Spirocyclic inhibitors of hepatitis B virus

Abstract

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

Description

Technical Field

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

Background Art

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

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

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

[0005] Vaccines that induce neutralizing antibodies against HBsAg and exhibit good tolerability can effectively prevent new HBV infections, but they have no therapeutic potential for the millions of people who are already persistently infected (Zoulim, Durantel D; Cold Spring Harb Perspect Med. April 1, 2015;5(4)). The treatment of these individuals mainly relies on direct-acting antiviral (DAA) drugs (such as tenofovir, lamivudine, adefovir, entecavir, or telbivudine) that suppress virus production but do not eradicate HBV from the liver and require lifelong treatment. Patient cohorts still receive treatment based on pegylated interferon-α (PEG-IFN-α), which has the advantages of a limited treatment period and a higher HBsAg seroconversion rate but has the significant drawback of greater side effects. Therefore, the number of patients receiving PEG-IFN-α is gradually decreasing.

[0006] Inhibitors of various chemical classes (also called capsid assembly modulators or CAMs) that target the HBV capsid formation process are under development, including heteroaryldihydropyrimidines (HAP) and sulfamoylbenzamides (SBA). For example, Novira Therapeutics recently demonstrated in a humanized mouse model of HBV infection that the combination of CAM and PEG-IFN-α has higher antiviral activity than that previously observed using DAA. NVR3-778, the first member of this class of CAMs, showed a significant reduction in both HBV DNA and serum HBV RNA in a phase 1b proof-of-concept clinical study. This compound was recently discontinued. The compound JNJ-56136379 (or JNJ-6379) developed by Janssen recently demonstrated potent antiviral activity and is currently in a phase 2 clinical trial.

[0007] WO2017 / 001655A1, published on January 5, 2017, has the structure:

[0008]

Chemical formula

[0009] Relates to a cyclic sulfamoyl arylamide derivative having

[0010] The compounds disclosed in WO2017 / 001655A1 include 3,4-dihydro-2H,7H-pyrrolo[3,4-b][1,4,5]oxathiazepine 1,1-dioxide derivatives substituted at the 6-position by N-phenyl-carboxamide. Some of the derivatives disclosed herein have a spiro-fused oxetane, tetrahydrofuran or pyrroline ring. WO2017 / 001655A1 does not disclose or suggest compounds in which the spiro-fused ring is further functionalized with an amide group or an oxalamide group.

[0011] Among the problems that may be encountered by HBV direct-acting antiviral agents are toxicity, mutagenicity, lack of selectivity, insufficient efficacy, insufficient bioavailability, low solubility and / or off-target activity, and to date, there are no compounds approved as drugs for the treatment of HBV patients in any of the structural classes identified above.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Non-Patent Documents

[0013]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

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Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

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Summary of the Invention

Problems to be Solved by the Invention

[0014] There is a need for further HBV inhibitors that can overcome at least one of these drawbacks or have additional advantages such as increased potency, increased bioavailability, or an increased safety window.

Means for Solving the Problems

[0015] The present invention provides small molecule drugs obtained by chemical modification of known sulfamoylaryl amide derivatives. In particular, the compounds of the present invention are characterized by a tricyclic core structure containing a pyrrole ring and having an amide or oxalamide substituent at a specific position of the fused tricyclic core. The chemical species discovered in the present invention result in extremely potent HBV inhibitors having improved pharmacokinetic properties, good kinetic solubility, stability in mouse and human hepatocytes, low in vivo clearance, and a positive liver-to-plasma concentration. Considering the important role of the liver in metabolic regulation and the fact that it is the major tissue affected by hepatitis B disease, designing HBV inhibitors with a liver-selective distribution profile is an important strategy in the development of safe drug candidates (Tu M. et al., Current Topics in Medicinal Chemistry, 2013, 13, 857-866).

Modes for Carrying Out the Invention

[0016] The compounds of the present invention are inhibitors of hepatitis B virus (HBV).

[0017] Therefore, the object of the present invention is the general formula (I):

[0018]

Chemical formula

[0019] [wherein, Cy is aryl or heteroaryl, each of m and n is independently 1 or 2, R1 is H, F, Br, Cl or CH3, R2 is - OH, halogen, CN, C 1~6 alkyl, hydroxyC 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 a 5- or 6-membered heteroaryl ring optionally substituted with one or more substituents independently selected from the group consisting of alkoxy and NH2, - haloC 1~4 alkyl, and - C(=O)NR3R4 selected from the group consisting of each of R3 and R4 is - hydrogen - C 1~3 alkyl - haloC 1~4 alkyl, and - C 3~5 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of methyl, F, Cl, CHF2 and CF3, independently selected from the group consisting of 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 said cyclic amines optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine, CHF2 and CF3, Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, halogen, methyl, CN, CHF2 and CF3] and is a compound represented by the formula or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0020] The embodiments disclosed below in this specification can be combined with each other in any possible way that results in a stable compound. All such combinations are within the scope of the present invention.

[0021] In a preferred embodiment, R2 is a 5-membered heteroaryl ring optionally substituted with one or more substituents each independently selected from the group consisting of -OH, halogen, CN, methyl and trifluoromethyl, or -C(=O)NR3R4, where R3 is H and R4 is C 1~3 alkyl, haloC 1~4 alkyl, and C 3~5 cycloalkyl, each optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine and CF3, 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 optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine and CF3.

[0022] In a preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, Cl, F, methyl and CHF2.

[0023] 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.

[0024] In yet another preferred embodiment, R1 is H or Cl. Preferably, m is 1 and n is 2, and R1 is H or Cl. Preferably, m is 2 and n is 2, and R1 is H or Cl. Preferably, m is 1 and n is 1, and R1 is H or Cl.

[0025] In a more preferred embodiment, Cy is phenyl. Preferably, Cy is phenyl, and any two of Ra to Rd are independently F, Cl or CHF2, and the other two of Ra to Rd are H.

[0026] In an even more preferred embodiment,

[0027]

Chemical formula

[0028] represents

[0029]

Chemical formula

[0030] represents.

[0031] In another preferred embodiment, R2 is

[0032]

Chemical formula

[0033] is.

[0034] Preferably, the compound of the present invention is - 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; - 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; - 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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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; - 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; - (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; - 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; - (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[piperidine-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[piperidine-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 selected from the group consisting of, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0035] Next, the present invention also relates to formula (I-A), (I-B) and / or (I-C):

[0036]

Chemical formula

[0037] To provide a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, all substituents being as defined above.

[0038] Preferably, in the compound of formula (I-A), (I-B) or (I-C), R1 is Cl or H, and / or in the compound of formula (I-A), (I-B) or (I-C), R2 is -C(=O)NR3R4.

[0039] Preferably, the compounds of the present invention are of formula (I-AA), (I-AB) or (I-AC):

[0040]

Chemical formula

[0041] [wherein, R1 is H or Cl, R2 is a 5- or 6-membered heteroaryl ring optionally substituted with one or more substituents independently selected from the group consisting of -OH, halogen, CN, methyl, trifluormethyl, or -C(=O)NR3R4 and each of R3 and R4 is - hydrogen, - methyl, - haloC 1~4 alkyl, and - C 3~5 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluorine and CF3 independently selected from the group consisting of, 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] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0042] Any further combination of any of the embodiments is also envisaged to be within the scope of the present invention.

[0043] In a preferred embodiment, 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, hepatic decompensation and liver injury resulting from HBV infection.

[0044] Even more preferably, the compound, its pharmaceutically acceptable salt, solvate or stereoisomer as defined above is for use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury resulting from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from potential HBV infection.

[0045] Preferred compounds show HBV inhibition in excess of 50% at test concentrations (in the range of 1.0 micromolar to 0.1 micromolar) and / or an EC 50 as defined below in the present specification of less than 0.5 micromolar. HBV inhibition indicates inhibition of HBV expression and / or replication. The inhibitory activity of the compounds of the present invention can be measured as described below in the present specification or by any other technique known in the art.

[0046] Preferably, the compounds, pharmaceutically acceptable salts, solvates or stereoisomers as defined above are for use in combination with at least one further therapeutic agent. Preferably, use in said combination comprises administration of at least one further therapeutic agent.

[0047] An object of the present invention is also a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above, alone or in combination with at least one further therapeutic agent and at least one pharmaceutically acceptable excipient.

[0048] Preferably, at least one further therapeutic agent is an anti-HBV agent or an HBV antiviral agent. More preferably, at least one further therapeutic agent, anti-HBV agent or HBV antiviral agent is selected from the group consisting of therapeutic vaccines, RNA interference therapeutic agents / antisense oligonucleotides, immunomodulators, STING agonists, RIG-I modulators, NKT modulators, IL agonists, interleukins or other immunomodulatory proteins, therapeutic and prophylactic vaccines, immune checkpoint modulators / inhibitors, HBV entry inhibitors, cccDNA modulators, inhibitors of HBV protein expression, agents targeting HBV RNA, capsid assembly inhibitors / modulators, core or X protein targeting agents, nucleotide analogs, nucleoside analogs, interferons or modified interferons, HBV antiviral agents of distinct or unknown mechanisms, cyclophilin inhibitors, sAg release inhibitors, HBV polymerase inhibitors, dinucleotides, SMAC inhibitors, HDV targeting agents, viral maturation inhibitors, reverse transcriptase inhibitors, and HBV RNA destabilizing agents or other small molecule inhibitors of HBV protein expression, or combinations thereof.

[0049] Preferably, the therapeutic vaccine is selected from HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (also known as HB-110E), CVI-HBV-002, RG7944 (also known as INO-1800), TG-1050, FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204, NU-500, INX-102-00557, HBV MVA, and PepTcell.

[0050] 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.

[0051] Preferably, the immunomodulatory substance is a TLR agonist. Preferably, the TLR agonist is a TLR7, TLR8, or TLR9 agonist. Preferably, the TLR7, TLR8, or TLR9 agonist is selected from RG7795 (also known as RO-6864018), GS-9620, SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate), and ARB-1598.

[0052] Preferably, the RIG-I modulator is SB-9200. Preferably, the IL agonist or other immunomodulatory protein is INO-9112 or recombinant IL12. Preferably, the immune checkpoint modulator / inhibitor is BMS-936558 (Opdivo (nivolumab)) or KEYTRUDA® (pembrolizumab). Preferably, the HBV entry inhibitor is Myrcludex B, IVIG-Tonrol or GC-1102.

[0053] Preferably, the cccDNA modulator is selected from direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, and inhibitors of cccDNA transcription.

[0054] 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 BAY 41-4109, NVR 3-778, GLS-4, NZ-4 (also known as W28F), Y101, ARB-423, ARB-199, ARB-596, AB-506, JNJ-56136379, ASMB-101 (AB-V102), ASMB-103, CHR-101, CC-31326, AT-130, and RO7049389.

[0055] Preferably, the interferon or modified interferon is selected from interferon alpha (IFN-α), pegylated interferon alpha (PEG-IFN-α), interferon alpha-2a, recombinant interferon alpha-2a, peginterferon alpha-2a (Pegasys), interferon alpha-2b (Intron A), recombinant interferon alpha-2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta-1a, peginterferon beta-1a, interferon delta, interferon lambda (IFN-λ), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-γ), interferon alphacon-1, interferon alpha-n1, interferon alpha-n3, albumin interferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG-infergen, Belerofon, INTEFEN-IFN, albumin / interferon alpha2a fusion protein, rHSA-IFN alpha2a, rHSA-IFN alpha2b, PEG-IFN-SA and interferon alpha biobetter. Peginterferon alpha-2a, peginterferon alpha-2b, glycosylated interferon alpha-2b, peginterferon beta-1a and peginterferon lambda-1 are particularly preferred. More specifically, peginterferon alpha-2a is preferred.

[0056] Preferably, the HBV antiviral agent of a distinct or unknown mechanism is selected from AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), its analogs, REP-9AC (REP-2055), REP-9AC' (REP-2139), REP-2165, and HBV-0259.

[0057] Preferably, the cyclophilin inhibitor is selected from OCB-030 (also known as NVP-018), SCY-635, SCY-575, and CPI-431-32.

[0058] Preferably, the HBV polymerase inhibitor is selected from entecavir (Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevudine, besifovir, adefovir (hepsera), and tenofovir. Preferably, tenofovir is in a salt form. Preferably, tenofovir is tenofovir disoproxil fumarate (Viread), tenofovir alafenamide fumarate (TAF), tenofovir disoproxil orotate (also known as DA-2802), tenofovir disoproxil aspartate (also known as CKD-390), AGX-1009, and a salt form selected from CMX157.

[0059] Preferably, the dinucleotide is SB9200. Preferably, the SMAC inhibitor is birinapant. Preferably, the HDV targeting agent is lonafarnib.

[0060] Preferably, the HBV RNA destabilizer or other small molecule inhibitor of HBV protein expression is RG7834 or AB-452.

[0061] Preferably, at least one further therapeutic agent is a drug useful in the treatment and prevention of hepatitis B. Preferably, at least one further therapeutic agent is an anti-HDV agent, an anti-HCV agent, and / or an anti-HIV agent.

[0062] Preferably, at least one further therapeutic agent is selected from the group consisting of HBV polymerase inhibitors, interferons, virus entry inhibitors, BAY 41-4109, reverse transcriptase inhibitors, TLR-agonists, AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and combinations thereof, and the HBV polymerase inhibitor is preferably at least one of lamivudine, entecavir, tenofovir, adefovir, telbivudine, clevudine, and the TLR agonist is preferably selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate), and combinations thereof.

[0063] Preferably, the compounds of the present invention are for use in combination with one, two, or more further therapeutic agents as defined above.

[0064] Preferably, the pharmaceutical composition of the present invention comprises one, two, or more further therapeutic agents as defined above.

[0065] The preferred embodiment is that the pharmaceutical composition is for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection, and the conditions associated with HBV infection are preferably selected from the group consisting of chronic hepatitis B, HBV / HDV co-infection, HBV / HCV co-infection, HBV / HIV co-infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and liver injury resulting from HBV infection. Preferably, the pharmaceutical composition is for use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of the viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of the recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury resulting from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from latent HBV infection.

[0066] In one embodiment, the present invention provides a kit comprising at least one pharmaceutically acceptable vial or container containing one or more doses of a compound of the present invention or a pharmaceutical composition of the present invention, and optionally a) instructions for use thereof in mammals and / or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

[0067] A further object of the present invention is a method for treating, alleviating 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, hepatic decompensation and liver injury resulting from HBV infection, the method comprising administering to a subject a therapeutically effective amount of a compound as defined above.

[0068] A further 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 synthetic schemes included in the examples. In particular, the present invention provides a method for synthesizing a compound, pharmaceutically acceptable salt, solvate or stereoisomer as defined above, the method comprising the following steps:

[0069] [Chemical formula]

[0070] - A step of reacting the compound of formula (6) with a drug selected from the group consisting of the compound of formula (9), the acid of formula R2COOH, and the acyl chloride of formula R2COCl

[0071] [Chemical formula]

[0072] - A step of reacting the compound of formula (7) or (8) with the amine of formula NHR3R4 includes at least one of The method includes the following steps: - A step of reacting the compound of formula (6) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (7) - A step of hydrolyzing the compound of formula (7) in the presence of a base to obtain the compound of formula (8) may further include at least one of

[0073] The step of reacting the compound of formula (6) with the compound 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 RT.

[0074] The step of reacting 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, pp. 606-631).

[0075] The step of reacting the compound of formula (6) with an acyl chloride of formula R2COCl can be carried out under standard conditions, for example, in a polar aprotic solvent (e.g., MeCN), and / or in the presence of an organic base (e.g., TEA), and / or at a temperature of 0 °C to room temperature.

[0076] The step of reacting the 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 at a high temperature in a solvent such as THF.

[0077] The compounds of formula (6), (7) or (8) can be prepared as described in the synthetic schemes of the examples.

[0078] In particular, the step of reacting 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 (e.g., MeCN), and / or in the presence of an organic base (e.g., DIPEA), and / or at 0 °C to RT.

[0079] Also in particular, the step of hydrolyzing the compound of formula (7) in the presence of a base to obtain the compound 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 (e.g., THF), and / or at 0 °C to RT.

[0080] A further object of the present invention is a pharmaceutical composition comprising an effective amount of a compound as defined above in one or more or a pharmaceutically acceptable prodrug thereof, alone or in combination with other active compounds and at least one pharmaceutically acceptable excipient.

[0081] The present invention includes within its scope prodrugs of the compounds of formula (I), formula (I-A) or formula (I-AA) above. Generally, such prodrugs are functional derivatives of the compounds of formula (I), formula (I-A) or formula (I-AA) and are readily convertible in vivo to the required compounds of formula (I), formula (I-A) or formula (I-AA). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", H. Bundgaard, edited by Elsevier, 1985.

[0082] A prodrug can be a pharmacologically inactive derivative of a bioactive substance ("parent drug" or "parent molecule") that requires transformation in the body to release the active drug and has improved delivery properties over the parent drug molecule. The in vivo transformation can be the result of several metabolic processes such as chemical or enzymatic hydrolysis of carboxylic acids, phosphates or sulfate esters or reduction or oxidation of sensitive functional groups.

[0083] The present invention also includes all suitable isotope variations of the compounds of the present disclosure. Examples of isotopes that can be incorporated into the compounds of the present disclosure include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F and 36 Cl and the like. Certain isotope variations of the present disclosure, for example, 3 H or 14 C and the like incorporating radioactive isotopes are useful in drug and / or substrate tissue distribution studies. Further, deuterium 2Substitutions using isotopes such as H can provide certain therapeutic advantages resulting from greater metabolic stability. Isotope variations of the compounds of the present disclosure can generally be prepared herein by conventional procedures such as by exemplary methods or by the preparations described in the Examples below using appropriate isotope variations of suitable reagents.

[0084] The present invention includes within its scope solvates, such as hydrates, alcoholates, etc., of compounds of formula (I), formula (I-A) or formula (I-AA), or related salts.

[0085] Furthermore, the compounds disclosed herein may exist as tautomers, and all tautomeric forms are to be included within the scope of the present invention even if only one tautomeric structure is shown.

[0086] The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (as described in E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and occur as racemic compounds, racemic mixtures, and as individual diastereomers, having all possible isomers, including optical isomers, and mixtures thereof, and all such stereoisomers are included in the present invention.

[0087] Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by applying procedures known in the art and are intended to be encompassed by the scope of the present invention. In particular, "pure stereoisomeric form" or "stereoisomerically pure" refers to a compound that is at least 80%, preferably at least 85% stereoisomerically in excess. For example, enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts or by chromatographic techniques using a chiral stationary phase. Pure stereoisomeric isomeric forms can also be derived from the corresponding pure stereoisomeric isomeric forms of the appropriate starting materials, provided that the reactants are stereoisomerically generated. The term "enantiomerically pure" should be interpreted similarly taking into account the enantiomer ratio.

[0088] If any variable (e.g., R1 and R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of all other occurrences. Also, substitutions and combinations of variables are only acceptable if such combinations result in stable compounds. A line drawn from a substituent into a ring structure indicates that the indicated bond may be attached to any of the ring atoms that can be substituted. When the ring structure is polycyclic, it is intended that the bond be attached only to any suitable carbon atom of the proximal ring.

[0089] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art in order to provide compounds that are chemically stable from readily available starting materials and can be easily synthesized by techniques known in the art and the methods shown below. When a substituent is itself substituted with two or more groups, it is understood that these groups can be on the same carbon or on different carbons as long as a stable structure results. The phrase "optionally substituted" should be taken as equivalent to the phrase "unsubstituted or substituted with one or more substituents", and in such cases, preferred embodiments have 0 to 3 substituents. More specifically, there are 0 to 2 substituents.

[0090] The expression "one or more substituents" particularly refers to 1, 2, 3, 4 or more substituents, particularly 1, 2, 3 or 4 substituents, more particularly 1, 2 or 3 substituents.

[0091] As used herein, "alkyl" shall include 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 or 6 carbons in a straight-chain or branched arrangement, specifically including methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, etc. Preferably, "C 1~6 alkyl" refers to "C 1~4 alkyl" or "C 1~3 alkyl". More preferably, "C 1~6 alkyl" or "C 1~3 alkyl" refers to methyl.

[0092] As used herein, "alkoxy" represents an alkyl group of the indicated number of carbon atoms bonded by an oxygen bridge. "Alkoxy" thus encompasses the above definition of alkyl. Preferably, alkoxy is a straight-chain or branched C 1~6 alkoxy group, C 1~4 alkoxy group, C 1~3 alkoxy group, or C 1~2 alkoxy group. Examples of suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy or t-butoxy. Preferred alkoxy groups include methoxy, ethoxy and t-butoxy.

[0093] As used herein, the terms "haloC 1~6 alkyl" and "haloC 1~6 alkoxy" mean a C 1~6 alkyl or C 1~6 alkoxy group in which one or more (particularly 1 - 3) hydrogen atoms are replaced by halogen atoms, particularly fluorine or chlorine atoms. HaloC1~6 The alkoxy group is preferably a linear or branched halo C 1~4 alkoxy group, more preferably a halo C 1~3 alkoxy group, even more preferably a halo C 1~2 alkoxy group, for example, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most preferably, OCF3 or OCHF2. The halo C 1~6 alkyl group is preferably a linear or branched halo C 1~4 alkyl group, more preferably a halo C 1~3 alkyl group, even more preferably a halo C 1~2 alkyl group, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 or CH(CH3)CF3. Even more preferably, a halo C 1~6 alkyl, halo C 1~4 alkyl group, halo C 1~3 Any one of the alkyl groups refers to CF3, CHF2, CH(CH3)CF3, CH2CF3 or (CH3)2CF3.

[0094] As used herein, the term "hydroxy C 1~6 alkyl" means a C 1~6 alkyl group in which one or more (especially 1 to 3) hydrogen atoms are replaced by hydroxy groups. Exemplary examples include, but are not limited to, CH2OH, CH2CH2OH, CH(CH3)OH and CHOHCH2OH.

[0095] As used herein, the term "aryl" means a monocyclic or polycyclic aromatic ring containing carbon and hydrogen atoms. When shown, such an aromatic ring may contain one or more heteroatoms and thus is also referred to as "heteroaryl". Exemplary examples of heteroaryl groups according to the present invention include 5- or 6-membered heteroaryl, such as thiophene, oxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine, and pyridine. Preferred aryl according to the present invention is phenyl. Preferred heteroaryl according to the present invention is pyridyl. More preferred 5-membered heteroaryl rings are oxadiazole and oxazole. The oxadiazole is preferably substituted with one methyl group.

[0096] As used herein, "C" 3~5 The term "cycloalkyl" means 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 may contain one or more heteroatoms (also referred to as "heterocyclyl" or "heterocyclic ring" or "heterocycloalkyl") such that at least one carbon atom is replaced by a heteroatom selected from N, O, and S, particularly from N and O. Preferably, the C 3~5 Cycloalkyl is cyclopropyl.

[0097] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine, among which fluorine, chlorine, and bromine are preferred. In particular, fluorine and chlorine are preferred for the halogen at positions Ra, Rb, Rc, or Rd. Also in particular, chlorine is preferred for the halogen at position R1. Even more particularly, fluorine is preferred for the halogen which is a substituent of C 3~5 Cycloalkyl or cyclic amine.

[0098] The term "heteroatom" refers to an atom other than carbon or hydrogen in a ring structure or saturated backbone as defined herein. Common heteroatoms include N(H), O, and S.

[0099] The free bases of the compounds of formula (I), (I-A) or (I-AA), as well as their pharmaceutically acceptable salts and stereoisomers, are included in the present invention. Some of the specific compounds exemplified herein are protonated salts of amine compounds. Compounds of formula (I), (I-A) or (I-AA) containing one or more N atoms can be protonated at any one, some or all of the N atoms. The term "free base" refers to an amine compound in non-salt form. The pharmaceutically acceptable salts included are not only the salts exemplified for the specific compounds described herein, but also the common pharmaceutically acceptable salts of the free forms of the compounds of formula (I), (I-A) or (I-AA). The free forms of the described specific salt compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treatment with a dilute aqueous base, such as dilute NaOH, potassium carbonate, ammonia and aqueous sodium bicarbonate. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the present invention.

[0100] The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of the present invention containing a basic or generating moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography in a suitable solvent or various combinations of solvents, or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base. In a preferred embodiment, the compounds of the present invention have at least one acidic proton and, for example, the corresponding sodium or potassium salts can be formed by reaction with a suitable base.

[0101] Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting 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 those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Further examples of conventional non-toxic salts include those prepared from inorganic bases such as potassium, sodium hydroxide, magnesium hydroxide or calcium, and those prepared from organic bases such as ethylenediamine, lysine, tromethamine, meglumine, etc. Preferably, the pharmaceutically acceptable salts of the present invention contain 1 equivalent of a compound of formula (I), formula (I-A) or formula (I-AA) and 1, 2 or 3 equivalents of an inorganic or organic acid or base. More specifically, pharmaceutically acceptable salts of the present invention include tartrate, trifluoroacetate or chloride salts.

[0102] When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include those containing aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, for example, arginine, betaine caffeine, choline, N,N 1-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like can be mentioned.

[0103] The preparation of the above-mentioned pharmaceutically acceptable salts and other ordinary pharmaceutically acceptable salts is fully described by Berg et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977: 66: 1-19.

[0104] Under physiological conditions, the deprotonated acidic moiety in the compound, for example, the carboxyl group may be anionic, and then this electronic charge may lose internal balance with respect to the cationic charge of the protonated or alkylated basic moiety, for example, the quaternary nitrogen atom. Therefore, it should also be noted that the compounds of the present invention are potentially internal salts or zwitterions.

[0105] The compounds of the present invention find use in various applications for the health of humans and animals. The compounds of the present invention are inhibitors of hepatitis B virus (HBV).

[0106] In the context of the present invention, HBV can be any known isolate, genotype, strain, etc. of HBV. In particular, hepatitis B virus is classified into eight main genotypes (named A - H), and two additional genotypes (I and J) have been tentatively proposed. HBV genotypes are further divided into several sub - genotypes that differ by 4.0 - 7.5% in the entire nucleotide sequence. HBV genotypes are substantially different in a number of virological and perhaps some clinical parameters, but the exact role of HBV genotypes in the evolution of infection remains a matter of debate. Due to geographical distribution, in most regions of the world, only two or three HBV genotypes co - circulate, thereby limiting genotype comparisons.

[0107] The compounds of the present invention are inhibitors of hepatitis B virus (HBV) that are useful for the treatment and / or prevention of HBV infection. In particular, the compounds of the present invention are inhibitors of hepatitis B virus (HBV) core (HBc) protein that are useful for the treatment and / or prevention of HBV infection.

[0108] The compounds, compositions and methods provided herein are thought to be particularly useful for the treatment, remission or prevention of HBV infection and related conditions, including chronic hepatitis B, HBV / HDV co - infection, HBV / HCV co - infection, HBV / HIV co - infection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation and liver injury resulting from HBV infection.

[0109] In the present invention, the expression "HBV infection" includes, but is not limited to, any and all conditions resulting from infection with HBV, including hepatitis B, preferably chronic hepatitis B, HBV / HDV co - infection, HBV / HCV co - infection, HBV / HIV co - infection.

[0110] HBV infection leads to a wide range of liver complications, all of which are intended as conditions associated with HBV infection. As used herein, "conditions associated with HBV infection" preferably includes hepatitis B, chronic hepatitis B, HBV / HDV coinfection, HBV / HCV coinfection, HBV / HIV coinfection, inflammation, necrosis, cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver injury resulting from HBV infection, and is selected from the group consisting of these.

[0111] Expressions such as "treating, eradicating, reducing, decelerating, or inhibiting HBV infection" are used to indicate the application or administration of a therapeutic agent, i.e., a compound of the present invention (alone or in combination with another pharmaceutical), to a patient having HBV infection, symptoms of HBV infection, or the potential to develop HBV infection, for the purpose of treating, curing, alleviating, mitigating, altering, remedying, improving, ameliorating, or affecting HBV infection, symptoms of HBV infection, or the potential to develop HBV infection, or the application or administration of a therapeutic agent to an excised tissue or cell line obtained from a patient (e.g., for diagnostic or ex vivo application). Such treatment can be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0112] The effectiveness of treatment can be determined by quantifying the viral load or using other evidence of infection, such as measurement of HBeAg, HBsAg, HBV DNA levels, ALT activity levels, serum HBV levels, etc., thereby enabling adjustment of the treatment dose, treatment frequency, and treatment duration.

[0113] HBeAg represents hepatitis B e-antigen. This antigen is a protein derived from the hepatitis B virus that circulates in the blood of an infected person when the virus is actively replicating.

[0114] ALT represents alanine transaminase, an enzyme involved in the transfer of an amino group from the amino acid alanine to alpha-ketoglutaric acid, producing glutamic acid and pyruvic acid. ALT is mainly localized in the liver and kidneys and is present in lesser amounts in the heart and skeletal muscles. ALT is generally clinically measured as part of liver function tests.

[0115] The compounds of the present invention can reduce the viral load in individuals suffering from HBV infection. In non-limiting embodiments, the compounds of the present invention can effect a reduction in viral load during treatment in an individual in need thereof, from a minimum of 1 or 2 log reduction to a maximum of about 8 log reduction.

[0116] As used herein, the expression "alleviation of liver injury from HBV infection" means that the chronic necroinflammatory liver disease has stopped due to the fact that the viral antigen has disappeared from the organ (and the immune system no longer attacks liver cells).

[0117] As used herein, the term "treating prophylactically" means, in the absence of anything occurring, the absence of the occurrence of a disorder or disease, or, in the presence of an already-occurring disorder or disease, the absence of further occurrence of a disorder or disease. Also considered is the ability to prevent some or all of the symptoms associated with the disorder or disease. An example of prophylactic treatment can also indicate the need to reduce the risk of infection of a liver graft (in the case of liver transplantation in a chronically infected patient) or of a neonate (in the case of a chronically infected mother infecting the virus during childbirth).

[0118] As used herein, "reducing the recurrence of HBV infection" means that a patient may have reactivation of HBV replication and conditions associated with HBV infection, such as exacerbation of hepatitis, after several years of quiescence. These patients may still be at risk of developing conditions associated with HBV infection, such as the development of hepatocellular carcinoma. Antiviral therapy is also recommended as prophylaxis for patients who are HBsAg-positive and for patients who are HBsAg-negative and hepatitis B core antibody-positive and who require treatment with immunosuppressive therapy and are predicted to have a moderate to high risk of HBV reactivation.

[0119] The compounds of the present invention can be administered to mammals, preferably humans, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including administration by intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes.

[0120] The present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing the active ingredient can be in forms suitable for oral use such as, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid, binding agents such as starch, gelatin, polyvinyl-pyrrolidone or gum arabic, and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble flavor masking materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose or time delay materials such as ethylcellulose, cellulose acetate butyrate can be used.

[0121] Preparations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein 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.

[0122] The aqueous suspension contains the active material in a mixture with excipients suitable for the manufacture of the aqueous suspension. Such excipients include anti-settling agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum and gum arabic, and the dispersing or wetting agents can 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 aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, 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 can also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0123] The oily suspension can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspension can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. To provide a palatable oral preparation, sweetening agents, such as those indicated above, and flavoring agents can be added. These compositions can be preserved by the addition of antioxidants, such as butylated hydroxyanisole or alpha-tocopherol.

[0124] Dispersants and granulating agents suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already described above. Further excipients, such as sweetening agents, flavoring agents and coloring agents, may also be present. These compositions can be preserved by the addition of antioxidants, such as ascorbic acid.

[0125] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents can be naturally occurring phosphatides, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0126] Syrups and elixirs can be formulated using sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain demulcents, preservatives, flavoring agents, coloring agents and antioxidants.

[0127] The pharmaceutical composition can be in the form of a sterile aqueous solution for injection. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.

[0128] The sterile injectable preparation can also be a sterile oil-in-water microemulsion for injection in which the active ingredient is dissolved in the oily phase. For example, the active ingredient can first be dissolved in a mixture of soybean oil and lecithin. The oil solution is then placed in a mixture of water and glycerol and treated to form a microemulsion.

[0129] By local bolus injection, an injectable solution or microemulsion can be placed into the patient's bloodstream. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a certain circulating concentration of the compound. To maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is the Deltec CADD-PLUS (trademark) Model 5400 intravenous pump.

[0130] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension can be formulated according to known techniques using the suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Further, sterile hardened oils are conventionally used as the solvent or suspension medium. For this purpose, any sterile hardened oil containing synthetic mono- or diglycerides can be used. Further, fatty acids, such as oleic acid, are useful in the preparation of injectable substances.

[0131] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Examples of such materials include cocoa butter, glycerinated gelatin, hardened vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0132] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. (For the purposes of this application, topical application must include mouse washes and gargles)

[0133] The compounds of the present invention can be administered intranasally by topical use of a suitable intranasal vehicle and delivery device, or by a transdermal route using a transdermal skin patch well known to those skilled in the art in the form of an intranasal form. For administration in the form of a transdermal delivery system, of course, the dosage administered will be more continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention can also be delivered as suppositories using bases such as cocoa butter, glycerinated gelatin, hardened vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0134] The compounds of the present invention can be presented in liposomes or other microparticles or other nanoparticles designed to target the compound. Acceptable liposomes can be neutral, negatively charged, or positively charged, and the charge is a function of the charge of the liposome components and the pH of the liposome solution. Liposomes can generally be prepared using a mixture of phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol. Polyethylene glycol can be added to improve the blood circulation time of liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

[0135] When the compounds of the present invention are administered in a human subject, the daily dosage is generally determined by the prescribing physician and will generally vary according to age, weight, sex and the individual patient's response and the severity of the patient's symptoms.

[0136] In one exemplary application, a suitable amount of the compound is administered to a mammal undergoing anti-HBV treatment. The administration generally occurs at an amount between about 0.01 mg / kg body weight to about 100 mg / kg body weight per day, preferably between about 0.01 mg / kg body weight to about 60 mg / kg body weight per day, preferably between about 0.1 mg / kg body weight to about 50 mg / kg body weight per day, preferably between about 0.5 mg / kg body weight to about 40 mg / kg body weight per day.

[0137] The compound is also useful in combination with known therapeutic agents for simultaneous, separate or sequential administration.

[0138] In one embodiment, the compounds of the invention can be used in combination with at least one or more additional therapeutic agents, particularly anti-HBV agents.

[0139] Showing that the compounds of the invention are for use in the treatment and / or prevention of HBV infection indicates that the compounds are effective for the treatment, eradication, reduction, deceleration or inhibition of HBV infection.

[0140] The therapeutic agent is any agent commonly used in the treatment and / or prevention and / or remission of HBV infection or conditions associated with HBV infection. Therapeutic agents are known in the art.

[0141] The term "anti-HBV agent" or more simply "HBV antiviral agent" also includes compounds that are therapeutic nucleic acids, antibodies or proteins, either in their native form or chemically modified and / or stabilized. Since hepatitis B virus (HBV) strains can be resistant to at least one anti-HBV agent, it is also defined as "drug resistance". The term therapeutic nucleic acid includes, but is not limited to, nucleotides and nucleosides, oligonucleotides, polynucleotides, non-limiting examples of which include antisense oligonucleotides, miRNAs, siRNAs, shRNAs, therapeutic vectors and DNA / RNA editing components.

[0142] The term "anti-HBV agent" also includes compounds that can treat HBV infection by immunomodulation, i.e., immunomodulatory substances or immunomodulatory compounds. Examples of immunomodulatory substances include interferon-α (IFN-α), pegylated interferon-α, or stimulants of the innate immune system, such as Toll-like receptor 7 and / or 8 agonists, as well as therapeutic or prophylactic vaccines. One embodiment of the present invention relates to a combination of a compound of formula (I), (I-A) or (I-AA) or any subgroup thereof, as detailed herein, with an immunomodulatory compound, more particularly a Toll-like receptor 7 and / or 8 agonist.

[0143] Further HBV antiviral agents can be selected, for example, from therapeutic vaccines, RNA interference therapeutics / antisense oligonucleotides (e.g., siRNA, ddRNA, shRNA), immunomodulatory substances (e.g., TLR agonists (e.g., TLR7, TLR8 or TLR9 agonists), STING agonists, RIG-I modulators, NKT modulators, IL agonists, interleukins or other immunologically active proteins, therapeutic and prophylactic vaccines and immune checkpoint modulators, HBV entry inhibitors, cccDNA modulators (e.g., direct cccDNA inhibitors, inhibitors of cccDNA formation or maintenance, cccDNA epigenetic modifiers, inhibitors of cccDNA transcription, etc.), inhibitors of HBV protein expression, agents that target HBV RNA, capsid assembly inhibitors / modulators, core or X protein targeting agents, nucleotide analogs, nucleoside analogs, interferons or modified interferons, HBV antiviral agents of distinct or unknown mechanisms, cyclophilin inhibitors, sAg release inhibitors, HBV polymerase inhibitors, dinucleotides, SMAC inhibitors, HDV targeting agents, viral maturation inhibitors, reverse transcriptase inhibitors, HBV RNA destabilizing agents and other small molecule inhibitors of HBV protein expression.

[0144] In particular, an anti-HBV agent known from before, for example, interferon-α (IFN-α), pegylated interferon-α, 3TC, tenofovir, lamivudine, entecavir, telbivudine, and adefovir, or a combination thereof, and a compound of formula (I), (I-A), or (I-AA), or any subgroup thereof, can be used as a medicine in combination therapy. Further examples of additional therapeutic agents that can be combined with the compounds of the present invention include zidovudine, didanosine, zalcitabine, stavudine, abacavir, ddA emtricitabine, apricitabine, ataviripine, ribavirin, acyclovir, valacyclovir, famciclovir, ganciclovir, valganciclovir, cidofovir, efavirenz, nevirapine, delavirdine, and etravirine.

[0145] As used in connection with the compounds of the present invention, the term "administer" and its variations (e.g., "administering" a compound) mean introducing a compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the present invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administer" and its variations are each understood to include the simultaneous and sequential introduction of the compound or its prodrug and the other agent.

[0146] In some embodiments, pulsed dosing is more effective than continuous treatment because the total pulse dose is often lower than that predicted from continuous dosing of the same composition. Each pulse dose can be reduced, and the total amount of drug administered over the course of treatment is minimized. The individual pulses can be delivered continuously to the patient over a period of hours, for example, about 2, 4, 6, 8, 10, 12, 14, or 16 hours, or over several days, for example, 2, 3, 4, 5, 6, or 7 days.

[0147] As used herein, the term "composition" is intended to encompass a product containing a specified amount of a specified ingredient and any product directly or indirectly resulting from a specified amount of a specified ingredient.

[0148] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0149] The present invention is illustrated by the following non-limiting examples and presents biological data.

[0150] Materials and Methods Chemistry General Unless otherwise specified, commercially available reagents and solvents (HPLC grade) were used without further purification.

[0151] Specifically, the following abbreviations may be used in the description of the experimental methods: NMR: Nuclear magnetic resonance, 1H: 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: micromole, M: molarity or molar concentration, Rt: retention time in minutes, anh: anhydride, ss: saturated solution, aq: aqueous solution, sat.aq.: saturated aqueous solution, MW: microwave, Boc: tert-butyloxycarbonyl protecting group, DCM: dichloromethane, DIAD: diisopropyl azodicarboxylate, DMF: dimethylformamide, DIPEA: N,N-diisopropylethylamine, 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-pyrrolidino-phosphonium hexafluorophosphate, TFA: trifluoroacetic acid, eq.: equivalent, RT: room temperature, TBDMS: tert-butyldimethylsilyl, TEA: triethylamine, THF: tetrahydrofuran, pTSA: para-toluenesulfonic acid, TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

[0152] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius) or K (kelvin).

[0153] 1 1H-NMR spectra were obtained using an Avance II 300 MHz Bruker spectrometer. Chemical shifts are reported in parts per million (ppm, δ units). Coupling constants are reported in hertz (Hz), and splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).

[0154] LC-MS analysis was performed using an UPLC Acquity Waters System equipped with an SQD spectrometer, a single quadrupole mass detector, and a TUV detector, with column 1: ACQUITY UPLC BEH SHIELD, RP 18 (2.1×50 mm, id = 1.7 μM), column 2: ACQUITY UPLC HSS T3, RP 18 (2.1×50 mm, id = 1.8 μM) and column 3: ACQUITY UPLC BEH SHIELD, RP 18 (2.1×100 mm, id = 1.7 μM). The column temperature was 40 °C. The sample temperature was 25 °C. Phase A was composed of water (HiPerSolv Chromanorm water VWR HPLC-MS grade) + 0.05% trifluoroacetic acid, and phase B was composed of CH3CN (HiPerSolv Chromanorm acetonitrile SuperGradient VWR, suitable for UPLC / UHPLC instruments) + 0.05% trifluoroacetic acid. The flow rate was 0.5 mL / min, UV detection (DIODE array) at 200 nm, and ESI+ and ESI- detection in the range of 100 - 1000 m / z.

[0155] Method 1: Column 1, run time: 3 minutes, run gradient: 5%B - 100%B in 2.80 minutes + 100%B for 0.2 minutes, equilibration time: 0.8 minutes, ionization mode: ESI + 。 Method 2: Column 2, run time: 4 minutes, run gradient: 0%B - 45%B in 3.5 minutes + 45%B - 100%B in 0.05 minutes + 100%B for 0.45 minutes, equilibration time: 0.8 minutes, ionization mode: ESI + 。 Method 3: Column 3, run time: 6 minutes, run gradient: 5%B - 100%B in 5 minutes + 100%B for 1 minute, equilibration time: 2 minutes. Method 4: Column 3, run time: 6 minutes, run gradient: 5%B - 50%B in 5 minutes + 50%B - 100%B in 0.2 minutes + 100%B for 0.8 minutes, equilibration time: 2 minutes, ionization mode: ESI + 。 Method 5: Column 1, Run time: 3 minutes, Run gradient: 5%B to 100%B in 2.80 minutes + 100%B for 0.2 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 6: Column 2, Run time: 4 minutes, Run gradient: 0%B to 45%B in 3.5 minutes + 45%B to 100%B in 0.05 minutes + 100%B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 7: Column 3, Run time: 6 minutes, Run gradient: 5%B to 100%B in 5 minutes + 100%B for 1 minute, Equilibration time: 2 minutes, Ionization mode: ESI + 。 Method 8: Column 3, Run time: 6 minutes, Run gradient: 5%B to 50%B in 5 minutes + 50%B to 100%B in 0.2 minutes + 100%B for 0.8 minutes, Equilibration time: 2 minutes, Ionization mode: ESI + 。 Method 9: Column 1, Run time: 4 minutes, Run gradient: 5%B to 100%B in 3.00 minutes + 100%B for 1 minute, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 10: Column 1, Run time: 4 minutes, Run gradient: 5%B to 100%B in 3.00 minutes + 100%B for 1 minute, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 11: Column 1, Run time: 3 minutes, Run gradient: 40%B to 100%B in 2.80 minutes + 100%B for 0.2 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 12: Column 3, Run time: 6 minutes, Run gradient: 25%B to 70%B in 5 minutes + 100%B for 1 minute, Equilibration time: 2 minutes, Flow rate: 0.5 mL / min, Ionization mode: ESI + 。 Method 13: Column 2, Run time: 4 minutes, Run gradient: 0%B to 60%B in 3.5 minutes + 60%B to 100%B in 0.05 minutes + 100%B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。 Method 14: Column 2, Run time: 4 minutes, Run gradient: 0% B to 30% B in 3.5 minutes + 30% B to 100% B in 0.05 minutes + 100% B for 0.45 minutes, Equilibration time: 0.8 minutes, Ionization mode: ESI + 。

[0156] Synthesis According to a further aspect of the present invention, there is provided a method for preparing a compound of formula (I) or a salt thereof. The following schemes are examples of synthetic schemes that can be used to synthesize the compounds of the present invention. In the following schemes, protecting groups can be used to protect and deprotect reactive groups according to well-established techniques. In the following schemes, protecting groups can be used to protect and deprotect reactive groups according to well-established techniques. In the following schemes and paragraphs, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Cy, n and m are as defined above in formula (I) and herein.

[0157] It will be understood by those skilled in the art that certain compounds of the present invention can be converted to other compounds of the present invention according to standard chemical methods. The compounds of the present invention can be prepared according to the general routes shown in Scheme 1 and Scheme 2 below:

[0158]

Chemical formula

[0159] Ethyl 4-(chlorosulfonyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate, shown as compound (1) in Scheme 1 where R1 = H, was prepared according to the procedure described in WO2017 / 001655. According to Scheme 1, a primary amine derivative (2) having a nucleophilic -OH substituent is reacted with compound (1) in the presence of a suitable base to obtain the corresponding sulfonamide product (3). The reaction of (3) with an arylamine or heteroarylamine in the presence of a strong non-nucleophilic base, such as LiHMDS, in a solvent such as tetrahydrofuran converts the ethyl carboxylate to an arylamide derivative (4). The subsequent cyclization step by an intramolecular nucleophilic attack of OH on fluorine gives the tricyclic core of compound (5). Depending on the specific protecting group (PG, as shown in Scheme 1) in compound (5), the product can be further refined by deprotection and / or further functionalization steps. In particular, when nitrogen is an N-Boc derivative, Boc can be removed by an acidic treatment, and the resulting NH can be further converted, for example, to an amide or oxalamide derivative, or alkylated, for example, via reductive amination chemistry. In a particular embodiment of the present invention, in the compound of general formula (5), the protected nitrogen is N-COOEt or N-PMB, and the protecting group can be cleaved via standard chemistry, such as trimethylsilyl iodide for ethyl carbamate and hydrogenation for the p-methoxybenzyl group (PMB). Of further note is that the efficiency of the synthetic strategy can be optimized by changing the specific order of the steps shown in Scheme 1.

[0160] Deprotection of the compound (5) shown in Scheme 1 gives a highly advanced intermediate of general structure (6), where Z is Cl shown in Scheme 1 - , CF3COO - , p-tolylSO3 -They are counterions such as etc. The compound of formula (6) is reacted with an R2-COOH or its derivative such as acyl chloride or ester under appropriate coupling conditions to obtain the compound of formula (I). In particular, the compound of formula (I) in which R2 is -(C=O)NR3R4 is obtained as shown in Scheme 2.

[0161]

Chemical Structure

[0162] The compound of formula (I) in which R1 is H can be converted to the compound of formula (I) in which R1 is halogen via standard halogenation methods (see, for example, Journal of Organic Chemistry (1981), 46(11), pages 2221-2225).

[0163] The procedures in the scheme can be used for the synthesis of the compounds shown below and, by selecting starting materials with appropriate stereochemical configurations, can likewise be used for the synthesis of compounds as single diastereoisomers and / or enantiomers.

[0164] Unless otherwise indicated, starting materials and / or intermediates were obtained from commercial sources or could be obtained via synthetic procedures known in the chemical literature. The indication of a commercial source for a particular compound in the description of the test procedure, when provided, is for ease of reference only for the skilled chemist and should not be construed as indicating the use of only that particular commercial compound.

[0165] In the following paragraphs, Preparations 1 - 28 illustrate the preparation of intermediates used to make the compounds of the invention and their salts. The Examples illustrate the preparation of the compounds of the invention and their salts. It is understood that when a compound has more than one chiral center, it may exist as a mixture of diastereoisomers or as a single isomer. Both racemic and chiral compounds are within the scope of the invention. The procedures shown are provided merely as an aid to the skilled chemist. Starting materials may not necessarily be prepared from the batches of Preparations or Examples referred to.

[0166] Preparation D1: rac-Ethyl 4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (D1) Compound D1 was prepared according to the following scheme:

[0167]

Chemical formula

[0168] 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, washed with 5% citric acid solution and brine, dried over Na2SO4 (anhydrous), filtered, and the solvent removed under reduced pressure. Crude D1 (131 mg, 0.29 mmol, yield = 78.6%) was used as such in the next synthetic step. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + 。

[0169] 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-ium 1',1'-dioxide chloride (D2) The compound was prepared according to the following scheme:

[0170]

Chemical Structure

[0171] Step 1: 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) dropwise at room temperature. After 60 minutes, the reaction was quenched with water, diluted with DCM, and washed with 5% aqueous citric acid and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 3-((5-((3,4-difluorophenyl)carbamoyl)-4-fluoro-1-methyl-1H-pyrrol-3-yl)sulfonamido)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (154 mg, 0.289 mmol, quantitative yield) as a foamy substance, which was used without further purification. Method 1: Rt = 1.70 min; m / z = 533.4 (M+H) + 。

[0172] Step 2: To a solution of the compound obtained from Step 1 (154 mg, 0.289 mmol) in DMF (2.9 mL), cesium carbonate (282.7 mg, 0.868 mmol) was added, 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 (×3). The organic layer was dried over Na2SO4 (anhydrous), filtered, concentrated under vacuum, and tert-butyl 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-carboxylate 1',1'-dioxide (148 mg, 0.289 mmol, quantitative yield) was obtained as a solid. Method 1: Rt = 2.19 min; m / z = 513.2 (M+H) + .

[0173] Step 3: The compound obtained from Step 2 (148 mg, 0.290 mmol) was dissolved in DCM (2 mL) and treated with 1 M HCl in dioxane (0.29 mL, 0.290 mmol) all at once. After stirring at room temperature for 1 hour, the solvent was removed to obtain D2 (130 mg, quantitative yield) as the hydrochloride salt, which was used in the next step without any formation. Method 1: Rt = 1.33 min; m / z = 413.2 (M+H) + .

[0174] Described D3: Methyl (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D3)

[0175]

Chemical Structure

[0176] To an equimolar solution of (2R)-1,1,1-trifluoro-2-propanamine 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 mixture was stirred at 0 °C for 30 minutes and then quenched with ice and water. The organic phase was washed with 1 N HCl (3 × 20 mL) and brine. The organic phase was dried over Na2SO4 (anhydrous), then filtered and concentrated to give D3 (567 mg, yield = 85%) as a colorless solid, which was used as such in the next synthetic step. Method 1: Rt = 1.12 min, m / z = 200.1 (M+H) + 。

[0177] Described D4: Sodium (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D4)

[0178]

Chem.

[0179] To a solution of D3 (567 mg, 2.85 mmol) in THF (2 mL, 0.025 mol) was added sodium hydroxide (113.89 mg, 2.85 mmol) previously dissolved in water (1 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room temperature overnight and then diluted with toluene (30 mL) and evaporated to dryness under reduced pressure. This procedure was repeated twice to obtain a white powder. The product was further dried under a vacuum pump overnight to give D4 (562 mg, yield = 95%) as a white powder. Method 13: Rt = 1.25 min, m / z = 130.1 (M+H) + 。

[0180] Description D5: tert-Butyl (3R)-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (D5)

[0181]

Chem.

[0182] Step 1: A mixture of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (Fluorochem, catalog number 237078, CAS: 889949-18-2) (500 mg, 2.31 mmol) and (-)-O,O'-di-p-toluoyl-D-tartrate (0.5 equiv, 445 mg, 1.15 mmol) was suspended in IPA (2.5 mL, 0.033 mol), and the mixture was sonicated until almost dissolved. The resulting suspension was heated at 65 °C for several minutes, sonicated again to obtain a homogeneous mixture. The pale yellow solution was heated at 65 °C. After 5 minutes, the mixture became a white suspension and was stirred at 65 - 70 °C for 18 hours. The suspension was cooled to room temperature over 1 hour. The suspension was filtered, and the solid was rinsed with a small amount of isopropanol. The crude material was dried under vacuum overnight to obtain tert-butyl (3R)-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate - hemi-(-)-O,O'-di-p-toluoyl-D-tartrate (tatrate) (345 mg, 0.43 mmol, y = 36.4%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 1.62 - 1.79 (m, 1 H) 1.79 - 2.03 (m, 1 H) 2.35 (s, 3 H) 3.03 - 3.51 (m, 6 H) 5.57 (s, 1 H) 6.83 - 8.03 (m, 1 H) 7.28 (d, J = 8.07 Hz, 2 H) 7.80 (d, J = 8.16 Hz, 1 H).

[0183] Step 2: tert-Butyl (3R)-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate hemi-(-)-O,O'-di-p-toluoyl-D-tartrate (350 mg, 0.43 mmol) was suspended in water (1 mL) and ethyl acetate (1 mL). The mixture was cooled in an ice bath and 6N HCl (0.14 mL, 0.840 mmol) was added dropwise. The resulting biphasic mixture was stirred at 0 °C for 1 h. The layers were separated and the aqueous phase was washed with EtOAc (×1). The aqueous phase was cooled to 0 °C and treated with 3M aqueous NaOH (0.28 mL, 0.840 mmol). The mixture was stirred at 0 °C for 1 h. The resulting solution was extracted with MeTHF (5 × 10 mL) and concentrated under reduced pressure to give tert-butyl (3R)-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (134 mg, 0.620 mmol) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ ppm 1.45 (s, 9 H) 1.67 - 1.85 (m, 1 H) 1.86 - 2.05 (m, 1 H) 2.40 (br s, 2 H) 3.14 - 3.59 (m, 6 H).

[0184] Description D6: tert-Butyl (3S)-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (D6)

[0185]

Chem.

[0186] D6 was prepared as described for D5 starting from tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (Fluorochem, catalog number 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). 11H NMR (300 MHz, chloroform-d) δ ppm 1.45 (s, 9 H) 1.61 - 1.81 (m, 1 H) 1.82 - 2.15 (m, 3 H) 3.51 (m, 6 H).

[0187] Description D7: Ethyl (R)-4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (D7)

[0188]

Chemical Structure

[0189] D7 was prepared starting from D5 instead of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate as described for D1. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + .

[0190] Description D8: Ethyl (S)-4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (D8)

[0191]

Chemical Structure

[0192] D8 was prepared starting from D6 instead of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate as described for D1. Method 1: Rt = 1.70 min; m / z = 450.3 (M+H) + .

[0193] Description D9: tert-Butyl 4-((5-(ethoxycarbonyl)-4-fluoro-1-methyl-1H-pyrrole)-3-sulfonamide)-4-(hydroxymethyl)piperidine-1-carboxylate (D9)

[0194]

Chem.

[0195] D9 was prepared as described for D1 starting from 1-Boc-4-amino-4-(hydroxymethyl)piperidine (Fluorochem, 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) + .

[0196] Description D10: Ethyl 4-(N-(1-(tert-butoxycarbonyl)-3-(hydroxymethyl)azetidin-3-yl)sulfamoyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxylate (D10)

[0197]

Chem.

[0198] D10 was prepared as described for D1 starting from 1-Boc-3-amino-3-(hydroxymethyl)azetidine (Fluorochem, cat 502710, CAS: 1262411-27-7) instead of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate. Method 1: Rt = 1.83 min; m / z = 436.4 (M+H) + .

[0199] Description D11: (R)-N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide hydrochloride (D11)

[0200]

Chemical formula

[0201] Starting from D7 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) in step 1 instead of 3,4-difluoroaniline, it was prepared in the same manner as described for compound D2. Method 1: Rt = 1.42 min; m / z = 429.23 (M + H) + 。

[0202] Description D12: (S)-N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide hydrochloride (D12)

[0203]

Chemical formula

[0204] Starting from D8 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) in step 1 instead of 3,4-difluoroaniline, it was prepared in the same manner as described for compound D2.

[0205] Description D13: N-(3-chloro-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide hydrochloride (D13)

[0206]

Chem.

[0207] Instead of 3,4-difluoroaniline, starting from D9 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) in Step 1, it was prepared in the same manner as described for Compound D2. Method 1: Rt = 1.44 min; m / z = 443.3 (M + H) + 。

[0208] 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)

[0209]

Chem.

[0210] Instead of 3,4-difluoroaniline, starting from D10 and 3-chloro-4-fluoroaniline (001682, Fluorochem, CAS: 367-21-5) in Step 1, it was prepared in the same manner as described for Compound D2. Method 1: Rt = 1.40 min; m / z = 415.3 (M + H) + 。

[0211] 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)

[0212]

Chem.

[0213] Instead of 3,4-difluoroaniline, starting from D7 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) in Step 1, it was prepared in the same manner as described for Compound D2. Method 1: Rt = 1.37 min; m / z = 445.16 (M+H) + 。

[0214] 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)

[0215]

Chemical formula

[0216] Instead of 3,4-difluoroaniline, starting from D8 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) in Step 1, it was prepared in the same manner as described for Compound D2. Method 1: Rt = 1.37 min; m / z = 445.16 (M+H) + 。

[0217] Description D17: N-(3-(Difluoromethyl)-4-fluorophenyl)-7'-methyl-2'H,4'H,7'H-spiro[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide hydrochloride (D17)

[0218]

Chemical formula

[0219] Starting from D9 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8), D17 was prepared in a similar manner as described for compound D2. Method 1: Rt=1.39 min; m / z=459.3 (M+H). + .

[0220] 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)

[0221] [ka]

[0222] Prepared similarly as described for compound D2, starting from D10 and 3-(difluoromethyl)-4-fluoroaniline (101786, Fluorochem, CAS: 445303-96-8) in step 1 instead of 3,4-difluoroaniline. Method 1: Rt = 1.35 min; m / z = 431.25 (M+H) + .

[0223] Description D19: Ethyl (S)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D19)

[0224] [ka]

[0225] Prepared similarly as described for compound D3, starting from ethyl 2-chloro-2-oxoacetate and using (2S)-1,1,1-trifluoro-2-propanamine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propanamine hydrochloride, D19 was obtained as a colorless oil. Method 2; Rt=2.84 min. m / z=214.34 (M+H). + .

[0226] Description D20: Sodium (S)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate (D20)

[0227] [ka]

[0228] Prepared similarly as described for compound D4, starting from D19. Method 6; Rt=1.34 min. m / z=186.3 (M+H) + .

[0229] Description D21: Ethyl 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D21)

[0230] [ka]

[0231] Prepared similarly as 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-propanamine hydrochloride, D21 was obtained as a white solid, which was used as such in the next synthetic step. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.11 Hz, 3 H) 3.83 - 4.08 (m, 2 H) 4.27 (q, J=7.12 Hz, 2 H) 9.35 - 9.70 (m, 1 H). Method 6; Rt = 2.32 min. m / z = 200.2 (M+H) + .

[0232] Description D22: Sodium 2-oxo-2-((2,2,2-trifluoroethyl)amino)acetate (D22)

[0233]

Chem.

[0234] Starting from D21, it was prepared in the same manner as described for compound D4. Method 6; Rt = 1.22 min. m / z = 172.1 (M+H) + 。

[0235] Description D23: Ethyl 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D23)

[0236]

Chem.

[0237] Starting from ethyl 2-chloro-2-oxoacetate and using 2,2,2-trifluoro-1,1-dimethylethylamine hydrochloride instead of (2R)-1,1,1-trifluoro-2-propanamine hydrochloride, it was prepared in the same manner as described for compound D3 to obtain D23 as a colorless oil, which was used as such in the next synthetic step. Method 6; Rt = 3.54 min. m / z = 228.13 (M+H) + 。

[0238] Description D24: Sodium 2-oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)acetate (D24)

[0239]

Chem.

[0240] Starting from D23, it was prepared in the same manner as described for compound D4. Method 6; Rt = 1.07 min. m / z = 200.15 (M+H) + .

[0241] Description D25: Ethyl 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D25)

[0242]

Chem.

[0243] Starting from ethyl 2-chloro-2-oxoacetate and using 3,3-difluoroazetidine hydrochloride instead of (2R)-1,1,1-trifluoropropan-2-amine hydrochloride, it was prepared in the same manner as described for compound D3 to obtain D25 as a pale orange solid, which was used as such in the next synthetic step. Method 2; Rt = 2.40 min. m / z = 194.12 (M+H) + .

[0244] Description D26: Sodium 2-(3,3-difluoroazetidin-1-yl)-2-oxoacetate (D26)

[0245]

Chem.

[0246] Starting from D25, it was prepared in the same manner as described for compound D4. Method 6; Rt = 0.92 min. m / z = 166 (M+H) + .

[0247] Description D27: Methyl 2-(cyclopropylamino)-2-oxoacetate (D27)

[0248]

Chem.

[0249] (2R)-1,1,1-Trifluoro-2-propanamine hydrochloride was replaced with 3,3-difluoroazetidine hydrochloride and prepared in the same manner as described for Compound D3 to obtain 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) + .

[0250] Description D28: Sodium 2-(cyclopropylamino)-2-oxoacetate (D28)

[0251]

Chem.

[0252] Starting from D27, it was prepared in the same manner as described for Compound D4 to obtain D28 (984 mg, 6.51 mmol) as a white powder. Method 13: Rt = 0.78 min; m / z = 130.11 (M + H) + 。

Example

[0253] (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)

[0254]

Chem.

[0255] To a solution of D2 (30 mg, 0.070 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29.56 mg, 0.070 mmol), and sodium (R)-2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetate D4 (13.84 mg, 0.070 mmol) in DMF (1 mL, 0.013 mol) was added dropwise DIPEA (47 μL, 0.270 mmol) at room temperature. The reaction mixture was stirred for 30 minutes under the same conditions, 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 material was purified by Fraction-Lynx (H2O / CH3CN + 1‰ TFA) to obtain E1 in approximately 40% yield. NMR: 1 1H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.22 - 1.39 (m, 3 H) 1.92 - 2.40 (m, 2 H) 3.44 - 4.18 (m, 7 H) 4.40 - 4.72 (m, 3 H) 7.30 - 7.57 (m, 3 H) 7.75 - 7.92 (m, 1 H) 8.29 (m, 1 H) 9.21 - 9.37 (m, 1 H) 9.44 (br dd, J = 8.16, 2.84 Hz, 1 H). Method 3: Rt = 3.54 min; m / z = 580.32 (M+H) + .

[0256] (Example E2) N-(3,4-Difluorophenyl)-7'-methyl-1-(5-methyl-1,3,4-oxadiazole-2-carbonyl)-2'H,4'H,7'H-spiro[piperidine-3,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E2)

[0257]

Chem.

[0258] D2 (8.96 mg, 0.02 mmol) was suspended in MeCN (1 mL), treated with TEA (8 μL, 0.06 mmol) all at once to obtain a white suspension. To this mixture, 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride (1.17 M in MeCN, 30 μL) (Org. Proc. Res. Develop, 2011, 15, 73 - 83) was added all at once at 0 °C. The reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched with MeOH, the solvent was removed, then it was dissolved in DCM and washed with brine and 5% aqueous citric acid solution. The organic layer was concentrated under reduced pressure, and the residue was dissolved in MeOH (15 mL) and concentrated slowly. This procedure was repeated 5 times to obtain the crude product, which was purified by preparative HPLC (H2O, CH3CN 0.1% HCOOH) to obtain E2 in an approximate yield of 40%. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.04 - 2.45 (m, 2 H) 2.60 (s, 3 H) 3.82 (d, J = 4.68 Hz, 5 H) 3.98 - 4.40 (m, 2 H) 4.45 - 4.70 (m, 2 H) 7.28 - 7.57 (m, 3 H) 7.73 - 7.93 (m, 1 H) 8.20 - 8.63 (m, 1 H) 9.37 - 9.62 (m, 1 H). Method 3: Rt = 3.08 min; m / z = 523.25 (M+H) + .

[0259] (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)

[0260]

Chem.

[0261] To a stirred solution of E1 (13.45 mg, 0.020 mmol) in DCM (1 mL), sulfuryl dichloride (2 μL, 0.020 mmol) (using 200 μL from a pre-prepared stock solution of 20 μL of SO2Cl2 in 2 mL of DCM) was added at 0 °C. 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 and then quenched by the addition of saturated NaHCO3 solution, diluted with DCM, the organic phase was separated by a phase separator and concentrated under reduced pressure. The crude material was purified by preparative HPLC (H2O, CH3CN 0.1% TFA) to give E3 in approximately 20% yield. 1 H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.25 - 1.40 (m, 3 H) 1.89 - 2.38 (m, 2 H) 3.38 - 4.18 (m, 7 H) 4.37 - 4.80 (m, 3 H) 7.25 - 7.55 (m, 2 H) 7.66 - 7.95 (m, 1 H) 8.48 - 8.67 (m, 1 H) 9.14 - 9.40 (m, 1 H) 9.64 (t, J=3.94 Hz, 1 H). Method 3: Rt = 3.74 min; m / z = 614.22 (M+H) + .

[0262] (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)

[0263]

Chem.

[0264] 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 one portion. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with MeCN and purified by preparative HPLC (H2O, CH3CN 0.1% TFA) to give E4 (31.3 mg, 0.052 mmol, y = 70%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 6.88 Hz, 3 H) 1.96 - 2.38 (m, 2 H) 3.48 - 3.67 (m, 2 H) 3.75 - 4.12 (m, 5 H) 4.39 - 4.74 (m, 3 H) 7.41 (t, J = 9.08 Hz, 1 H) 7.51 (d, J = 2.93 Hz, 1 H) 7.61 - 7.69 (m, 1 H) 7.96 (dt, J = 6.79, 2.57 Hz, 1 H) 8.30 (d, J = 10.18 Hz, 1 H) 9.30 (dd, J = 13.94, 9.08 Hz, 1 H) 9.42 (d, J = 4.68 Hz, 1 H). Method 3: Rt = 3.69 min; m / z = 596.2 (M+H) + .

[0265] (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)

[0266]

Chem.

[0267] Starting from D12 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E5 (23.54 mg, 0.039 mmol, y = 61%). 1 H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (dd, J = 7.01, 2.15 Hz, 3 H) 1.99 - 2.39 (m, 2 H) 3.83 (s, 7 H) 4.44 - 4.72 (m, 3 H) 7.39 (t, J = 9.12 Hz, 1 H) 7.46 - 7.55 (m, 1 H) 7.58 - 7.72 (m, 1 H) 7.96 (dd, J = 6.79, 2.48 Hz, 1 H) 8.28 (d, J = 6.05 Hz, 1 H) 9.30 (t, J = 9.26 Hz, 1 H) 9.41 (d, J = 11.65 Hz, 1 H). Method 3: Rt = 3.69 min; m / z = 596.1 (M+H) + .

[0268] (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)

[0269] [Chemistry]

[0270] Starting from D15 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E6 (20.62 mg, 0.034 mmol, y = 65%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (t, J = 6.79 Hz, 3 H) 2.04 - 2.37 (m, 2 H) 3.20 - 4.16 (m, 7 H) 4.42 - 4.74 (m, 3 H) 7.02 - 7.45 (m, 2 H) 7.51 (d, J = 3.03 Hz, 1 H) 7.81 (br dd, J = 8.25, 3.85 Hz, 1 H) 8.02 (br d, J = 5.14 Hz, 1 H) 8.30 (d, J = 9.81 Hz, 1 H) 9.30 (dd, J = 14.21, 9.08 Hz, 1 H) 9.49 (d, J = 4.31 Hz, 1 H). Method 3: Rt = 3.54 min; m / z = 612.28 (M+H) + .

[0271] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E7)

[0272] [Chemistry]

[0273] Starting from D13 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E7 (19.45 mg, 0.032 mmol, y = 61%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.21 - 1.38 (m, 3 H) 1.44 - 1.72 (m, 2 H) 2.00 - 2.20 (m, 2 H) 2.99 - 3.20 (m, 1 H) 3.27 - 4.19 (m, 6 H) 4.36 - 4.48 (m, 2 H) 4.57 - 4.75 (m, 1 H) 7.41 (t, J=9.08 Hz, 1 H) 7.51 (s, 1 H) 7.59 - 7.68 (m, 1 H) 7.88 - 7.92 (m, 1 H) 7.96 (dd, J=6.79, 2.57 Hz, 1 H) 9.33 (dd, J=8.80, 4.77 Hz, 1 H) 9.40 (s, 1 H). Method 3: Rt = 3.61 min; m / z = 610.25 (M+H) + .

[0274] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E8)

[0275]

Chem.

[0276] Starting from D17 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E8 (17.64 mg, 0.028 mmol, y = 58%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (dd, J = 6.97, 3.48 Hz, 3 H) 1.45 - 1.71 (m, 2 H) 2.10 (br d, J = 13.11 Hz, 2 H) 3.10 (br s, 1 H) 3.47 - 3.56 (m, 2 H) 3.83 (s, 3 H) 4.02 - 4.16 (m, 1 H) 4.35 - 4.49 (m, 2 H) 4.55 - 4.77 (m, 1 H) 6.98 - 7.44 (m, 2 H) 7.51 (s, 1 H) 7.81 (br dd, J = 8.57, 3.53 Hz, 1 H) 7.90 (s, 1 H) 8.01 (dd, J = 6.24, 2.38 Hz, 1 H) 9.33 (dd, J = 8.80, 4.58 Hz, 1 H) 9.45 (s, 1 H). Method 3: Rt = 3.46 min; m / z = 626.3 (M+H) + .

[0277] (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)

[0278] [Chemical Structure]

[0279] Starting from D14 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E9 (11.49 mg, 0.02 mmol, y = 41%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (dd, J=7.01, 1.97 Hz, 3 H) 3.75 - 3.91 (m, 3 H) 4.01 - 4.20 (m, 2 H) 4.45 - 4.77 (m, 5 H) 7.41 (t, J=9.12 Hz, 1 H) 7.53 (s, 1 H) 7.63 - 7.76 (m, 1 H) 7.91 - 8.05 (m, 1 H) 8.63 (d, J=5.41 Hz, 1 H) 9.30 (t, J=9.17 Hz, 1 H) 9.44 (d, J=4.22 Hz, 1 H). Method 3: Rt = 3.71 min; m / z = 582.23 (M+H) + .

[0280] (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)

[0281]

Chem.

[0282] Starting from D18 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E10 (17.04 mg, 0.028 mmol, y = 61%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (dd, J=7.01, 2.25 Hz, 3 H) 3.84 (s, 3 H) 4.07 - 4.16 (m, 2 H) 4.46 - 4.77 (m, 5 H) 6.97 - 7.46 (m, 2 H) 7.53 (s, 1 H) 7.79 - 7.90 (m, 1 H) 8.04 (br d, J=6.14 Hz, 1 H) 8.62 (d, J=5.41 Hz, 1 H) 9.30 (t, J=8.89 Hz, 1 H) 9.51 (d, J=4.13 Hz, 1 H). Method 3: Rt = 3.56 min; m / z = 598.16 (M+H) + .

[0283] (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)

[0284]

Chem.

[0285] Starting from D16 instead of D11, it was prepared in the same manner as described for compound E4 to obtain E11 (22.24 mg, 0.036 mmol, y = 50%). 1 1H NMR (300 MHz, DMSO-d 6+TFA) δ ppm 1.24 - 1.38 (m, 3 H) 2.02 - 2.39 (m, 2 H) 3.53 - 4.10 (m, 7 H) 4.40 - 4.77 (m, 3 H) 6.94 - 7.42 (m, 2 H) 7.49 (d, J=2.48 Hz, 1 H) 7.71 - 7.87 (m, 1 H) 7.98 - 8.07 (m, 1 H) 8.27 (d, J=6.97 Hz, 1 H) 9.30 (t, J=9.17 Hz, 1 H) 9.48 (d, J=11.28 Hz, 1 H). Method 3: Rt = 3.54 min; m / z = 612.34 (M+H) + .

[0286] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E12)

[0287] [Chemical formula]

[0288] 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, and then benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (9.28 mg, 0.02 mmol) was added all at once. The reaction mixture was stirred at room temperature overnight and then purified directly by preparative HPLC (H2O, CH3CN 0.1% TFA) to give E12 (4.44 mg, 0.007 mmol, y = 35%) as a white solid. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (dd, J = 6.97, 3.21 Hz, 3 H) 1.43 - 1.72 (m, 2 H) 2.02 - 2.19 (m, 2 H) 2.99 - 3.20 (m, 1 H) 3.47 - 3.59 (m, 2 H) 3.73 - 3.91 (m, 3 H) 4.09 (br dd, J = 12.98, 3.26 Hz, 1 H) 4.43 (br d, J = 2.29 Hz, 2 H) 4.56 - 4.77 (m, 1 H) 7.41 (t, J = 9.08 Hz, 1 H) 7.51 (s, 1 H) 7.64 (ddd, J = 9.03, 4.26, 2.66 Hz, 1 H) 7.90 (s, 1 H) 7.96 (dd, J = 6.88, 2.57 Hz, 1 H) 9.33 (dd, J = 8.80, 4.86 Hz, 1 H) 9.39 (s, 1 H). Method 3: Rt = 3.61 min; m / z = 610.25 (M+H) + .

[0289] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E13)

[0290]

Chemical Structure

[0291] Starting from D13 and using D22 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E13 (4.08 mg, 0.007 mmol, y = 32%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.44 - 1.73 (m, 2 H) 2.09 (br d, J=13.57 Hz, 2 H) 3.11 (br s, 1 H) 3.33 - 3.44 (m, 1 H) 3.53 - 3.55 (m, 1 H) 3.83 (s, 3 H) 3.92 - 4.18 (m, 3 H) 4.43 (s, 2 H) 7.41 (t, J=9.08 Hz, 1 H) 7.51 (s, 1 H) 7.64 (ddd, J=9.08, 4.26, 2.61 Hz, 1 H) 7.88 - 7.92 (m, 1 H) 7.96 (dd, J=6.79, 2.57 Hz, 1 H) 9.31 - 9.48 (m, 2 H). Method 3: Rt = 3.52 min; m / z = 596.14 (M+H) + .

[0292] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E14)

[0293]

Chem.

[0294] Starting from D17 and D20, it was prepared in the same manner as described for compound E12 to obtain E14 (6.25 mg, 0.01 mmol, y = 43%). 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.28 (br s, 3 H) 1.45 - 1.69 (m, 2 H) 2.10 (br d, J = 7.34 Hz, 2 H) 3.01 - 3.22 (m, 1 H) 3.30 - 3.64 (m, 2 H) 3.83 (br d, J = 9.26 Hz, 3 H) 4.02 - 4.22 (m, 1 H) 4.42 (br d, J = 6.97 Hz, 2 H) 4.52 - 4.78 (m, 1 H) 6.91 - 7.56 (m, 3 H) 7.66 - 8.17 (m, 3 H) 9.23 - 9.37 (m, 1 H) 9.37 - 9.49 (m, 1 H). Method 3: Rt = 3.46 min; m / z = 626.32 (M+H) + .

[0295] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E15)

[0296] [Chemical formula]

[0297] Starting from D17, using D24 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E15 (4.67 mg, 0.007 mmol, y = 31%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.44 - 1.70 (m, 8 H) 2.10 (br d, J=13.30 Hz, 2 H) 2.97 - 3.16 (m, 1 H) 3.43 (br s, 2 H) 3.79 - 3.88 (m, 3 H) 4.06 (br d, J=13.20 Hz, 1 H) 4.41 (s, 2 H) 7.00 - 7.45 (m, 2 H) 7.47 - 7.57 (m, 1 H) 7.74 - 7.85 (m, 1 H) 7.85 - 7.93 (m, 1 H) 8.01 (dd, J=6.10, 2.15 Hz, 1 H) 8.65 - 8.90 (m, 1 H) 9.32 - 9.56 (m, 1 H). Method 3: Rt = 3.57 min; m / z = 640.36 (M+H) + .

[0298] (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)

[0299]

Chem.

[0300] Starting from D14, it was prepared in the same manner as described for compound E12 to obtain E16 (3.11 mg, 0.005 mmol, y = 25%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (dd, J=7.06, 2.02 Hz, 3 H) 3.75 - 3.91 (m, 3 H) 4.01 - 4.20 (m, 2 H) 4.46 - 4.79 (m, 5 H) 7.41 (t, J=9.12 Hz, 1 H) 7.53 (s, 1 H) 7.69 (ddt, J=9.09, 4.44, 2.45, 2.45 Hz, 1 H) 7.98 (dt, J=6.79, 2.34 Hz, 1 H) 8.63 (d, J=5.41 Hz, 1 H) 9.30 (t, J=9.22 Hz, 1 H) 9.44 (d, J=4.13 Hz, 1 H). Method 3: Rt = 3.71 min; m / z = 582.23 (M+H) + .

[0301] (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)

[0302]

Chemical formula

[0303] Starting from D14, using D26 instead of D20, it was prepared in the same manner as described for compound E12, and E17 (1.05 mg, 0.002 mmol, y = 9%) was obtained. 11H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (broad doublet, J = 7.43 Hz, 3 H) 3.94 - 4.17 (multiplet, 2 H) 4.29 - 4.46 (multiplet, 2 H) 4.52 (broad doublet, J = 6.88 Hz, 2 H) 4.66 (broad doublet, J = 6.33 Hz, 2 H) 4.80 (broad singlet, 2 H) 7.24 - 7.42 (multiplet, 1 H) 7.44 - 7.56 (multiplet, 1 H) 7.59 - 7.78 (multiplet, 1 H) 7.85 - 8.10 (multiplet, 1 H) 8.48 - 8.71 (multiplet, 1 H) 9.33 - 9.53 (multiplet, 1 H). Method 3: Rt = 3.52 min; m / z = 562.11 (M+H) + .

[0304] (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)

[0305]

Chemical Structure

[0306] Starting from D18, it was prepared in the same manner as described for compound E12 to obtain E18 (3.69 mg, 0.006 mmol, y = 31%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.28 - 1.37 (m, 3 H) 3.72 - 3.95 (m, 3 H) 3.99 - 4.23 (m, 2 H) 4.39 - 4.82 (m, 5 H) 6.98 - 7.44 (m, 2 H) 7.49 - 7.57 (m, 1 H) 7.77 - 7.91 (m, 1 H) 7.99 - 8.10 (m, 1 H) 8.62 (d, J=5.32 Hz, 1 H) 9.24 - 9.36 (m, 1 H) 9.51 (d, J=4.22 Hz, 1 H). Method 3: Rt = 3.57 min; m / z = 598.23 (M+H) + .

[0307] (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)

[0308]

Chemical formula

[0309] Starting from D18 and using D28 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E19 (2.6 mg, 0.005 mmol, y = 21%). 11H NMR (300 MHz, DMSO-d6) δ ppm 0.51 - 0.74 (m, 4 H) 2.72 - 2.77 (m, 1 H) 3.77 - 3.91 (m, 3 H) 3.95 - 4.17 (m, 2 H) 4.45 - 4.74 (m, 4 H) 6.94 - 7.46 (m, 2 H) 7.48 - 7.57 (m, 1 H) 7.77 - 7.92 (m, 1 H) 7.99 - 8.12 (m, 1 H) 8.55 - 8.65 (m, 1 H) 8.76 (d, J=5.32 Hz, 1 H) 9.50 (s, 1 H). Method 3: Rt = 3.22 min; m / z = 542.26 (M+H) + . 0.05

[0310] (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)

[0311] [Chemical formula]

[0312] Starting from D11 and using D22 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E20 (5.87 mg, 0.01 mmol, y = 13%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.94 - 2.41 (m, 2 H) 3.47 - 4.26 (m, 9 H) 4.38 - 4.73 (m, 2 H) 7.38 (t, J=9.08 Hz, 1 H) 7.50 (d, J=4.13 Hz, 1 H) 7.57 - 7.71 (m, 1 H) 7.89 - 8.04 (m, 1 H) 8.29 (s, 1 H) 9.26 - 9.46 (m, 2 H). Method 3: Rt = 3.59 min; m / z = 582.16 (M+H) + .

[0313] (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)

[0314]

Chemical formula

[0315] Starting from D11 and using D24 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E21 (4.95 mg, 0.008 mmol, y = 25%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.44 - 1.62 (m, 6 H) 1.99 - 2.37 (m, 2 H) 3.45 - 4.02 (m, 7 H) 4.34 - 4.72 (m, 2 H) 7.38 (t, J=9.08 Hz, 1 H) 7.50 (s, 1 H) 7.65 (dtd, J=8.85, 4.29, 4.29, 2.75 Hz, 1 H) 7.96 (dd, J=6.79, 2.57 Hz, 1 H) 8.29 (d, J=2.48 Hz, 1 H) 8.55 (d, J=26.00 Hz, 1 H) 9.40 (d, J=17.15 Hz, 1 H). Method 3: Rt = 3.85 min; m / z = 610.25 (M+H) + .

[0316] (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)

[0317] [Chemical Structure Diagram]

[0318] Starting from D11, it was prepared in the same manner as described for compound E12 to obtain E22 (5.79 mg, 0.01 mmol, y = 45%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (dd, J = 7.01, 2.52 Hz, 3 H) 2.08 - 2.30 (m, 2 H) 3.53 - 4.13 (m, 7 H) 4.44 - 4.72 (m, 3 H) 7.41 (t, J = 9.08 Hz, 1 H) 7.51 (d, J = 2.38 Hz, 1 H) 7.61 - 7.69 (m, 1 H) 7.96 (dd, J = 6.79, 2.48 Hz, 1 H) 8.28 (d, J = 6.14 Hz, 1 H) 9.32 (t, J = 9.35 Hz, 1 H) 9.42 (d, J = 11.74 Hz, 1 H). Method 3: Rt = 3.69 min; m / z = 596.21 (M+H) + .

[0319] (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)

[0320]

Chemical Structure

[0321] Starting from D15, it was prepared in the same manner as described for compound E12 to obtain 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, 3 H) 2.01 - 2.38 (m, 2 H) 3.45 - 4.18 (m, 7H) 4.37 - 4.80 (m, 3 H) 7.00 - 7.45 (m, 2 H) 7.51 (d, J = 2.66 Hz, 1 H) 7.72 - 7.87 (m, 1 H) 7.95 - 8.09 (m, 1 H) 8.27 (d, J = 7.15 Hz, 1 H) 9.32 (t, J = 9.26 Hz, 1 H) 9.49 (d, J = 11.28 Hz, 1 H). Method 3: Rt = 3.55 min; m / z = 612.21 (M+H) + .

[0322] (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)

[0323] [Chemical Structure Diagram]

[0324] Starting from D15, using D24 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E24 (6.4 mg, 0.01 mmol, y = 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 - 1.62 (m, 6 H) 2.05 - 2.34 (m, 2 H) 3.24 - 4.12 (m, 7 H) 4.36 - 4.70 (m, 2 H) 6.95 - 7.44 (m, 2 H) 7.51 (s, 1 H) 7.71 - 7.87 (m, 1 H) 7.95 - 8.10 (m, 1 H) 8.28 (s, 1 H) 8.57 (d, J = 29.00 Hz, 1 H) 9.49 (d, J = 16.41 Hz, 1 H). Method 3: Rt = 3.69 min; m / z = 626.32 (M+H) + .

[0325] (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)

[0326] [Chemical formula]

[0327] Starting from D12, using D22 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E25 (9 mg, 0.015 mmol, y = 42%). 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.94 - 2.41 (m, 2 H) 3.47 - 4.26 (m, 9 H) 4.38 - 4.73 (m, 2 H) 7.38 (t, J = 9.08 Hz, 1 H) 7.50 (d, J = 4.13 Hz, 1 H) 7.57 - 7.71 (m, 1 H) 7.89 - 8.04 (m, 1 H) 8.29 (s, 1 H) 9.26 - 9.46 (m, 2 H). Method 3: Rt = 3.58 min; m / z = 582.30 (M+H) + .

[0328] (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)

[0329] [Chemical formula]

[0330] Starting from D12, using D24 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E26 (6 mg, 0.01 mmol, y = 27%). 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.44 - 1.62 (m, 6 H) 1.99 - 2.37 (m, 2 H) 3.45 - 4.02 (m, 7 H) 4.34 - 4.72 (m, 2 H) 7.38 (t, J=9.08 Hz, 1 H) 7.50 (s, 1 H) 7.65 (dtd, J=8.85, 4.29, 4.29, 2.75 Hz, 1 H) 7.96 (dd, J=6.79, 2.57 Hz, 1 H) 8.29 (d, J=2.48 Hz, 1 H) 8.55 (d, J=26.00 Hz, 1 H) 9.40 (d, J=17.15 Hz, 1 H). Method 3: Rt = 3.84 min; m / z = 610.32 (M+H) + .

[0331] (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)

[0332] [Chemical formula]

[0333] Starting from D16 and using D22 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E27 (10 mg, 0.017 mmol, y = 39%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.99 - 2.36 (m, 2 H) 3.43 - 4.28 (m, 9 H) 4.43 - 4.72 (m, 2 H) 6.97 - 7.43 (m, 2 H) 7.49 (d, J = 4.03 Hz, 1 H) 7.72 - 7.86 (m, 1 H) 8.02 (br d, J = 5.78 Hz, 1 H) 8.28 (s, 1 H) 9.26 - 9.41 (m, 1 H) 9.48 (s, 1 H). Method 3: Rt = 3.43 min; m / z = 598.30 (M+H) + .

[0334] (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)

[0335] [Chemical formula]

[0336] Starting from D16 and using D24 instead of D20, it was prepared in the same manner as described for compound E12 to obtain E28 (8.36 mg, 0.013 mmol, y = 31%). 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.46 - 1.59 (m, 6 H) 1.98 - 2.38 (m, 2 H) 3.42 - 4.11 (m, 7 H) 4.35 - 4.70 (m, 2 H) 6.90 - 7.42 (m, 2 H) 7.43 - 7.56 (m, 1 H) 7.70 - 7.90 (m, 1 H) 7.92 - 8.11 (m, 1 H) 8.28 (s, 1 H) 8.39 - 8.69 (m, 1 H) 9.47 (d, J=16.05 Hz, 1 H). Method 3: Rt = 3.69 min; m / z = 626.32 (M+H) + .

[0337] (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)

[0338]

Chem.

[0339] Starting from E11, it was prepared in the same manner as described for compound E3 to obtain E29 (1.07 mg, 0.002 mmol, y = 6%). 11H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.97 Hz, 3 H) 1.99 - 2.38 (m, 2 H) 3.39 - 4.23 (m, 7 H) 4.39 - 4.77 (m, 3 H) 6.96 - 7.48 (m, 2 H) 7.81 (br dd, J=8.30, 3.90 Hz, 1 H) 7.91 - 8.08 (m, 1 H) 8.58 (d, J=5.78 Hz, 1 H) 9.32 (t, J=9.17 Hz, 1 H) 9.70 (d, J=7.61 Hz, 1 H). Method 3: Rt = 3.73 min; m / z = 646.24 (M+H) + .

[0340] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E30)

[0341]

Chem.

[0342] Starting from E7, it was prepared in the same manner as described for compound E3 to obtain E30 (1.52 mg, 0.002 mmol, y = 9%). 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.25 - 1.33 (m, 3 H) 1.44 - 1.73 (m, 3 H) 1.99 - 2.19 (m, 2 H) 3.00 - 3.23 (m, 1 H) 3.28 - 3.45 (m, 1 H) 3.45 - 3.62 (m, 1 H) 3.81 (s, 3 H) 4.01 - 4.17 (m, 1 H) 4.43 (s, 2 H) 4.55 - 4.74 (m, 1 H) 7.39 (t, J = 9.03 Hz, 1 H) 7.56 - 7.69 (m, 1 H) 7.94 (dd, J = 6.79, 2.57 Hz, 1 H) 8.21 (s, 1 H) 9.32 (dd, J = 8.85, 4.54 Hz, 1 H) 9.57 (s, 1 H). Method 3: Rt = 3.80 min; m / z = 644.28 (M+H) + .

[0343] (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)

[0344] [Chemical formula]

[0345] Starting from E9, it was prepared in the same manner as described for compound E3, and E31 (0.6 mg, 0.001 mmol, y = 6%) was obtained. 11H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (dd, J = 6.97, 2.38 Hz, 3 H) 3.82 (d, J = 1.47 Hz, 3 H) 4.01 - 4.24 (m, 2 H) 4.45 - 4.82 (m, 5 H) 7.38 (t, J = 9.08 Hz, 1 H) 7.62 - 7.74 (m, 1 H) 7.91 - 8.01 (m, 1 H) 9.01 (d, J = 5.04 Hz, 1 H) 9.27 (t, J = 9.26 Hz, 1 H) 9.59 (d, J = 5.23 Hz, 1 H). Method 3: Rt = 3.90 min; m / z = 616.19 (M+H) + .

[0346] (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)

[0347] [Chemical formula]

[0348] Starting from E10, it was prepared in the same manner as described for compound E3, and E32 (0.47 mg, 0.001 mmol, y = 3%) was obtained. 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.31 (dd, J=7.01, 2.61 Hz, 3 H) 3.77 - 3.87 (m, 3 H) 4.01 - 4.23 (m, 2 H) 4.46 - 4.80 (m, 5 H) 6.97 - 7.43 (m, 2 H) 7.76 - 7.91 (m, 1 H) 8.02 (br d, J=4.95 Hz, 1 H) 9.01 (d, J=5.04 Hz, 1 H) 9.27 (t, J=8.94 Hz, 1 H) 9.67 (d, J=5.13 Hz, 1 H). Method 3: Rt = 3.74 min; m / z = 632.5 (M+H) + .

[0349] (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)

[0350]

Chemical Structure

[0351] Starting from E4, it was prepared in the same manner as described for compound E3 to obtain E33 (4 mg, 0.006 mmol, y = 14%). 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.31 (dd, J=6.83, 5.27 Hz, 3 H) 1.97 - 2.38 (m, 2 H) 3.42 - 4.16 (m, 7 H) 4.44 - 4.75 (m, 3 H) 7.41 (t, J=9.12 Hz, 1 H) 7.64 (ddd, J=9.06, 4.29, 2.61 Hz, 1 H) 7.95 (dt, J=6.79, 2.48 Hz, 1 H) 8.61 (d, J=12.20 Hz, 1 H) 9.30 (dd, J=13.57, 8.99 Hz, 1 H) 9.62 (s, 1 H). Method 3: Rt = 3.88 min; m / z = 630.2 (M+H) + .

[0352] (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)

[0353]

Chem.

[0354] Starting from E6, it was prepared in the same manner as described for compound E3 to obtain E34 (2.75 mg, 0.001 mmol, y = 16%). 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.30 (dd, J=6.74, 5.36 Hz, 3 H) 2.07 - 2.35 (m, 2 H) 3.39 - 4.18 (m, 7 H) 4.33 - 4.83 (m, 3 H) 6.91 - 7.48 (m, 2 H) 7.72 - 7.88 (m, 1 H) 8.00 (br d, J=6.14 Hz, 1 H) 8.60 (d, J=12.01 Hz, 1 H) 9.29 (dd, J=14.08, 9.03 Hz, 1 H) 9.69 (s, 1 H). Method 3: Rt = 3.73 min; m / z = 646.3 (M+H) + .

[0355] (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[piperidine-4,3'-pyrrolo[3,4-b][1,4,5]oxathiazepine]-6'-carboxamide 1',1'-dioxide (E35)

[0356]

Chemical formula

[0357] Starting from E8, it was prepared in the same manner as described for compound E3 to obtain E35 (1.6 mg, 0.002 mmol, y = 11%). 11H NMR (300 MHz, DMSO-d6 + TFA) δ ppm 1.25 - 1.35 (m, 3 H) 1.43 - 1.73 (m, 2 H) 1.99 - 2.17 (m, 2 H) 2.99 - 3.19 (m, 1 H) 3.28 - 3.45 (m, 1 H) 3.45 - 3.61 (m, 1 H) 3.81 (s, 3 H) 3.99 - 4.20 (m, 1 H) 4.42 (s, 2 H) 4.55 - 4.75 (m, 1 H) 7.22 (t, J = 54.00 Hz, 1 H) 7.32 - 7.38 (m, 1 H) 7.74 - 7.87 (m, 1 H) 7.99 (dd, J = 6.24, 2.29 Hz, 1 H) 8.21 (s, 1 H) 9.32 (dd, J = 8.89, 4.49 Hz, 1 H) 9.64 (s, 1 H). Method 3: Rt = 3.65 min; m / z = 660.41 (M+H) + .

[0358] (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)

[0359]

Chemical formula

[0360] The compound was prepared from D2 as described for the synthesis of E1 using D20 instead of D4. NMR: 11H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.22 - 1.39 (m, 3 H) 1.92 - 2.40 (m, 2 H) 3.44 - 4.18 (m, 7 H) 4.40 - 4.72 (m, 3 H) 7.30 - 7.57 (m, 3 H) 7.75 - 7.92 (m, 1 H) 8.29 (m, 1 H) 9.21 - 9.37 (m, 1 H) 9.44 (br dd, J=8.16, 2.84 Hz, 1 H). Method 3: Rt = 3.54 min; m / z = 580.32 (M+H) + .

[0361] (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)

[0362]

Chemical formula

[0363] The compound was prepared from E36 using the same procedure as described for the synthesis of E3. 1 1H NMR (300 MHz, DMSO-d6+TFA) δ ppm 1.25 - 1.40 (m, 3 H) 1.89 - 2.38 (m, 2 H) 3.38 - 4.18 (m, 7 H) 4.37 - 4.80 (m, 3 H) 7.25 - 7.55 (m, 2 H) 7.66 - 7.95 (m, 1 H) 8.48 - 8.67 (m, 1 H) 9.14 - 9.40 (m, 1 H) 9.64 (t, J=3.94 Hz, 1 H). Method 3: Rt = 3.74 min; m / z = 614.22 (M+H) + .

[0364] Biology Assay Cells and culture conditions The HepAD38 cell line (Ladner et al., Antimicrob Agents Chemother, 1997, 41, 1715 - 20) was used for the HBV inhibition assay. HepAD38 is a subclone derived from the hepatoblastoma cell line HepG2 (ATCC® number: HB - 8065™) and expresses the HBV genome under the transcriptional control of a tetracycline - responsive promoter in the TET - OFF system: addition of antibiotics belonging to the class of doxycycline and tetracycline suppresses HBV replication, while removal of them switches on a process that allows the release of HBV viral particles in the cell supernatant. The HepAD38 cell line is maintained in DMEM / F12 supplemented with 10% fetal bovine serum, 1% glutamine, 1% penicillin / streptomycin, 0.4 mg / ml G418 and 0.3 μg / ml tetracycline. For the HBV inhibition assay, doxycycline - free medium is used to allow virion production.

[0365] Anti - HBV activity in vitro The HBV inhibition activity in vitro was performed in 96 - well plates. During the first (primary) screening, compounds were first tested in triplicate at concentrations of 0.02 μM, 0.1 μM, 0.5 μM and 1 μM. For the selected compounds, an 8 - point dose - response curve was obtained using 1:2 serial dilutions (starting from 0.01 μM, 0.1 μM, 0.4 μM or 5 μM depending on the degree of inhibition observed during the primary screening). From the dose - response curve, the half - maximal effective concentration (EC 50 ) can be calculated (see also below).

[0366] More specifically, usually, the compound dissolved in DMSO stock solution was diluted to 2× the final desired concentration in 100 μl of the above medium (without doxycycline) and plated in 96 - well plates in triplicate.

[0367] Meanwhile, HepAD38 cells that had been thoroughly pre-washed in doxycycline-free medium to induce HBV production were suspended in 100 μl of doxycycline-free medium at 2×10 4 cells and added to each well of the plate to obtain a final assay volume of 200 μl of DMSO used for the stock solution and compound dilution, with DMSO always present in the assay at a final concentration of 0.5%.

[0368] The plates were incubated at 37 °C for 96 hours and then subjected to a cell viability assay and extracellular HBV quantification to evaluate both the cytotoxic performance and antiviral agent activity of the compounds.

[0369] Cytotoxicity was evaluated by a commercially available fluorescence assay that measures the metabolic activity of the cells, which is directly related to cell viability (Cell Titer Blue, Promega). Antiviral activity was evaluated by quantification of extracellular HBV DNA using direct qPCR. Specifically, the supernatant was collected, centrifuged for cell debris clarification, and viral DNA was extracted from the virions by the addition of lysis buffer (1 mM 1,4-dithiothreitol, 0.2% sodium dodecyl sulfate) and incubated at 95 °C for 10 minutes. The samples were then diluted 1:40 and real-time PCR amplification was performed using a SYBR green assay (Power SYBR™ Green PCR Master Mix - Thermo Fisher Scientific) and specific HBV primers (HBV-DF: 5'-ATTTGTTCAGTGGTTCGTAGGG-3' (SEQ ID NO: 1), HBV-DR: 5'-CGGTAAAAAGGGACTCAAGATG-3' (SEQ ID NO: 2)).

[0370] The antiviral activity data for each compound are reported as an EC 50 value (see legend to Table 1). Excel and Graphpad Prism programs are commonly used for data refinement and EC 50 calculation.

[0371] Results The exemplified compounds described in this specification were tested in the above assay. All compounds did not show significant cytotoxicity at all concentrations of the dose - response curve (the maximum test dose among 0.01 μM, 0.1 μM, 0.4 μM or 5 μM, depending on compound potency).

[0372] The results of HBV inhibition are reported in Table 1 below.

[0373]

Table 1A

[0374]

Table 1B

[0375]

Table 1C

[0376]

Table 1D

Claims

1. General formula (I): 【Chemical 1】 [In the formula, Cy is aryl or heteroaryl, each of m and n is independently 1 or 2, R 1 is H, F, Br, Cl or CH 3 and R 2 is a 5-membered heteroaryl ring optionally substituted with one or more substituents each independently selected from the group consisting of -OH, halogen, CN, methyl and trifluoromethyl, or -C(=O)NR 3 R 4 (wherein R 3 is H, and R 4 is C 1-3 alkyl, halo C 1-4 alkyl, and C 3-5 cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine and CF 3, or R 3 and R 4 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, and each of said cyclic amines is optionally substituted with one or more substituents each independently selected from the group consisting of methyl, fluorine and CF 3 ) and Ra, Rb, Rc and Rd are each independently selected from the group consisting of hydrogen, Cl, F, methyl and CHF 2 ) A compound represented by or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

2. m is 1, n is 2, or m is 2, n is 2, or m is 1, n is 1, or R 1 is H or Cl, The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. 【Fig. 2】 is [Chemical Formula 3] represents a compound according to claim 1 or 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. R 2 is 【Chemical Formula 4】 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

5. 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; - N-(3,4-Difluorophenyl)-7'-methyl-1-(5-methyl-1,3,4-oxadiazole-2-carbonyl)-2'H,4'H,7'H-spiro[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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[piperidine-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; - 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; - (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; - 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; - (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[piperidine-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[piperidine-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 A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof selected from

6. A composition for medical use comprising the compound, pharmaceutically acceptable salt, solvate or stereoisomer according to any one of claims 1 to 5.

7. The composition according to claim 6 for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection.

8. For use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from potential HBV infection, the composition according to claim 6 or 7.

9. A composition according to any one of claims 6 to 8, wherein said use is in combination with at least one further therapeutic agent.

10. A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt, solvate or stereoisomer according to any one of claims 1 to 5, alone or in combination with at least one further therapeutic agent and at least one pharmaceutically acceptable excipient.

11. The pharmaceutical composition according to claim 10 for use in the treatment and / or prevention of HBV infection and / or conditions associated with HBV infection.

12. For use in the treatment, eradication, reduction, deceleration or inhibition of HBV infection in an individual in need thereof, and / or in the reduction of viral load associated with HBV infection in an individual in need thereof, and / or in the reduction of recurrence of HBV infection in an individual in need thereof, and / or in the induction of remission of liver injury from HBV infection in an individual in need thereof, and / or in the prophylactic treatment of HBV infection in an individual suffering from potential HBV infection, the pharmaceutical composition according to claim 10 or 11.

13. A method for synthesizing the compound, pharmaceutically acceptable salt, solvate or stereoisomer according to any one of claims 1 to 5, comprising the following steps: 【Chemical Formula 5】 - Reacting the compound of formula (6) with a drug selected from the group consisting of the compound of formula (9), an acid of formula R 2 COOH, and an acyl chloride of formula R 2 COCl; ​ - reacting a compound of formula (7) or (8) with an amine of formula NHR 3 R 4 ​ including at least one of the following steps: - A step of reacting the compound of formula (6) with methyl 2-chloro-2-oxoacetate to obtain the compound of formula (7); - A step of hydrolyzing the compound of formula (7) in the presence of a base to obtain the compound of formula (8) The method may further include at least one of the above steps.

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