol, quantitative yield). Method 1: Rt = 2.19 min; m / z = 513.2 (M+H) + .

[0258] Step 3:

[0259] The compound from step 2 (148 mg, 0.290 mmol) was dissolved in DCM (2 mL) and treated with a single portion of 1 M HCl in dioxane (0.29 mL, 0.290 mmol). After stirring at room temperature for 1 hour, the solvent was removed to give D2 as the hydrochloride salt (130 mg, quantitative yield), which was used in the next step without any purification. Method 1: Rt = 1.33 min; m / z = 413.2 (M+H) + .

[0260] Description D3: (R)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetic acid methyl ester (D3)

[0261]

[0262] To an equimolar solution of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride (U23940, Aurum Pharmaceuticals, CAS: 177469-12-4; 500 mg, 3.34 mmol) 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 a 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 x 20 mL) and brine. The organic phase was dried over Na2SO4 (anhydrous), then filtered and concentrated to afford D3 (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 = 200.1 (M+H)+ .

[0263] Description D4: Sodium (R)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate (D4)

[0264]

[0265] To a solution of D3 (567.mg, 2.85mmol) in THF (2mL, 0.025mol) at room temperature was added sodium hydroxide (113.89mg, 2.85mmol) previously dissolved in water (1mL, 0.056mol). The reaction was stirred at room temperature overnight, then diluted with toluene (30mL) and evaporated to dryness under reduced pressure. This process was repeated twice to give a white powder. The product was dried under vacuum pump overnight to give D4 (562mg, yield = 95%) as a white powder. Method 13: Rt = 1.25 min, m / z = 130.1 (M+H) + .

[0266] Description D5: (3R)-tert-Butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (D5)

[0267]

[0268] Step 1:

[0269] A mixture of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (Fluorochem, cat n°237078, CAS:889949-18-2) (500 mg, 2.31 mmol) and (-)-O,O'-di-p-toluoyl-D-tartrate (0.5 eq, 445 mg, 1.15 mmol) was suspended in IPA (2.5 mL, 0.033 mol) and the mixture was sonicated until most of it dissolved. The resulting suspension was heated at 65 ° C for a few minutes and sonicated again to obtain a homogeneous mixture. The light yellow solution was heated at 65 ° C. After 5 minutes, the mixture became a white suspension and stirring was continued at 65-70 ° C for 18 hours. The suspension was allowed to cool to room temperature within 1 hour. The suspension was filtered and the solid was rinsed with a small amount of isopropanol. The crude product was dried under vacuum pump overnight to give (3R)-tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate hemi-(-)-O,O'-di-p-toluoyl-D-tartaric acid ester (345 mg, 0.43 mmol, y=36.4%). 1H NMR(300MHz,DMSO-d6)δppm 1.39(s,9H)1.62-1.79(m,1H)1.79-2.03(m,1H)2.35(s,3H)3.03-3.51(m,6H )5.57(s,1H)6.83-8.03(m,1H)7.28(d,J=8.07Hz,2H)7.80(d,J=8.16Hz,1H).

[0270] Step 2:

[0271] (3R) -3-amino -3- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester - half - (-) -O, O'- two - toluene acyl -D- tartaric acid ester (350.mg, 0.43mmol) is suspended in water (1mL) and ethyl acetate (1mL). The mixture is cooled in an ice bath and 6N HCl (0.14mL, 0.840mmol) is added dropwise. The resulting biphasic mixture is stirred at 0°C for 1 hour. The layers are separated and the aqueous phase is washed with EtOAc (x1). The aqueous layer is cooled to 0°C and treated with 3M NaOH aqueous solution (0.28mL, 0.840mmol). The mixture is stirred at 0°C for 1 hour. The resulting solution is extracted with MeTHF (5x10mL) and concentrated under reduced pressure to obtain (3R) -3-amino -3- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester (134mg, 0.620mmol) as a white solid. 1 H NMR (300MHz, CHLOROFORM-d) δppm 1.45 (s, 9H) 1.67-1.85 (m, 1H) 1.86-2.05 (m, 1H) 2.40 (br s, 2H) 3.14-3.59 (m, 6H).

[0272] Description D6: (3S)-tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (D6)

[0273]

[0274] D6 was prepared as described for D5 starting from tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (Fluorochem, cat n° 237078, CAS: 889949-18-2) (500 mg, 2.31 mmol) and (+)-O,O′-di-p-toluoyl-D-tartaric acid ester (0.5 eq., 445 mg, 1.15 mmol). 1 H NMR (300MHz, CHLOROFORM-d) δppm 1.45 (s, 9H) 1.61-1.81 (m, 1H) 1.82-2.15 (m, 3H) 3.51 (m, 6H).

[0275] Description D7: (R)-4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (D7)

[0276]

[0277] D7 was prepared as described for D1 starting from D5 in place of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + .

[0278] Description D8: (S)-4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (D8)

[0279]

[0280] D8 was prepared as described for D1 starting from D6 in place of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + .

[0281] Description D9: tert-Butyl 4-((5-(ethoxycarbonyl)-4-fluoro-1-methyl-1H-pyrrole)-3-sulfonylamino)-4-(hydroxymethyl)piperidine-1-carboxylate (D9)

[0282]

[0283] D9 was prepared as described for D1 starting with 1-Boc-4-amino-4-(hydroxymethyl)piperidine (Flurocohem, cat 469124, CAS: 203186-96-3) instead of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate. Method 1: Rt = 1.89 min; m / z = 464.4 (M+H) + .

[0284] Description D10: 4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)azetidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (D10)

[0285]

[0286] D10 was prepared as described for D1 starting with 1-Boc-3-amino-3-(hydroxymethyl)azetidine (Fluorochem, cat 502710, CAS: 1262411-27-3) instead of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate. Method 1: Rt = 1.83 min; m / z = 436.4 (M+H) + .

[0287] Description D11: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D11)

[0288]

[0289] The preparation method is similar to that described for compound D2, starting with D7 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.42 min; m / z = 429.23 (M+H) + .

[0290] Description D12: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D12)

[0291]

[0292] The preparation method was similar to that described for compound D2, starting from D8 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) instead of 3,4-difluoroaniline in step 1.

[0293] Description D13: N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D13)

[0294]

[0295] The preparation method is similar to that described for compound D2, starting with D9 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.44 min; m / z = 443.3 (M+H) + .

[0296] Description D14: N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D14)

[0297]

[0298] The preparation method is similar to that described for compound D2, starting with D10 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.40 min; m / z = 415.3 (M+H) + .

[0299] Description D15: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D15)

[0300]

[0301] The preparation method is similar to that described for compound D2, starting with D7 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.37 min; m / z = 445.16 (M+H) + .

[0302] Description D16: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D16)

[0303]

[0304] The preparation method is similar to that described for compound D2, starting with D8 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.37 min; m / z = 445.16 (M+H) + .

[0305] Description D17: N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D17)

[0306]

[0307] The preparation method is similar to that described for compound D2, starting from D9 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) to obtain D17. Method 1: Rt = 1.39 min; m / z = 459.3 (M+H) + .

[0308] Description D18: N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide hydrochloride (D18)

[0309]

[0310] The preparation method is similar to that described for compound D2, starting with D10 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) instead of 3,4-difluoroaniline in step 1. Method 1: Rt = 1.35 min; m / z = 431.25 (M+H) + .

[0311] Description D19: (S)-ethyl 2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D19)

[0312]

[0313] The preparation method is similar to that described for compound D3, starting from ethyl 2-chloro-2-oxoacetate and using (2S)-1,1,1-trifluoro-2-propylamine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride to obtain D19 as a colorless oil. Method 2; Rt = 2.84 min. m / z = 214.34 (M+H) + .

[0314] Description D20: Sodium (S)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetate (D20)

[0315]

[0316] Prepared analogously to compound D4 starting from D19. Method 6; Rt = 1.34 min. m / z = 186.3 (M+H) + .

[0317] Description D21: Ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D21)

[0318]

[0319] The preparation method was similar to that described for compound D3, starting from ethyl 2-chloro-2-oxoacetate and using 2,2,2-trifluoroethylamine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride to afford D21 as a white solid, which was used as such in the next synthetic step. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (t, J = 7.11 Hz, 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) + .

[0320] Description D22: Sodium 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D22)

[0321]

[0322] Prepared analogously to compound D4 starting from D21. Method 6; Rt = 1.22 min. m / z = 172.1 (M+H) + .

[0323] Description D23: Ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D23)

[0324]

[0325] The preparation method is similar to that described for compound D3, starting from ethyl 2-chloro-2-oxoacetate and using 2,2,2-trifluoro-1,1-dimethyl-ethylamine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride to obtain D23 as a colorless oil, which was used as is in the next synthetic step. Method 6; Rt = 3.54 min. m / z = 228.13 (M+H) + .

[0326] Description D24: Sodium 2-oxo-2-((1,1,1-trifluoro-2-methylpropane-2-yl)amino)acetate (D24)

[0327]

[0328] Prepared analogously to compound D4 starting from D23. Method 6; Rt = 1.07 min. m / z = 200.15 (M+H) + .

[0329] Description D25: ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D25)

[0330]

[0331] The preparation method was similar to that described for compound D3, starting from ethyl 2-chloro-2-oxoacetate and using 3,3-difluoroazetidine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride to obtain D25 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) + .

[0332] Description D26: Sodium 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D26)

[0333]

[0334] Prepared analogously to compound D4 starting from D25. Method 6; Rt = 0.92 min. m / z = 166 (M+H) + .

[0335] Description D27: Methyl 2-(cyclopropylamino)-2-oxoacetate (D27)

[0336]

[0337] The preparation method was similar to that described for compound D3, using 3,3-difluoroazetidine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propylamine hydrochloride to give D27 (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) + .

[0338] Description D28: Sodium 2-(cyclopropylamino)-2-oxoacetate (D28)

[0339]

[0340] Prepared analogously to compound D4 starting from D27, D28 (984 mg, 6.51 mmol) was obtained as a white powder. Method 13: Rt = 0.78 min; m / z = 130.11 (M+H) + .

[0341] Example E1: N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E1)

[0342]

[0343] To a solution of D2 (30 mg, 0.070 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29.56 mg, 0.070 mmol) and (R)-2-oxo-2-((1,1,1-trifluoropropane-2-yl)amino)acetic acid sodium D4 (13.84 mg, 0.070 mmol) in DMF (1 mL, 0.013 mol) was added DIPEA (47 uL, 0.270 mmol) at room temperature. The reaction mixture was stirred under the same conditions for 30 minutes; then diluted with EtOAc and washed with 1N NaOH (aqueous solution). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Fraction-Lynx (H2O / CH3CN+1‰TFA) to give E11 in a yield of approximately 40%. NMR: 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.22-1.39 (m, 3H) 1.92-2.40 (m, 2H) 3.44-4.18 (m, 7H) 4.40-4.72 (m, 3H) 7.30-7.57 (m, 3H) 7.75-7.92 (m, 1H) 8.29 (m, 1H) 9.21-9.37 (m, 1H) 9.44 (br dd, J = 8.16, 2.84 Hz, 1H). Method 3: Rt = 3.54 min; m / z = 580.32 (M+H) + .

[0344] Example E2: N-(3,4-difluorophenyl)-7'-methyl-1-(5-methyl-1,3,4-oxadiazole-2-carbonyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E2)

[0345]

[0346] D2 (8.96 mg, 0.02 mmol) was suspended in MeCN (1 mL) and treated with a single portion of TEA (8 μL, 0.06 mmol) to give a white suspension. 5-Methyl-1,3,4-oxadiazole-2-yl chloride (1.17 M in MeCN, 30 μL) (Org. Proc. Res. Develop. 2011, 15, 73-83) was added to the mixture in a single portion at 0°C. The reaction was stirred at room temperature for 15 minutes. The reaction was quenched with MeOH, the solvent was removed, and then dissolved in DCM and washed with brine and 5% aqueous citric acid solution. The organic layer was concentrated under reduced pressure; the residue was dissolved in MeOH (15 mL) and slowly concentrated. This process was repeated 5 times to give a crude product, which was purified by preparative HPLC (H2O, CH3CN 0.1% HCOOH) to give E2 in a yield of approximately 40%. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.04-2.45 (m, 2H) 2.60 (s, 3H) 3.82 (d, J = 4.68 Hz, 5H) 3.98-4.40 (m, 2H) 4.45-4.70 (m, 2H) 7.28-7.57 (m, 3H) 7.73-7.93 (m, 1H) 8.20-8.63 (m, 1H) 9.37-9.62 (m, 1H). Method 3: Rt = 3.08 min; m / z = 523.25 (M+H) + .

[0347] Example E3: 8'-Chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E3)

[0348]

[0349] To a stirred solution of E1 (13.45 mg, 0.020 mmol) in DCM (1 mL) at 0°C was added sulfuryl chloride (2 uL; 0.020 mmol) (using 200 uL from a previously prepared stock solution of 20 uL SO2Cl2 in 2 mL DCM). The reaction was stirred at 0°C for 30 minutes and a second equivalent of SO2Cl2 was added. The reaction was stirred for 1 hour; then stopped by the addition of NaHCO3 ss and diluted with DCM; the organic phase was separated by a phase separator and concentrated under reduced pressure. The crude product was purified by preparative HPLC (H2O, CH3CN 0.1% TFA) to afford E3 in approximately 20% yield. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.25-1.40 (m, 3H) 1.89-2.38 (m, 2H) 3.38-4.18 (m, 7H) 4.37-4.80 (m, 3H) 7.25-7.55 (m, 2H) 7.66-7.95 (m, 1H) 8.48-8.67 (m, 1H) 9.14-9.40 (m, 1H) 9.64 (t, J = 3.94 Hz, 1H). Method 3: Rt = 3.74 min; m / z = 614.22 (M+H) + .

[0350] Example E4: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E4)

[0351]

[0352] To a stirred solution of D11 (35 mg, 0.08 mmol) and D3 (24.05 mg, 0.11 mmol) in ethanol (1.1572 mL, 0.020 mol) was added DBU (22.9 mg, 0.150 mmol) in a single portion. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with MeCN and purified by preparative HPLC (H O, CH CN 0.1% TFA) to afford E4 (31.3 mg, 0.052 mmol, y = 70%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δppm 1.31(t,J=6.88Hz,3H)1.96-2.38(m,2H)3.48-3.67(m,2H)3.75-4.12(m,5H)4.39-4.74(m,3H)7.41(t,J=9.08Hz,1H)7.51(d,J=2.93 Hz,1H)7.61-7.69(m,1H)7.96(dt,J=6.79,2.57Hz,1H)8.30(d,J=10.18Hz,1H)9.30(dd,J=13.94,9.08Hz,1H)9.42(d,J=4.68Hz,1H). Method 3: Rt = 3.69 min; m / z = 596, 2 (M+H) + .

[0353] Example E5: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E5)

[0354]

[0355] The preparation was carried out similarly to that described for compound E4 starting with D12 in place of D11 to give E5

[0356] (23.54 mg, 0.039 mmol, y=61%). 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (dd, J = 7.01, 2.15 Hz, 3H) 1.99-2.39 (m, 2H) 3.83 (s, 7H) 4.44-4.72 (m, 3H) 7.39 (t, J = 9.12 Hz, 1H) 7.46-7.55 (m, 1H) 7.58-7.72 (m, 1H) 7.96 (dd, J = 6.79, 2.48 Hz, 1H) 8.28 (d, J = 6.05 Hz, 1H) 9.30 (t, J = 9.26 Hz, 1H) 9.41 (d, J = 11.65 Hz, 1H). Method 3: Rt = 3.69 min; m / z = 596, 1 (M+H) + .

[0357] Example E6: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E6)

[0358]

[0359] Prepared analogously to that described for compound E4 starting from D15 instead of D11 to give E6 (20.62 mg, 0.034 mmol, y = 65%). 1 H NMR(300MHz,DMSO-d6)δppm 1.31(t,J=6.79Hz,3H)2.04-2.37(m,2H)3.20-4.16(m,7H)4.42-4.74(m,3H)7. 02-7.45(m,2H)7.51(d,J=3.03Hz,1H)7.81(brdd,J=8.25,3.85Hz,1H)8.02(br d, J=5.14Hz, 1H) 8.30 (d, J=9.81Hz, 1H) 9.30 (dd, J=14.21, 9.08Hz, 1H) 9.49 (d, J=4.31Hz, 1H). Method 3: Rt = 3.54 min; m / z = 612,28 (M+H) + .

[0360] Example E7: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E7)

[0361]

[0362] Prepared analogously to what was described for compound E4 starting from D13 instead of D11 to give E7 (19.45 mg, 0.032 mmol, y = 61%). 1 H NMR(300MHz,DMSO-d6)δppm 1.21-1.38(m,3H)1.44-1.72(m,2H)2.00-2.20(m,2H)2.99-3.20(m,1H)3.27-4.19(m,6H)4.36-4.48(m,2H)4.57-4.75(m,1H)7.41(t, J=9.08Hz,1H)7.51(s,1H)7.59-7.68(m,1H)7.88-7.92(m,1H)7.96(dd,J=6.79,2.57Hz,1H)9.33(dd,J=8.80,4.77Hz,1H)9.40(s,1H). Method 3: Rt = 3.61 min; m / z = 610.25 (M+H) + .

[0363] Example E8: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E8)

[0364]

[0365] Prepared analogously to that described for compound E4 starting from D17 instead of D11 to give E8 (17.64 mg, 0.028 mmol, y = 58%). 1H NMR (300MHz, DMSO-d6) δppm 1.29 (dd, J=6.97, 3.48Hz, 3H) 1.45-1.71 (m, 2H) 2.10 (br d, J=13.11Hz, 2H) 3.10 (br s,1H)3.47-3.56(m,2H)3.83(s,3H)4.02-4.16(m,1H)4.35-4.49(m,2H)4.55-4.77(m,1H)6.98-7.44(m,2H)7.51(s,1H)7.81(br dd, J = 8.57, 3.53 Hz, 1H) 7.90 (s, 1H) 8.01 (dd, J = 6.24, 2.38 Hz, 1H) 9.33 (dd, J = 8.80, 4.58 Hz, 1H) 9.45 (s, 1H). Method 3: Rt = 3.46 min; m / z = 626.3 (M+H) + .

[0366] Example E9: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E9)

[0367]

[0368] Prepared analogously to compound E4 starting from D14 instead of D11 to give E9 (11.49 mg, 0.02 mmol, y = 41%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (dd, J = 7.01, 1.97 Hz, 3H) 3.75-3.91 (m, 3H) 4.01-4.20 (m, 2H) 4.45-4.77 (m, 5H) 7.41 (t, J = 9.12 Hz, 1H) 7.53 (s, 1H) 7.63-7.76 (m, 1H) 7.91-8.05 (m, 1H) 8.63 (d, J = 5.41 Hz, 1H) 9.30 (t, J = 9.17 Hz, 1H) 9.44 (d, J = 4.22 Hz, 1H). Method 3: Rt = 3.71 min; m / z = 582, 23 (M+H) + .

[0369] Example E10: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E10)

[0370]

[0371] Prepared analogously to what was described for compound E4 starting from D18 instead of D11 to give E10 (17.04 mg, 0.028 mmol, y = 61%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (dd, J = 7.01, 2.25 Hz, 3H) 3.84 (s, 3H) 4.07-4.16 (m, 2H) 4.46-4.77 (m, 5H) 6.97-7.46 (m, 2H) 7.53 (s, 1H) 7.79-7.90 (m, 1H) 8.04 (br d, J = 6.14 Hz, 1H) 8.62 (d, J = 5.41 Hz, 1H) 9.30 (t, J = 8.89 Hz, 1H) 9.51 (d, J = 4.13 Hz, 1H). Method 3: Rt = 3.56 min; m / z = 598, 16 (M+H) + .

[0372] Example E11: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E11)

[0373]

[0374] Prepared analogously to that described for compound E4 starting from D16 instead of D11 to give E11 (22.24 mg, 0.036 mmol, y=50%). 1 H NMR (300 MHz, DMSO-d 6+TFA)δppm1.24-1.38 (m, 3H)2.02-2.39 (m, 2H)3.53-4.10 (m, 7H)4.40-4.77 (m, 3H)6.94-7.42 (m, 2H)7.49 (d, J=2.48 Hz, 1H)7.71-7.87 (m, 1H)7.98-8.07 (m, 1H)8.27 (d, J=6.97 Hz, 1H)9.30 (t, J=9.17 Hz, 1H)9.48 (d, J=11.28 Hz, 1H). Method 3: Rt=3.54 min; m / z=612.34 (M+H) + .

[0375] Example E12: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E12)

[0376]

[0377] A solution of D13 (10 mg, 0.020 mmol) and D20 (6.48 mg, 0.030 mmol) in DMF (0.5 mL) was treated with N,N-diisopropylethylamine (0.01 mL, 0.060 mmol) at room temperature; then benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (9.28 mg, 0.02 mmol) was added in a single portion. The reaction was stirred at room temperature overnight and then directly purified by preparative HPLC (HO, CHCN 0.1% TFA) to give E12 (4.44 mg, 0.007 mmol, y = 35%) as a white solid. 1H NMR(300MHz,DMSO-d6)δppm 1.29(dd,J=6.97,3.21Hz,3H)1.43-1.72(m,2H)2.02-2.19(m,2H)2.99-3.20(m,1H)3.47-3.59(m,2H)3.73-3.91(m,3H)4.09(br dd,J=12.98,3.26Hz,1H)4.43(br d, J = 2.29 Hz, 2H) 4.56-4.77 (m, 1H) 7.41 (t, J = 9.08 Hz, 1H) 7.51 (s, 1H) 7.64 (ddd, J = 9.03, 4.26, 2.66 Hz, 1H) 7.90 (s, 1H) 7.96 (dd, J = 6.88, 2.57 Hz, 1H) 9.33 (dd, J = 8.80, 4.86 Hz, 1H) 9.39 (s, 1H). Method 3: Rt = 3.61 min; m / z = 610.25 (M+H) + .

[0378] Example E13: N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E13)

[0379]

[0380] Prepared analogously as described for compound E12 starting from D13 using D22 instead of D20 to give E13 (4.08 mg, 0.007 mmol, y = 32%). 1 H NMR(300MHz,DMSO-d6)δppm1.44-1.73(m,2H)2.09(br d,J=13.57Hz,2H)3.11(br s,1H)3.33-3.44(m,1H)3.53-3.55(m,1H)3.83(s,3H)3.92-4.18(m,3H)4.43(s,2H)7.41(t,J=9.08Hz,1H)7.51 (s,1H)7.64(ddd,J=9.08,4.26,2.61Hz,1H)7.88-7.92(m,1H)7.96(dd,J=6.79,2.57Hz,1H)9.31-9.48(m,2H). Method 3: Rt = 3.52 min; m / z = 596.14 (M+H) + .

[0381] Example E14: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E14)

[0382]

[0383] Prepared analogously to what was described for compound E12 starting from D17 and D20 to give E14 (6.25 mg, 0.01 mmol, y = 43%). 1 H NMR (300MHz, DMSO-d6+TFA) δppm1.28 (br s, 3H) 1.45-1.69 (m, 2H) 2.10 (br d, J = 7.34Hz, 2H) 3.01-3.22 (m, 1H) 3.30-3.64 (m, 2H) 3.83 (br d,J=9.26Hz,3H)4.02-4.22(m,1H)4.42(br d,J=6.97Hz,2H)4.52-4.78(m,1H)6.91-7.56(m,3H)7.66-8.17(m,3H)9.23-9.37(m,1H)9.37-9.49(m,1H). Method 3: Rt = 3.46 min; m / z = 626.32 (M+H) + .

[0384] Example E15: N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E15)

[0385]

[0386] Prepared analogously as described for compound E12 starting from D17 using D24 instead of D20 to give E15 (4.67 mg, 0.007 mmol, y = 31%). 1H NMR(300MHz, DMSO-d6)δppm1.44-1.70(m,8H)2.10(br d,J=13.30Hz,2H)2.97-3.16(m,1H)3.43(br s,2H)3.79-3.88(m,3H)4.06(br d,J=13.20Hz,1H)4.41(s,2H)7.00-7.45(m,2H)7.47-7.57(m,1H)7.74-7.85(m,1H) 7.85-7.93(m,1H)8.01(dd,J=6.10,2.15Hz,1H)8.65-8.90(m,1H)9.32-9.56(m,1H). Method 3: Rt = 3.57 min; m / z = 640, 36 (M+H) + .

[0387] Example E16: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E16)

[0388]

[0389] Prepared analogously as described for compound E12 starting from D14 to give E16 (3.11 mg, 0.005 mmol, y=25%). 1 H NMR(300MHz,DMSO-d6)δppm 1.33(dd,J=7.06,2.02Hz,3H)3.75-3.91(m,3H)4.01-4.20(m,2H)4.46-4.79(m,5H)7.41(t,J=9.12Hz,1H)7.53(s,1H)7.69(ddt,J =9.09, 4.44, 2.45, 2.45Hz, 1H) 7.98 (dt, J = 6.79, 2.34Hz, 1H) 8.63 (d, J = 5.41Hz, 1H) 9.30 (t, J = 9.22Hz, 1H) 9.44 (d, J = 4.13Hz, 1H). Method 3: Rt = 3.71 min; m / z = 582, 23 (M+H) + .

[0390] Example E17: N-(3-chloro-4-fluorophenyl)-1-(2-(3,3-difluoroazetidin-1-yl)-2-oxoacetyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E17)

[0391]

[0392] Prepared analogously as described for compound E12 starting from D14 using D26 instead of D20 to give E17 (1.05 mg, 0.002 mmol, y = 9%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (br d, J = 7.43 Hz, 3H) 3.94-4.17 (m, 2H) 4.29-4.46 (m, 2H) 4.52 (br d, J = 6.88 Hz, 2H) 4.66 (br d, J = 6.33 Hz, 2H) 4.80 (br s, 2H) 7.24-7.42 (m, 1H) 7.44-7.56 (m, 1H) 7.59-7.78 (m, 1H) 7.85-8.10 (m, 1H) 8.48-8.71 (m, 1H) 9.33-9.53 (m, 1H). Method 3: Rt = 3.52 min; m / z = 562, 11 (M+H) + .

[0393] Example E18: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E18)

[0394]

[0395] Prepared analogously to compound E12 starting from D18 to give E18 (3.69 mg, 0.006 mmol, y = 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28-1.37 (m, 3H) 3.72-3.95 (m, 3H) 3.99-4.23 (m, 2H) 4.39-4.82 (m, 5H) 6.98-7.44 (m, 2H) 7.49-7.57 (m, 1H) 7.77-7.91 (m, 1H) 7.99-8.10 (m, 1H) 8.62 (d, J = 5.32 Hz, 1H) 9.24-9.36 (m, 1H) 9.51 (d, J = 4.22 Hz, 1H). Method 3: Rt = 3.57 min; m / z = 598, 23 (M+H) + .

[0396] Example E19: 1-(2-(Cyclopropylamino)-2-oxoacetyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E19)

[0397]

[0398] Prepared analogously as described for compound E12 starting from D18 using D28 instead of D20 to give E19 (2.6 mg, 0.005 mmol, y = 21%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.51-0.74 (m, 4H) 2.72-2.77 (m, 1H) 3.77-3.91 (m, 3H) 3.95-4.17 (m, 2H) 4.45-4.74 (m, 4H) 6.94-7.46 (m, 2H) 7.48-7.57 (m, 1H) 7.77-7.92 (m, 1H) 7.99-8.12 (m, 1H) 8.55-8.65 (m, 1H) 8.76 (d, J = 5.32 Hz, 1H) 9.50 (s, 1H). Method 3: Rt = 3.22 min; m / z = 542, 26 (M+H) + 0.05

[0399] Example E20: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E20)

[0400]

[0401] Prepared analogously to compound E12 starting from D11 using D22 instead of D20 to give E20 (5.87 mg, 0.01 mmol, y=13%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.94-2.41 (m, 2H) 3.47-4.26 (m, 9H) 4.38-4.73 (m, 2H) 7.38 (t, J = 9.08 Hz, 1H) 7.50 (d, J = 4.13 Hz, 1H) 7.57-7.71 (m, 1H) 7.89-8.04 (m, 1H) 8.29 (s, 1H) 9.26-9.46 (m, 2H). Method 3: Rt = 3.59 min; m / z = 582, 16 (M+H) + .

[0402] Example E21: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E21)

[0403]

[0404] Prepared analogously to compound E12 starting from D11 using D24 instead of D20 to give E21 (4.95 mg, 0.008 mmol, y=25%). 1 H NMR(300MHz, DMSO-d6)δppm1.44-1.62(m,6H)1.99-2.37(m,2H)3.45-4.02(m,7H)4.34-4.72(m,2H)7.38(t,J=9.08Hz,1H)7.50(s,1H)7.65 (dtd,J=8.85,4.29,4.29,2.75Hz,1H)7.96(dd,J=6.79,2.57Hz,1H)8.29(d,J=2.48Hz,1H)8.55(d,J=26.00Hz,1H)9.40(d,J=17.15Hz,1H). Method 3: Rt = 3.85 min; m / z = 610, 25 (M+H) + .

[0405] Example E22: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E22)

[0406]

[0407] Prepared analogously to as described for compound E12 starting from D11 to give E22 (5.79 mg, 0.01 mmol, y = 45%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (dd, J = 7.01, 2.52 Hz, 3H) 2.08-2.30 (m, 2H) 3.53-4.13 (m, 7H) 4.44-4.72 (m, 3H) 7.41 (t, J = 9.08 Hz, 1H) 7.51 (d, J = 2.38 Hz, 1H) 7.61-7.69 (m, 1H) 7.96 (dd, J = 6.79, 2.48 Hz, 1H) 8.28 (d, J = 6.14 Hz, 1H) 9.32 (t, J = 9.35 Hz, 1H) 9.42 (d, J = 11.74 Hz, 1H). Method 3: Rt = 3.69 min; m / z = 596, 21 (M+H) + .

[0408] Example E23: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E23)

[0409]

[0410] Prepared similarly to compound E12 starting from D15 to give E23 (7.04 mg, 0.011 mmol, y = 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (dd, J = 7.01, 2.43 Hz, 3H) 2.01-2.38 (m, 2H) 3.45-4.18 (m, 7H) 4.37-4.80 (m, 3H) 7.00-7.45 (m, 2H) 7.51 (d, J = 2.66 Hz, 1H) 7.72-7.87 (m, 1H) 7.95-8.09 (m, 1H) 8.27 (d, J = 7.15 Hz, 1H) 9.32 (t, J = 9.26 Hz, 1H) 9.49 (d, J = 11.28 Hz, 1H). Method 3: Rt = 3.55 min; m / z = 612, 21 (M+H) + .

[0411] Example E24: (R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E24)

[0412]

[0413] Prepared similarly to compound E12 starting from D15 using D24 instead of D20 to give E24 (6.4 mg, 0.01 mmol, y = 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.62 (m, 6H) 2.05-2.34 (m, 2H) 3.24-4.12 (m, 7H) 4.36-4.70 (m, 2H) 6.95-7.44 (m, 2H) 7.51 (s, 1H) 7.71-7.87 (m, 1H) 7.95-8.10 (m, 1H) 8.28 (s, 1H) 8.57 (d, J = 29.00 Hz, 1H) 9.49 (d, J = 16.41 Hz, 1H). Method 3: Rt = 3.69 min; m / z = 626,32 (M+H) + .

[0414] Example E25: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E25)

[0415]

[0416] Prepared analogously as described for compound E12 starting from D12 using D22 instead of D20 to give E25 (9 mg, 0.015 mmol, y = 42%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.94-2.41 (m, 2H) 3.47-4.26 (m, 9H) 4.38-4.73 (m, 2H) 7.38 (t, J = 9.08 Hz, 1H) 7.50 (d, J = 4.13 Hz, 1H) 7.57-7.71 (m, 1H) 7.89-8.04 (m, 1H) 8.29 (s, 1H) 9.26-9.46 (m, 2H). Method 3: Rt = 3.58 min; m / z = 582, 30 (M+H) + .

[0417] Example E26: (S)-N-(3-Chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E26)

[0418]

[0419] Prepared analogously as described for compound E12 starting from D12 using D24 instead of D20 to give E26 (6 mg, 0.01 mmol, y = 27%). 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.44-1.62(m,6H)1.99-2.37(m,2H)3.45-4.02(m,7H)4.34-4.72(m,2H)7.38(t,J=9.08Hz,1H)7.50(s,1H)7.65(dtd,J=8.85, 4.29, 4.29, 2.75Hz, 1H) 7.96 (dd, J = 6.79, 2.57Hz, 1H) 8.29 (d, J = 2.48Hz, 1H) 8.55 (d, J = 26.00Hz, 1H) 9.40 (d, J = 17.15Hz, 1H). Method 3: Rt = 3.84 min; m / z = 610,32 (M+H) + .

[0420] Example E27: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E27)

[0421]

[0422] Prepared analogously as described for compound E12 starting from D16 using D22 instead of D20 to give E27 (10 mg, 0.017 mmol, y = 39%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.99-2.36 (m, 2H) 3.43-4.28 (m, 9H) 4.43-4.72 (m, 2H) 6.97-7.43 (m, 2H) 7.49 (d, J = 4.03 Hz, 1H) 7.72-7.86 (m, 1H) 8.02 (br d, J = 5.78 Hz, 1H) 8.28 (s, 1H) 9.26-9.41 (m, 1H) 9.48 (s, 1H). Method 3: Rt = 3.43 min; m / z = 598, 30 (M+H) + .

[0423] Example E28: (S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E28)

[0424]

[0425] Prepared analogously as described for compound E12 starting from D16 using D24 instead of D20 to give E28 (8.36 mg, 0.013 mmol, y = 31%). 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.46-1.59 (m, 6H) 1.98-2.38 (m, 2H) 3.42-4.11 (m, 7H) 4.35-4.70 (m, 2H) 6.90-7.42 (m, 2H) 7.43-7.56 (m, 1H) 7.70-7.90 (m, 1H) 7.92-8.11 (m, 1H) 8.28 (s, 1H) 8.39-8.69 (m, 1H) 9.47 (d, J = 16.05 Hz, 1H). Method 3: Rt = 3.69 min; m / z = 626, 32 (M+H) + .

[0426] Example E29: (S)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E29)

[0427]

[0428] Prepared analogously to what was described for compound E3 starting from E11 to give E29 (1.07 mg, 0.002 mmol, y = 6%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J = 6.97 Hz, 3H) 1.99-2.38 (m, 2H) 3.39-4.23 (m, 7H) 4.39-4.77 (m, 3H) 6.96-7.48 (m, 2H) 7.81 (br dd, J = 8.30, 3.90 Hz, 1H) 7.91-8.08 (m, 1H) 8.58 (d, J = 5.78 Hz, 1H) 9.32 (t, J = 9.17 Hz, 1H) 9.70 (d, J = 7.61 Hz, 1H). Method 3: Rt = 3.73 min; m / z = 646, 24 (M+H) + .

[0429] Example E30: (R)-8'-Chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E30)

[0430]

[0431] Prepared analogously to that described for compound E3 starting from E7 to give E30 (1.52 mg, 0.002 mmol, y = 9%). 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.25-1.33(m,3H)1.44-1.73(m,3H)1.99-2.19(m,2H)3.00-3.23(m,1H)3 .28-3.45(m,1H)3.45-3.62(m,1H)3.81(s,3H)4.01-4.17(m,1H)4.43(s, 2H)4.55-4.74(m,1H)7.39(t,J=9.03Hz,1H)7.56-7.69(m,1H)7.94(dd,J =6.79, 2.57Hz, 1H) 8.21 (s, 1H) 9.32 (dd, J = 8.85, 4.54Hz, 1H) 9.57 (s, 1H). Method 3: Rt = 3.80 min; m / z = 644.28 (M+H) + .

[0432] Example E31: (R)-8'-Chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E31)

[0433]

[0434] Prepared analogously to that described for compound E3 starting from E9 to give E31 (0.6 mg, 0.001 mmol, y = 6%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (dd, J = 6.97, 2.38 Hz, 3H) 3.82 (d, J = 1.47 Hz, 3H) 4.01-4.24 (m, 2H) 4.45-4.82 (m, 5H) 7.38 (t, J = 9.08 Hz, 1H) 7.62-7.74 (m, 1H) 7.91-8.01 (m, 1H) 9.01 (d, J = 5.04 Hz, 1H) 9.27 (t, J = 9.26 Hz, 1H) 9.59 (d, J = 5.23 Hz, 1H). Method 3: Rt = 3.90 min; m / z = 616, 19 (M+H) + .

[0435] Example E32: (R)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E32)

[0436]

[0437] Prepared analogously to what was described for compound E3 starting from E10 to give E32 (0.47 mg, 0.001 mmol, y = 3%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.31 (dd, J = 7.01, 2.61 Hz, 3H) 3.77-3.87 (m, 3H) 4.01-4.23 (m, 2H) 4.46-4.80 (m, 5H) 6.97-7.43 (m, 2H) 7.76-7.91 (m, 1H) 8.02 (br d, J = 4.95 Hz, 1H) 9.01 (d, J = 5.04 Hz, 1H) 9.27 (t, J = 8.94 Hz, 1H) 9.67 (d, J = 5.13 Hz, 1H). Method 3: Rt = 3.74 min; m / z = 632, 5 (M+H) + .

[0438] Example E33: (R)-8'-Chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E33)

[0439]

[0440] Prepared analogously to that described for compound E3 starting from E4 to give E33 (4 mg, 0.006 mmol, y = 14%). 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.31 (dd, J = 6.83, 5.27 Hz, 3H) 1.97-2.38 (m, 2H) 3.42-4.16 (m, 7H) 4.44-4.75 (m, 3H) 7.41 (t, J = 9.12 Hz, 1H) 7.64 (ddd, J = 9.06, 4.29, 2.61 Hz, 1H) 7.95 (dt, J = 6.79, 2.48 Hz, 1H) 8.61 (d, J = 12.20 Hz, 1H) 9.30 (dd, J = 13.57, 8.99 Hz, 1H) 9.62 (s, 1H). Method 3: Rt = 3.88 min; m / z = 630, 2 (M+H) + .

[0441] Example E34: (R)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E34)

[0442]

[0443] Prepared analogously to that described for compound E3 starting from E6 to give E34 (2.75 mg, 0.001 mmol, y = 16%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (dd, J = 6.74, 5.36 Hz, 3H) 2.07-2.35 (m, 2H) 3.39-4.18 (m, 7H) 4.33-4.83 (m, 3H) 6.91-7.48 (m, 2H) 7.72-7.88 (m, 1H) 8.00 (br d, J = 6.14 Hz, 1H) 8.60 (d, J = 12.01 Hz, 1H) 9.29 (dd, J = 14.08, 9.03 Hz, 1H) 9.69 (s, 1H). Method 3: Rt = 3.73 min; m / z = 646, 3 (M+H) + .

[0444] Example E35: (R)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E35)

[0445]

[0446] Prepared analogously to compound E3 starting from E8 to give E35 (1.6 mg, 0.002 mmol, y = 11%). 1 H NMR(300MHz,DMSO-d6+TFA)δppm 1.25-1.35(m,3H)1.43-1.73(m,2H)1.99-2.17(m,2H)2.99-3.19(m,1H)3.28- 3.45(m,1H)3.45-3.61(m,1H)3.81(s,3H)3.99-4.20(m,1H)4.42(s,2H)4.55- 4.75 (m, 1H) 7.22 (t, J = 54.00 Hz, 1H) 7.32-7.38 (m, 1H) 7.74-7.87 (m, 1H) 7.99 (dd, J = 6.24, 2.29 Hz, 1H) 8.21 (s, 1H) 9.32 (dd, J = 8.89, 4.49 Hz, 1H) 9.64 (s, 1H). Method 3: Rt = 3.65 min; m / z = 660.41 (M+H) + .

[0447] Example E36: N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E36)

[0448]

[0449] The compound was prepared from D2 as described for the synthesis of E1, using D20 instead of D4. NMR: 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.22-1.39 (m, 3H) 1.92-2.40 (m, 2H) 3.44-4.18 (m, 7H) 4.40-4.72 (m, 3H) 7.30-7.57 (m, 3H) 7.75-7.92 (m, 1H) 8.29 (m, 1H) 9.21-9.37 (m, 1H) 9.44 (br dd, J = 8.16, 2.84 Hz, 1H). Method 3: Rt = 3.54 min; m / z = 580.32 (M+H) + .

[0450] Example E37: 8'-Chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-Carboxamide 1',1'-dioxide (E37)

[0451]

[0452] Compound E36 was prepared using the same procedure described for the synthesis of E3. 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.25-1.40 (m, 3H) 1.89-2.38 (m, 2H) 3.38-4.18 (m, 7H) 4.37-4.80 (m, 3H) 7.25-7.55 (m, 2H) 7.66-7.95 (m, 1H) 8.48-8.67 (m, 1H) 9.14-9.40 (m, 1H) 9.64 (t, J = 3.94 Hz, 1H). Method 3: Rt = 3.74 min; m / z = 614.22 (M+H) + .

[0453] biology

[0454] test

[0455] Cells and culture conditions

[0456] 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 ( Serial No.: HB-8065 TM ) subclones expressing the HBV genome 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, whereas its removal initiates 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, 0.4 mg / ml G418, and 0.3 μg / ml tetracycline. For HBV inhibition assays, doxycycline-free medium was used to allow virion production.

[0457] In vitro anti-HBV activity

[0458] 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 (in triplicate). 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).

[0459] In more detail, compounds usually dissolved in DMSO stock solution were diluted in 100 μl of the above culture medium (without doxycycline) to twice the final desired concentration and plated in triplicate in 96-well plates.

[0460] At the same time, HepAD38 cells—extensively prewashed in doxycycline-free medium to induce HBV production—were cultured at 2 × 10 4 Cells were 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 of DMSO - used for stock solutions and compound dilutions - always present at a final concentration of 0.5% in the assay.

[0461] The plates were then incubated at 37°C for 96 hours, followed by cell viability assays and extracellular HBV quantification to assess the cytotoxic potential and antiviral activity of the compounds. 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). 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 the 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 amplified by real-time PCR 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)).

[0462] The antiviral activity data for each compound were reported as EC 50 Values (see Table 1). Excel and Graphpad Prism programs are commonly used for data refinement and EC 50 calculate.

[0463] result

[0464] Exemplary compounds described herein were tested in the assays described above. 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 compound potency).

[0465] The results of HBV inhibition are reported in Table 1 below.

[0466] Table 1 - HBV inhibition by compounds of the invention

[0467]

[0468]

[0469]

[0470] Sequence Listing <110> Promidis Srl Ospedale San Raffaele Srl National Institute of Molecular Genetics (INGM) (Istituto Nazionale di Genetica Molecolare -INGM) IRBM SPA <120> Spirocyclic inhibitors of hepatitis B virus <130> PCT 146332 <160> 2 <170> PatentIn version 3.5 <210> 1 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> Synthetic primers <400> 1 atttgttcag tggttcgtag gg 22 <210> 2 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> Synthetic primers <400> 2 cggtaaaaag ggactcaaga tg 22

Claims

1. A compound of general formula (I): in: Cy is phenyl; m and n are each independently 1 or 2; R1 is H or Cl; R2 is selected from: Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, halogen, methyl, CN, CHF2 and CF3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, Cl, F, methyl and CHF2, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein: m is 1, n is 2 and R1 is H or Cl; or m is 2, n is 2 and R1 is H or Cl; or m is 1, n is 1 and R1 is H or Cl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein: express or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is selected from the following list: -N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -8'-chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(S)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-Chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[azetidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-chloro-N-(3-chloro-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-(((R)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -(R)-8'-Chloro-N-(3-(difluoromethyl)-4-fluorophenyl)-7'-methyl-1-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[piperidin-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; -N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide; and -8'-chloro-N-(3,4-difluorophenyl)-7'-methyl-1-(2-oxo-2-(((S)-1,1,1-trifluoropropan-2-yl)amino)acetyl)-2'H,4'H,7'H-spiro[pyrrolidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine ]-6'-carboxamide 1',1'-dioxide, or a pharmaceutically acceptable salt thereof.

6. Use of a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing HBV infection and / or conditions associated with HBV infection, wherein the conditions associated with HBV infection are selected from the group consisting of chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection.

7. Use of a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament 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 prophylactically treating HBV infection in an individual with latent HBV infection.

8. The use according to claim 6 or 7, wherein: The use is in combination with at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is selected from the following group: therapeutic vaccines; RNA interference antisense oligonucleotides; immunomodulators; STING agonists; RIG-I regulators; NKT regulators; IL agonists; interleukins or other immune-affecting proteins; immune checkpoint regulators / inhibitors; HBV entry inhibitors; cccDNA regulators; HBV protein expression inhibitors; substances targeting HBV RNA; capsid assembly inhibitors / regulators; 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 destabilizer; or a combination thereof, wherein 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), REP-9AC (REP-2055), REP-9AC' (REP-2139), REP-2165 and HBV-0259.

9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient, wherein the at least one additional therapeutic agent is selected from the group consisting of a therapeutic vaccine; an RNA interference antisense oligonucleotide; an immunomodulator; a STING agonist; a RIG-I modulator; a NKT modulator; an IL agonist; an interleukin or other immune-affecting protein; an immune checkpoint regulator / inhibitor; an HBV entry inhibitor; a cccDNA regulator; an HBV protein expression inhibitor; a substance targeting HBV RNA; a capsid assembly inhibitor / regulator; a core or X protein targeting agent; a nucleotide analog; a nucleoside analog; an interferon or modified interferon; an HBV antiviral agent of a different or unknown mechanism; a cyclophilin inhibitor; an sAg release inhibitor; an HBV polymerase inhibitor; a dinucleotide; a SMAC inhibitor; an HDV targeting agent; a viral maturation inhibitor; a reverse transcriptase inhibitor; and an HBV RNA destabilizer; or a combination thereof, wherein 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), REP-9AC (REP-2055), REP-9AC' (REP-2139), REP-2165 and HBV-0259.

10. Use of the pharmaceutical composition as defined in claim 9 in the preparation of a medicament for treating and / or preventing HBV infection and / or conditions associated with HBV infection, wherein the conditions associated with HBV infection are selected from the group consisting of chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, liver decompensation and liver damage caused by HBV infection.

11. Use of a pharmaceutical composition as defined in claim 9 in the preparation of a medicament for the treatment, eradication, reduction, slowing or inhibition of 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.

12. A method for synthesizing a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, the method comprising at least one of the following steps: - reacting a compound of formula (6) with a reagent selected from the group consisting of a compound of formula (9), an acid of formula R2COOH and an acid chloride of formula R2COCl; - reacting a compound of formula (7) or (8) with an amine of formula NHR3R4; The method optionally further comprises at least one of the following steps: - reacting the compound of formula (6) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (7); - hydrolyzing the compound of formula (7) in the presence of a base to obtain the compound of formula (8).

Images