Pyrrole compounds

Abstract

To provide pharmaceutical compositions that include compounds for use in the treatment of HBV and / or HDV infections or pharmaceutically acceptable salts thereof.SOLUTION: Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of the compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and / or conditions with compounds of Formula (I), or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Incorporation by reference of any priority application) Any and all applications for which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application, including, for example, U.S. Provisional Patent Application No. 62 / 828,919, filed April 3, 2019, and U.S. Provisional Patent Application No. 62 / 932,686, filed November 8, 2019, are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6. background

[0002] FIELD OF THE INVENTION This application relates to the fields of chemistry, biochemistry, and medicine. Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharmaceutically acceptable salts of the compounds described herein), and methods for their synthesis. Also disclosed herein are methods for treating diseases and / or conditions with compounds of formula (I) or pharmaceutically acceptable salts thereof. [Background technology]

[0003] Hepatitis B virus (HBV) is a DNA virus and a member of the Hepadnaviridae family. HBV infects over 300 million people worldwide and is the causative agent of chronic hepatitis, cirrhosis, and liver cancer and liver diseases such as hepatocellular carcinoma. Although approved drugs exist to treat HBV by either boosting the immune system or slowing HBV viral replication, HBV remains problematic due to drawbacks associated with each of the approved drugs. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] TJ Liang, Hepatology (2009) 49(5 Suppl):S13-S21 Summary of the Invention [Means for solving the problem]

[0005] Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0006] Some embodiments disclosed herein relate to pharmaceutical compositions that can contain an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from an HBV and / or HDV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating HBV and / or HDV infection.

[0008] Some embodiments disclosed herein relate to methods of inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in inhibiting HBV and / or HDV replication. These and other embodiments are described in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0009] HBV is a partially double-stranded circular DNA of approximately 3.2 kilobase (kb) pairs and is classified into eight genotypes, A through H. The HBV replication pathway has been studied in great detail. TJ Liang, Hepatology (2009) 49(5 Suppl):S13-S21. Part of replication involves the formation of a covalently closed circular (cccDNA) form. The presence of cccDNA poses a risk of viral re-emergence throughout the lifespan of the host organism. HBV carriers can transmit the disease for several years. An estimated 300 million people live with hepatitis B virus infection, and more than 750,000 people worldwide are estimated to die from hepatitis B each year. In addition, immunosuppressed individuals or those undergoing chemotherapy are particularly at risk for reactivation of HBV infection. HBV can be acute and / or chronic. Acute HBV infection can be asymptomatic or present with symptomatic acute hepatitis.

[0010] HBV can be transmitted by blood, semen, and / or other bodily fluids. This can occur through direct blood-to-blood contact, unprotected sex, needle sharing, and from infected mothers to infants during the birth process. HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available medications do not cure HBV and / or HDV infections. Rather, the medications suppress viral replication.

[0011] Hepatitis D virus (HDV) is a DNA virus in the Hepadnaviridae family of viruses. HDV can only be transmitted in the presence of HBV. The transmission route of HDV is similar to that of HBV. HDV transmission can occur either through simultaneous infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carriage (superinfection). Both superinfection and coinfection with HDV result in more serious complications compared to infection with HBV alone. These complications include a higher likelihood of experiencing liver damage in acute infection, rapid progression to cirrhosis, and an increased risk of developing liver cancer in chronic infection. In combination with hepatitis B, hepatitis D has the highest case fatality rate of all hepatitis infections, at 20%. Currently, there is no cure or vaccine for hepatitis D. definition

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0013] Whenever a group is described as being "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are specified, it means that the specified "optionally substituted" or "substituted" group may be substituted with one or more groups individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino, and disubstituted amino.

[0014] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described by those definitions is assumed.

[0015] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms. (Whenever a numerical range such as "1 to 20" appears herein, it refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms; however, this definition also encompasses the term "alkyl" without a specified numerical range.) The alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0016] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. The length of the alkenyl can vary. For example, an alkenyl can be C 2~4 Alkenyl, C 2~6 Alkenyl, or C 2~8 It may be alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl, and ethenyl. The alkenyl group may be unsubstituted or substituted.

[0017] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. The length of an alkynyl group can vary. For example, an alkynyl group can be C 2~4 Alkynyl, C 2~6Alkynyl, or C 2~8 It may be alkynyl. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted.

[0018] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of more than one ring, the rings may be joined by fusion. A cycloalkyl group can contain 3 to 10 atoms in the ring(s); 3 to 8 atoms in the ring(s); or 3 to 6 atoms in the ring(s). A cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0019] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). When composed of more than one ring, the rings may be joined by fusion. A cycloalkenyl group can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. A cycloalkenyl group can be unsubstituted or substituted.

[0020] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0021] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0022] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with one to five heteroatoms, constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized π-electron system does not occur throughout all rings. The number of atoms in the rings of a heterocyclyl group may vary. For example, heterocyclyl groups can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined by fusion. Additionally, any nitrogen in a heterocyclyl may be quaternized. A heterocyclyl group can be substituted or unsubstituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, tetrahydro-1,4-thi ... Examples of suitable amines include, but are not limited to, thiazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrroldione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0023] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0024] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and benzo-fused analogs thereof.

[0025] "(Heterocyclyl)alkyl" refers to a heterocyclic group bonded as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of the heteroalicyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0026] A "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed in the definition of "substituted."

[0027] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxy can be substituted or unsubstituted.

[0028] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0029] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a hydroxy group. Representative hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl may be substituted or unsubstituted.

[0030] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0031] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

[0032] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl can be substituted or unsubstituted.

[0033] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0034] A "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0035] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxy can be substituted or unsubstituted.

[0036] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0037] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0038] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group where each X is a halogen.

[0039] The "trihalomethanesulfonamide" group is "X3CS(O)2N(R A )— group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0040] As used herein, the term "amino" refers to the group --NH.sub.2.

[0041] As used herein, the term "hydroxy" refers to an --OH group.

[0042] A "cyano" group refers to a "-CN" group.

[0043] As used herein, the term "azido" refers to the group --N.sub.3.

[0044] An "isocyanato" group refers to a "-NCO" group.

[0045] A "thiocyanato" group refers to a "-CNS" group.

[0046] An "isothiocyanato" group refers to a "-NCS" group.

[0047] A "mercapto" group refers to a "-SH" group.

[0048] A "carbonyl" group refers to a C=O group.

[0049] The "S-sulfonamide" group is defined as "-SO2N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0050] The "N-sulfonamide" group is "RSO2N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0051] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B ) group, where R A and R Bmay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0052] The "N-carbamyl" group is "ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0053] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0054] The "N-thiocarbamyl" group is "ROC(=S)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0055] A "C-amido" group is defined as "-C(=O)N(R A R B) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0056] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0057] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0058] As used herein, the term "α-amino acid" refers to any amino acid, both standard and non-standard. Examples of suitable α-amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

[0059] As used herein, the term "phosphate" is used in its ordinary sense as understood by those of ordinary skill in the art. [ka] in its protonated form (e.g., [ka] ) is included.

[0060] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0061] As used herein, the abbreviations for any protecting groups, amino acids, and other compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)) unless otherwise indicated.

[0062] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium or potassium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0063] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "comprising" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "comprising," "containing," or "featuring," and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "examples" is used to provide illustrative examples of items under description, not an exhaustive or limiting list thereof. Additionally, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0064] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate for context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality.

[0065] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0066] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0067] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of said element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0068] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment. compound

[0069] Some embodiments disclosed herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 represents unsubstituted or substituted C2 alkenyl, unsubstituted or substituted C2 alkynyl, unsubstituted C 1~4 The C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl may be independently selected from halogen, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl, and when the C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are substituted, the C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl may be independently selected from halogen, unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, and monocyclic heteroaryl. 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 cycloalkyl; R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5 alkoxyalkyl, and monocyclic C 3~6 When cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6 The cycloalkyl and monocyclic 3-6 heterocyclyl may be substituted with one or more substituents independently selected from halogen or hydroxy; 1~4 When alkyl is substituted, C 1~4 The alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, or R 2 and R 3is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6 The cycloalkyl and 3- to 6-membered heterocyclyl are optionally substituted with one or two substituents independently selected from halogen and hydroxy; R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 6 is hydrogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 3~4 alkenyl, provided that R 4 , R 5 and R 6 At least one of is not hydrogen, or R 5 is hydrogen, halogen, unsubstituted C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 4 and R 6 may be taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring, X 1 is CR A or N (nitrogen), and R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1~4 Haloalkyl, cyano, or unsubstituted C 1~4 may be alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH- (α-amino acid), or -CH-phosphate; R Ais hydrogen, halogen, unsubstituted C 1~4 It may be haloalkyl or cyano.

[0070] Various groups can be attached to the pyrrole ring of formula (I). As provided herein, the pyrrole ring can be any group including hydrogen, halogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl and / or unsubstituted C 2~4 alkenyl, provided that R 4 , R 5 and R 6 At least one of the C is not hydrogen. 1~4 Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 4 and R 5 One of the groups is halogen or unsubstituted C 1~4 alkyl and / or R 6 is the unsubstituted C 1~4 In other embodiments, R 4 and / or R 5 are each independently a halogen or unsubstituted C 1~4 alkyl and / or R 6 is the unsubstituted C 1~4 In yet another embodiment, R 4 and R 5 are each independently a halogen or unsubstituted C 1~4 alkyl, and R 6 is the unsubstituted C 1~4 In still other embodiments, R 4 , R 5 and R 6 One of them is unsubstituted C 1~4 alkyl, and R 4 , R 5 and R 6 One of them is unsubstituted C 3~4 R may be alkenyl. 4 , R 5 and R6 One of them is deuterated C 1~4 When it is alkyl, C 1~4 One or more hydrogen atoms in the alkyl group may be replaced with deuterium atoms. For example, R 4 , R 5 and R 6 One of R may be CH2D, CHD2, CD3, CH2CD3, CD2CD3, CH2CH2CD3, CH(CD3)2. In some embodiments, R 4 , R 5 and R 6 One of them is deuterated C 1~4 alkyl, and R 4 , R 5 and R 6 The other two are unsubstituted C 1~4 It may also be alkyl.

[0071] In some embodiments, R 4 may be hydrogen, and R 5 may be hydrogen, and R 6 is unsubstituted C 1~4 In other embodiments, R 4 may be halogen, R 5 may be hydrogen, and R 6 is unsubstituted C 1~4 In yet another embodiment, R 4 may be hydrogen, and R 5 may be halogen, R 6 is unsubstituted C 1~4 In yet another embodiment, R 4 may be hydrogen, and R 5 is unsubstituted C 1~4 may be alkyl, R 6 is unsubstituted C 3~4 It may also be alkenyl.

[0072] In some embodiments, R 4 may be hydrogen, and R 5 may be halogen, R 6 may be hydrogen. In other embodiments, R4 may be hydrogen, and R 5 may be halogen, R 6 may be hydrogen. In yet other embodiments, R 4 may be halogen, R 5 may be halogen, R 6 may be hydrogen. In still other embodiments, R 4 is unsubstituted C 1~4 may be alkyl, R 5 may be hydrogen, and R 6 is unsubstituted C 1~4 In some embodiments, R 4 is unsubstituted C 1~4 may be alkyl, R 5 may be halogen, R 6 is unsubstituted C 1~4 In other embodiments, R 4 is unsubstituted C 1~4 may be alkyl, R 5 is unsubstituted C 1~4 may be alkyl, R 6 is unsubstituted C 1~4 In yet another embodiment, R 4 , R 5 and / or R 6 is unsubstituted C 1~4 When alkyl, unsubstituted C 1~4 The alkyl may be methyl. For example, R 4 , R 5 and R 6 and R may each be methyl. 4 may be hydrogen, and R 5 and R 6 are unsubstituted C 1~4 In some embodiments, R 4 may be halogen, R 5 and R 6 are unsubstituted C 1~4 In other embodiments, R 5 may be halogen, R 4 and R6 are unsubstituted C 1~4 In yet another embodiment, R 4 and R 5 may each be hydrogen, and R 6 is unsubstituted C 1~4 In still other embodiments, R 4 may be hydrogen, and R 5 may be halogen, R 6 is unsubstituted C 1~4 In some embodiments, R 4 and R 5 may each be a halogen, and R 6 is unsubstituted C 1~4 In other embodiments, R 4 and R 5 are unsubstituted C 1~4 may be alkyl, R 6 is deuterated C 1~4 It may also be alkyl, for example CD3.

[0073] As provided herein, in some embodiments, R 5 is hydrogen, halogen, unsubstituted C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 4 and R 6 may be taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring. For example, R 4 and R 6 together, unsubstituted or substituted [ka] , or unsubstituted or substituted [ka] where N* represents the nitrogen of the pyrrolyl of formula (I). In some embodiments, R 5 may be hydrogen, and R 4 and R 6may be taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring, such as those described herein. In other embodiments, R 5 may be halogen, R 4 and R 6 may be taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring, such as those described herein. 5 is unsubstituted C 1~4 may be alkyl, R 4 and R 6 may be taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring, such as those described herein. In still other embodiments, R 5 is unsubstituted C 2~4 may be alkenyl, and R 4 and R 6 may be taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring such as those described herein.

[0074] X 1 The six-membered aromatic ring containing X may be an optionally substituted phenyl or an optionally substituted pyridine. 1 is CR A When X is, the six-membered ring may be an optionally substituted phenyl. 1 When is N (nitrogen), the six-membered aromatic ring may be an optionally substituted pyridine. 1 The six-membered aromatic ring, including the phenyl and / or pyridine, may be substituted. When substituted, the phenyl and / or pyridine may be substituted one, two, three or more times. The substituted phenyl ring may be substituted at the para position. Additionally or alternatively, the phenyl ring may be substituted at the meta position. In some embodiments, the phenyl ring may be substituted at the ortho position.

[0075] In some embodiments, X 1 may be CH. In other embodiments, X 1 is CR A X 1 is CR A When R Amay be a non-hydrogen group. For example, in some embodiments, R A may be halogen (e.g., F, Cl, or Br). In other embodiments, R A is the unsubstituted C 1~4 It may be haloalkyl. 1~4 Haloalkyl includes, but is not limited to, -CHF, -CF, CHF, CHClF, and CCl. In yet other embodiments, R A In still other embodiments, R A is unsubstituted C 1~4 It may also be alkoxy. Exemplary C 1~4 Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0076] As described herein, R 7b and / R 7c R may be hydrogen. A Similarly, R 7b and / R 7c is a non-hydrogen group, e.g., halogen, unsubstituted C 1~4 Haloalkyl, cyano, and unsubstituted C 1~4 In some embodiments, R 7b may be hydrogen. In other embodiments, R 7b may be halogen (e.g., F, Cl, or Br). In yet other embodiments, R 7b is the unsubstituted C 1~4 Haloalkyl, for example, as described herein, may include -CHF, -CF, and -CHF. In still yet other embodiments, R 7b In some embodiments, R 7b is an unsubstituted C, such as those described herein. 1~4 In some embodiments, R 7c may be hydrogen. In other embodiments, R 7c may be a halogen, such as F, Cl, or Br. In yet other embodiments, R7c is the unsubstituted C 1~4 It may also be haloalkyl, for example, —CHF, —CF, —CHF, —CHClF, and —CCl. In still other embodiments, R 7c In some embodiments, R 7c is the unsubstituted C 1~4 It may be alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0077] X 1 As well as other positions on the six-membered aromatic ring, including R 7a and / or R 7d may be hydrogen or a non-hydrogen group. In some embodiments, R 7a may be hydrogen. In other embodiments, R 7a may be a halogen, such as F, Cl, or Br. In yet other embodiments, R 7a is the unsubstituted C 1~4 It may also be haloalkyl, for example, —CHF, —CF, —CHF, —CHClF, and —CCl. In still other embodiments, R 7a In some embodiments, R 7a is an unsubstituted C, including but not limited to those described herein. 1~4 In some embodiments, R 7d may be hydrogen. In other embodiments, R 7d may be halogen (e.g., F, Cl, or Br). In yet other embodiments, R 7d is the unsubstituted C 1~4 and haloalkyl (including, but not limited to, -CHF, -CF, -CHF, -CHClF, and -CCl). In still yet other embodiments, R 7d In some embodiments, R 7d is the unsubstituted C 1~4 It may also be alkoxy. For example, R 7dmay be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0078] In some embodiments, R A may be a non-hydrogen group as described herein, and R 7b or R 7c may be a non-hydrogen group as described herein. In other embodiments, R A R may be a non-hydrogen group as described herein. 7b or R 7c may be a non-hydrogen group as described herein, and R 7a and R 7d Each is hydrogen. In yet another embodiment, R A R may be a non-hydrogen group as described herein. 7b and R 7c may be a non-hydrogen group as described herein, and R 7b and R 7c The other of R may be hydrogen; 7a and R 7d are hydrogen atoms. 1 is a six-membered aromatic ring containing [ka] This is an example.

[0079] In some embodiments, R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5 alkoxyalkyl, and monocyclic C 3~6 When cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6The cycloalkyl and monocyclic 3-6 heterocyclyl may be substituted with one or more substituents independently selected from halogen or hydroxy; 1~4 When alkyl is substituted, C 1~4 The alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy. 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6 The cycloalkyl and 3- to 6-membered heterocyclyl are independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy.

[0080] R 2 and R 3 The substituents in may be the same or different, or R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 In some embodiments, R can form a cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl. 2 and R 3 and R may each be hydrogen. 2 and R 3 are unsubstituted C 1~4 Suitable unsubstituted C 1~4 Examples of alkyl are described herein. For example, R 2 and R 3 may each be methyl.

[0081] As described herein, R 2 and R3 can be different. For example, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other is unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5 In some embodiments, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other is an unsubstituted C alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 1~4 In another embodiment, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other is unsubstituted C 1~4 It may be haloalkyl. Exemplary C 1~4 Haloalkyl is described herein and includes, but is not limited to, -CHF, -CF, CHF, CHClF, and CCl. In yet other embodiments, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other of which is an unsubstituted or substituted monocyclic C 3~6 It may also be cycloalkyl. For example, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other of R may be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, and unsubstituted cyclohexyl, or R 2 and R 3 One of R may be hydrogen; 2 and R3 The other of the two may be substituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When substituted, the substituted monocyclic C 3~6 Cycloalkyl may be substituted one, two, or three times with substituents independently selected from halogen (F, Cl, or Br) and hydroxy. In some embodiments, substituted monocyclic C 3~6 The cycloalkyl may be substituted with one or two halogens. For example, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other of [ka] In still other embodiments, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other of the two may be an unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl. Various monocyclic 3- to 6-membered heterocyclyls are 2 / R 3 In some embodiments, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other is unsubstituted C 1~4 It may also be hydroxyalkyl. For example, R 2 and R 3 One of R may be hydrogen; 2 and R 3 The other of R may be —CHOH. 2 and R 3 One of R may be hydrogen; 2 and R 3 The other is unsubstituted C 1~5 It may be an alkoxyalkyl. Unsubstituted C 1~5 Examples of alkoxyalkyl include -CH2OCH3, -CH2CH2OCH3, and -CH2OCH2CH3、 Examples include -CH2CH2OCH2CH3, -CH2OCH(CH3)2, -CH2OCH2CH(CH3)2, and -CH2CH2OCH(CH3)2.

[0082] The prodrug moiety is R 2 and R 3 In some embodiments, R 2 and R 3 One of them is unsubstituted C 1~4 may be alkyl (e.g., methyl), and R 2 and R 3 The other of these is substitution C 1~4 alkyl, where C 1~4 The alkyl is substituted with one or more substituents selected from phosphate, O-linked α-amino acid, and O-carboxy. Suitable α-amino acids are described herein and include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. As used herein, "-O-linked α-amino acid" refers to an α-amino acid that is attached to the indicated site via a hydroxyl derived from its backbone carboxylic acid group. When an α-amino acid is attached to an -O-linked α-amino acid, the hydrogen that is part of the hydroxyl from its backbone carboxylic acid group is absent, and the α-amino acid is attached via the oxygen. In some embodiments, R 2 or R 3 C 1~4 The -O-linked α-amino acid substituted on the alkyl may be an -O-linked-L-α-amino acid. 2 or R 3 C 1~4 The -O-linked α-amino acid substituted on the alkyl may be an -O-linked-D-α-amino acid. Examples of -O-linked α-amino acids are shown herein as R 8 It is shown in terms of R 2 or R 3Substitution of C 1~4 Another example of a prodrug moiety that may be present on an alkyl is O-carboxy. In some embodiments, R 2 and R 3 One of them is unsubstituted C 1~4 may be alkyl (e.g., methyl), and R 2 and R 3 The other of these is an O-carboxy substituted C 1~4 It may be an alkyl, for example, an O-carboxy substituted C 1~4 Alkyl has the structure -(CH2)4-OC(=O)(unsubstituted C 1~4 As described herein, R 2 or R 3 C 1~4 The alkyl may be substituted with a phosphate. For example, R 2 or R 3 Substituted C having phosphate 1~4 When it is alkyl, R 2 or R 3 is -CH2-OP(=O)(O - )2 or —CH2—OP(═O)(OH)2.

[0083] As provided herein, R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 The cycloalkyl and 3- to 6-membered heterocyclyl are independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy. In some embodiments, R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted monocyclic C 3~6 In other embodiments, R 2 and R 3 is R 2 and R3 together with the carbon to which it is attached to form a substituted monocyclic C 3~6 It can form a cycloalkyl. 3~6 The cycloalkyl may be unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl. 3~6 When cycloalkyl is substituted, C 3~6 Cycloalkyl may be substituted one, two, three or more times. When two or more substituents are present, the substituents may all be the same, or at least some of the substituents may be different. For example, in some embodiments, C 3~6 The cycloalkyl may be substituted with one or two halogens (e.g., one or two fluoro substituents). 3~6 The cycloalkyl may be substituted with hydroxy. 3~6 Examples of cycloalkyl include unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, fluoro-substituted cyclopropyl, fluoro-substituted cyclobutyl, fluoro-substituted cyclopentyl, fluoro-substituted cyclohexyl, hydroxy-substituted cyclopropyl, hydroxy-substituted cyclobutyl, hydroxy-substituted cyclopentyl, hydroxy-substituted cyclohexyl, [ka] Examples include:

[0084] In some embodiments, R 2 and R 3 is R 2 and R 3 can be taken together with the carbon to which R is attached to form an unsubstituted monocyclic 3- to 6-membered heterocyclyl. 2 and R 3 is R 2 and R 3 can be taken together with the carbon to which it is attached to form a substituted monocyclic 3- to 6-membered heterocyclyl. For example, R 2 and R 3 is R2 and R 3 is attached to form an unsubstituted or substituted monocyclic 3-membered heterocyclyl, an unsubstituted or substituted monocyclic 4-membered heterocyclyl, an unsubstituted or substituted monocyclic 5-membered heterocyclyl, or an unsubstituted or substituted monocyclic 6-membered heterocyclyl. 2 and R 3 is R 2 and R 3 can be taken together with the carbon to which it is attached to form an unsubstituted monocyclic oxygen-containing 3-6 membered heterocyclyl. 2 and R 3 is R 2 and R 3 can be taken together with the carbon to which it is attached to form an unsubstituted monocyclic nitrogen-containing 3- to 6-membered heterocyclyl. Suitable monocyclic 3- to 6-membered heterocyclyls include unsubstituted or substituted oxetane, unsubstituted or substituted thietane, unsubstituted or substituted [ka] , unsubstituted or substituted [ka] , unsubstituted or substituted [ka] , unsubstituted or substituted [ka] , unsubstituted or substituted [ka] , and unsubstituted or substituted [ka] In some embodiments, R 2 and R 3 is R 2 and R3 together with the carbon to which it is bonded, [ka] can be formed.

[0085] Various unsaturated substituents are present in R 1 As described herein, R 1 may be substituted or unsubstituted. In some embodiments, R 1 may be an unsubstituted C alkenyl. In other embodiments, R 1 is halogen, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 In some embodiments, R may be a substituted C alkenyl, which may be substituted with one or more substituents independently selected from cycloalkyl. 1 may be an unsubstituted C alkynyl. In other embodiments, R 1 may be a substituted C2 alkynyl. C2 alkynyl is substituted with halogen, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 For example, a C2 alkynyl group can be substituted one or more times with substituents independently selected from unsubstituted monocyclic C 3~6 cycloalkyl, or C alkynyl is an unsubstituted C 1~4 In some embodiments, R 1 is the unsubstituted C 1~4 It may also be haloalkyl, such as CF3.

[0086] As described herein, some cyclic moieties may be R 1 In some embodiments, R 1may be an unsubstituted monocyclic heteroaryl. In other embodiments, R 1 may be a substituted monocyclic heteroaryl. Some suitable monocyclic heteroaryls are described herein. In some embodiments, R 1 may be an unsubstituted or substituted nitrogen-containing monocyclic heteroaryl, for example, R 1 is an unsubstituted or substituted 1,2,3-triazole (e.g., [ka] ), unsubstituted or substituted thiazoles (e.g., [ka] ), unsubstituted or substituted pyridinyl (e.g., [ka] ), unsubstituted or substituted pyrimidines (e.g., [ka] ), unsubstituted or substituted pyrazoles (e.g., [ka] ), unsubstituted or substituted imidazoles (e.g., [ka] ), or unsubstituted or substituted oxadiazoles (e.g., [ka] ), where each of the depicted structures can be unsubstituted or substituted (including that the hydrogen on the nitrogen can be replaced with a non-hydrogen substituent). In some embodiments, R 1 may be an unsubstituted bicyclic heteroaryl. In other embodiments, R 1may be a substituted bicyclic heteroaryl. Exemplary bicyclic heteroaryls are provided herein and include benzimidazole. In some embodiments, R 1 may be an unsubstituted monocyclic heterocyclyl. In other embodiments, R 1 may be a substituted monocyclic heterocyclyl. Some examples of suitable monocyclic heterocyclyls are described herein. In some embodiments, R 1 R may be unsubstituted or substituted 2-oxo-1H-pyridinyl. 1 When the cyclic portion of R is substituted, various substituents can be present. 1 Examples of substituents that may be present on the monocyclic heteroaryl include unsubstituted C 1~4 alkyl, unsubstituted cyclopropyl, and unsubstituted cyclobutyl.

[0087] Various substituents are R 8 In some embodiments, R 8 may be hydrogen. In other embodiments, R 8 is -CH2OC(=O)-(unsubstituted C 1~4 alkyl). For example, R 8 may be pivaloyloxymethyl (POM). In yet other embodiments, R 8 is -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), for example, isopropyloxycarbonyloxymethyl (POC). In still other embodiments, R 8 may be -CH2- (α-amino acid). Suitable α-amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. R 8 When R contains an α-amino acid, the carboxylic acid moiety is the moiety linked to the -CH of the -CH (α-amino acid) and the carboxylic acid hydrogen is absent. 8teeth, [ka] In some embodiments, R 8 The α-amino acid of -CH-(α-amino acid) may be an L-α-amino acid. 8 The α-amino acid of -CH-(α-amino acid) may be a D-α-amino acid. 8 is -CH2-phosphate ( [ka] ) may also be used.

[0088] Compounds of formula (I), and pharmaceutically acceptable salts thereof, may have a variety of structures. In some embodiments, R 1 may be unsubstituted or substituted C2 alkenyl, unsubstituted or substituted C2 alkynyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl, and may be C2 alkenyl, C2 alkynyl, unsubstituted C 1~4 When haloalkyl and monocyclic heteroaryl are substituted, C alkenyl, C alkynyl, and monocyclic heteroaryl are independently selected from halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 cycloalkyl; and R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5alkoxyalkyl, and monocyclic C 3~6 When cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6 The cycloalkyl and monocyclic 3-6 heterocyclyl are substituted with one or more substituents independently selected from halogen or hydroxy; 1~4 When alkyl is substituted, C 1~4 The alkyl is substituted with one or more substituents selected from phosphate, O-linked α-amino acid, and O-carboxy, provided that R 2 and R 3 At least one of them is not hydrogen, and R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 6 is hydrogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 3~4 alkenyl, provided that R 4 , R 5 and R 6 At least one of them is not hydrogen, and X 1 is CR A or N, R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1~4 Haloalkyl, cyano, or unsubstituted C 1~4 may be alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH- (α-amino acid), or -CH-phosphate; R A is hydrogen, halogen, unsubstituted C 1~4 In this paragraph, R 2 and R 3When at least one of the groups is not hydrogen, R 2 and R 3 Regarding (1)R 2 and R 3 are unsubstituted C 1~4 alkyl, e.g., methyl, (2) phosphate, O-linked α-amino acid, or O-carboxy-substituted C 1~4 Alkyl (e.g., —O(C═O)(unsubstituted C 1~4 alkyl), (3) unsubstituted C 1~4 haloalkyl (e.g., CF), (4) unsubstituted cyclopropyl, and (5) unsubstituted C 1~4 provided that it may be hydroxyalkyl (e.g., —CH 2 OH).

[0089] In other embodiments, R 1 may be unsubstituted or substituted C2 alkenyl, unsubstituted or substituted C2 alkynyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl, and may be C2 alkenyl, C2 alkynyl, unsubstituted C 1~4 When haloalkyl and monocyclic heteroaryl are substituted, C alkenyl, C alkynyl, and monocyclic heteroaryl are independently selected from halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 cycloalkyl; and R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6The cycloalkyl and 3- to 6-membered heterocyclyl are substituted with one or two substituents independently selected from halogen and hydroxy; R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 6 is hydrogen, unsubstituted C 1~4 Alkyl, deuterated C 1~4 Alkyl or unsubstituted C 3~4 alkenyl, provided that R 4 , R 5 and R 6 At least one of them is not hydrogen, and X 1 is CR A or N, R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1~4 Haloalkyl, cyano, or unsubstituted C 1~4 may be alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH- (α-amino acid), or -CH-phosphate; R A is hydrogen, halogen, unsubstituted C 1~4 As provided herein, R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted cyclobutyl, a fluorine-substituted cyclobutyl, a hydroxy-substituted cyclobutyl, or an unsubstituted oxetane.

[0090] In yet other embodiments, R 1 represents unsubstituted or substituted C2 alkenyl, unsubstituted or substituted C2 alkynyl, unsubstituted C 1~4The C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl may be independently selected from halogen, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl, and when the C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are substituted, the C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl may be independently selected from halogen, unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, and monocyclic heteroaryl. 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, unsubstituted monocyclic C 3~6 Cycloalkyl- and hydroxy-substituted monocyclic C 3~6 cycloalkyl; R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1~4 Hydroxyalkyl and unsubstituted C 1~5 alkoxyalkyl, and monocyclic C 3~6 When cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6 The cycloalkyl and monocyclic 3-6 heterocyclyl may be substituted with one or more substituents independently selected from halogen or hydroxy; 1~4 When alkyl is substituted, C 1~4 The alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, or R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3~6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6The cycloalkyl and 3- to 6-membered heterocyclyl are optionally substituted with one or two substituents independently selected from halogen and hydroxy; R 5 is hydrogen, halogen, unsubstituted C 1~4 Alkyl or unsubstituted C 2~4 may be alkenyl, and R 4 and R 6 may be taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring, X 1 is CR A or N (nitrogen), and R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1~4 Haloalkyl, cyano, or unsubstituted C 1~4 may be alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH- (α-amino acid), or -CH-phosphate; R A is hydrogen, halogen, unsubstituted C 1~4 It may be haloalkyl or cyano.

[0091] Examples of compounds of formula (I), or pharmaceutically acceptable salts thereof, include the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the above.

[0092] Further examples of compounds of formula (I), or pharmaceutically acceptable salts thereof, include the following: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the above.

[0093] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may not be one or more of the following compounds: [ka] or a pharmaceutically acceptable salt of any of the above. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may not be a compound provided in WO 2017 / 156255. In some embodiments, R 1In some embodiments, R 1 X cannot be unsubstituted or substituted tetrazole, unsubstituted or substituted 1,2,3 triazole, and / or unsubstituted or substituted imidazole. 1 is CR A This is not possible, R A is a halogen (e.g., F), and R 7B cannot be a halogen (such as F or Cl). In some embodiments, at least R A , R 7a , R 7b , R 7c and R 7d is the unsubstituted C 1~4 haloalkyl, such as CF. In some embodiments, R 4 and R 5 At least one of R is halogen. 4 , R 5 , and R 6 At least one of is a halogen. synthesis

[0094] Compounds of formula (I), as well as the compounds described herein, may be prepared in a variety of ways. General synthetic routes for preparing compounds of formula (I), along with some examples of starting materials used to synthesize the compounds described herein, are shown and described herein. The routes shown and described herein are exemplary only and are not intended to, and should not be construed as, limiting the scope of the claims in any way. Those skilled in the art will recognize modifications to the disclosed synthesis and will be able to devise alternative routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims. [ka]

[0095] The synthesis of compounds of formula (I) can be carried out as outlined in Scheme 1. Esters of formula (Ia) can be coupled with amines of formula (Ib) in a suitable solvent (such as THF) in the presence of a base, such as LiHMDS, to give amides of formula (Ic). Reaction of formula (Ic) with ethyl 2-chloro-2-oxoacetate in the presence of aluminum chloride in a suitable solvent (such as DCM) can give ketoesters of formula (Id). Subsequently, formula (Id) can be saponified under basic conditions, for example, using lithium hydroxide in a mixture of methanol and water, to give keto acid derivatives of formula (Ie). Coupling of formula (Ie) with substituted amines of formula (If) can be carried out in a suitable solvent (such as DCM) in the presence of a peptide coupling agent, such as HATU or EDCI / HOAT, and an organic amine base (e.g., EtN or DIPEA) to give compounds of formula (I) and pharmaceutically acceptable salts thereof. Pharmaceutical Composition

[0096] Some embodiments described herein relate to pharmaceutical compositions, which can include an effective amount of a compound described herein (e.g., a compound described herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and / or veterinary use.

[0097] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0098] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmacologically active but may be pharmaceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the composition of human blood.

[0099] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0100] Appropriate formulation design depends on the selected administration route.The techniques for formulation and administration of the compounds described herein are known to those skilled in the art.There are multiple techniques for administering compounds in the art, including but not limited to oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injection.Pharmaceutical compositions are generally tailored to the specific intended administration route.

[0101] Alternatively, the compounds can be administered locally rather than systemically, for example, by injecting the compound directly into the site of infection, often in a depot or sustained-release formulation. Additionally, the compounds can be administered in a targeted drug delivery system, for example, in liposomes coated with tissue-specific antibodies. Liposomes can be targeted to and taken up selectively by organs.

[0102] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts with pharmaceutically compatible counterions. How to use

[0103] Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from an HBV and / or HDV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0104] Some embodiments disclosed herein relate to methods of treating HBV and / or HDV infection, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HBV and / or HDV infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of HBV and / or HDV infection.

[0105] Some embodiments disclosed herein relate to methods for inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting HBV and / or HDV replication. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting HBV and / or HDV replication.

[0106] In some embodiments, the HBV infection can be an acute HBV infection. In some embodiments, the HBV infection can be a chronic HBV infection.

[0107] Some embodiments disclosed herein relate to methods for treating cirrhosis, developed for HBV and / or HDV infection, which may include administering to a subject suffering from cirrhosis an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV- and / or HDV-infected cells in a subject suffering from cirrhosis with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cirrhosis with an effective amount of the compound or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, to treat cirrhosis.

[0108] Some embodiments disclosed herein relate to methods for treating liver cancer (e.g., hepatocellular carcinoma) developed for HBV and / or HDV infection, which may include administering to a subject suffering from liver cancer an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV- and / or HDV-infected cells in a subject suffering from liver cancer with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating liver cancer (e.g., hepatocellular carcinoma). Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, to treat liver cancer (e.g., hepatocellular carcinoma).

[0109] Some embodiments disclosed herein relate to methods for treating liver damage developed for HBV and / or HDV infection, which may include administering to a subject suffering from liver damage an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV- and / or HDV-infected cells in a subject suffering from liver damage with the compound. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating liver damage. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, to treat liver damage.

[0110] Various indicators for determining the effectiveness of a method for treating HBV and / or HDV infection are also known to those skilled in the art. Examples of suitable indicators include viral load (or burden) indicated by a reduction in HBV DNA (e.g., <10 in serum). 5 These include, but are not limited to, reduction in HBV surface antigen (HBsAg) and HBV e-antigen (HBeAg), reduction in plasma viral load, reduction in viral replication, shortened time to seroconversion (undetectable virus in patient serum), increased rate of sustained viral response to therapy, improved liver function, and / or reduced morbidity or mortality in clinical outcomes.

[0111] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily imply a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Furthermore, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0112] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold- and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject is a human.

[0113] The term "effective amount" is used to refer to the amount of an active compound or drug that elicits the indicated biological or medical response. For example, an effective amount of a compound may be the amount necessary to alleviate or ameliorate the symptoms of a disease or prolong the survival of the treated subject. This response may occur in a tissue, system, animal, or human and includes alleviation of the signs or symptoms of the disease being treated. Determining an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be tailored to achieve the desired effect, depending on factors such as body weight, diet, concurrent medications, and other factors that one skilled in the medical field would recognize.

[0114] In some embodiments, an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof is an amount effective to achieve a sustained viral response, for example, a sustained viral response 12 months after completion of treatment.

[0115] Subjects clinically diagnosed with HBV and / or HDV infection include "naive" subjects (e.g., subjects not previously treated for HBV and / or HDV) and subjects who have failed prior HBV and / or HDV treatment ("treatment-failed" subjects). Treatment-failed subjects include "non-responders" (subjects who fail to achieve a sufficient reduction in ALT (alanine aminotransferase) levels, e.g., subjects who fail to achieve a greater than 1 log reduction from baseline within 6 months of initiating anti-HBV and / or anti-HDV therapy) and "relapsers" (subjects previously treated for HBV and / or HDV who have increased ALT levels, e.g., ALT >2x upper normal limit and detectable serum HBV DNA by hybridization assay). Further examples of subjects include subjects with asymptomatic HBV and / or HDV infection.

[0116] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be provided to a treatment-failed subject suffering from HBV and / or HDV. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be provided to a non-responder subject suffering from HBV and / or HDV. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be provided to a relapser subject suffering from HBV and / or HDV. In some embodiments, the subject may have HBeAg-positive chronic hepatitis B. In some embodiments, the subject may have HBeAg-negative chronic hepatitis B. In some embodiments, the subject may have cirrhosis. In some embodiments, the subject may be asymptomatic, e.g., the subject may be infected with HBV and / or HDV but does not exhibit any symptoms of viral infection. In some embodiments, the subject may be immunocompromised. In some embodiments, the subject may be undergoing chemotherapy.

[0117] Examples of drugs used to treat HBV and / or HDV include immunomodulators and nucleosides / nucleotides. Examples of immunomodulators include interferons (IFN-α and PEGylated interferons, including PEG-IFN-α-2a), and examples of nucleosides / nucleotides include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. However, some of the drawbacks associated with interferon therapy include adverse side effects, the need for subcutaneous administration, and high cost. Potential advantages of the compound of Formula (I), or a pharmaceutically acceptable salt of any of the foregoing, may include fewer adverse side effects, delayed onset of adverse side effects, and / or reduced severity of adverse side effects. A drawback of nucleoside / nucleotide therapy may be the development of resistance, including cross-resistance.

[0118] Resistance can be a cause of treatment failure. As used herein, the term "resistance" refers to a viral strain that exhibits a delayed, diminished, and / or ineffective response to an antiviral agent. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof can be provided to a subject infected with an HBV and / or HDV strain that is resistant to one or more anti-HBV and / or anti-HDV agents. Examples of antiviral agents to which resistance may develop include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. In some embodiments, when a subject is treated with a compound described herein or a pharmaceutically acceptable salt thereof, the development of resistant HBV and / or HDV strains is delayed compared to the development of HBV and / or HDV strains resistant to other HBV and / or HDV antiviral agents, such as those described.

[0119] Known compounds, such as those provided in WO 2017 / 156255, have been shown to form adducts with glutathione in in vitro assays. The formation of glutathione adducts can be an indicator that a compound may induce liver injury. Thus, the formation of glutathione adducts can be used as an indicator for predicting safety. Unexpectedly, many compounds described herein, such as compounds of formula (I) and pharmaceutically acceptable salts thereof, have been shown not to form adducts with glutathione in in vitro assays. Furthermore, known compounds (e.g., those described in WO 2017 / 156255) have been shown to be effective against the EC 100 / 100 standard. 50 Many of the compounds described herein, such as the compound of formula (I) and pharmaceutically acceptable salts thereof, unexpectedly exhibited potency in a HepG2.2.15 cell-based assay with an EC of >1000 pM. 50The compounds of formula (I) and pharmaceutically acceptable salts thereof exhibit improved potency in a HepG2.2.15 cell-based assay, with a RI of <1000 pM. Thus, the compounds described herein, including compounds of formula (I) and pharmaceutically acceptable salts thereof, may have at least 16-fold higher potency than known compounds. In some embodiments, the improved potency may result in significantly lower dosage requirements, thus improving daily dosage tolerance and improving safety margins. Combination therapy

[0120] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be used in combination with one or more additional agents for treating and / or inhibiting replicating HBV and / or HDV. Additional agents include, but are not limited to, interferon, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (such as antisense oligonucleotides and siRNAs), nucleic acid polymers (NAPs, e.g., nucleic acid polymers that reduce HBsAg levels), entry inhibitors, and / or small molecule immunomodulators. Examples of additional agents include recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. Examples of NAPs include, but are not limited to, REP2139, REP2165, and those described in U.S. Patent Application No. 62 / 757,632, filed November 8, 2018, which is incorporated herein by reference for purposes of the NAPs described herein.

[0121] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in a single pharmaceutical composition. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in two or more separate pharmaceutical compositions. Furthermore, the order of administration of a compound described herein or a pharmaceutically acceptable salt thereof with one or more additional agents may vary. [Example]

[0122] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below. Example 1 Compound A [ka]

[0123] A 250 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of N was charged with 3-tert-butyl 4-methyl 2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (5.00 g, 19.3 mmol, 1.00 equiv.) and toluene (50 mL). Diisobutylaluminum hydride (38.6 mL, 38.6 mmol, 2.00 equiv., 1 M in toluene) was added slowly at −78 °C. The addition rate was adjusted to maintain an internal temperature below −65 °C. The resulting solution was stirred at −78 °C for 2 h, and the reaction was quenched by the slow addition of cold CHOH (10 mL). The mixture was slowly poured into ice-cold 1 M HCl (100 mL), and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give tert-butyl 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.20 g, crude) as a colorless oil.

[0124] A 40 mL vial was charged with tert-butyl 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.20 g, 18.3 mmol, 1.00 equiv.), dimethyl (1-diazo-2-oxopropyl)phosphonate (4.22 g, 22.0 mmol, 1.20 equiv.), K2CO3 (5.06 g, 36.6 mmol, 2.00 equiv.), and methanol (20 mL). The resulting solution was stirred at room temperature (rt) overnight. The reaction was quenched with water (20 mL) and diluted with ethyl acetate (3 × 20 mL). The mixture was washed with brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate (EA):petroleum ether (PE) (1:10) to give 3.20 g (70% yield) of tert-butyl 4-ethynyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as a yellow oil.

[0125] A solution of tert-butyl 4-ethynyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.00 g, 4.44 mmol), 4 M hydrochloric acid in 1,4-dioxane (5 mL), and ethanol (10 mL) was stirred overnight at 60° C. The mixture was concentrated under reduced pressure to give 2-aminobut-3-yn-1-ol hydrochloride (538 mg, crude) as a yellow solid. 1 H NMR (300 MHz, methanol-d₄) δ 4.14 (br, 1H), 3.89 (dd, J = 11.6, 4.2 Hz, 1H), 3.75-3.68 (m, 1H), 3.25 (d, J = 2.4 Hz, 1H). LCMS (ES) m / z = 86 (M + H - HCl). + . Example 2 Compound B [ka]

[0126] A mixture of 3-(benzyloxy)cyclobutan-1-one (5.00 g, 28.4 mmol, 1.00 equiv), titanium isopropylate (8.80 g, 30.9 mmol, 1.09 equiv), tert-butanesulfinamide (3.70 g, 30.5 mmol, 1.08 equiv), and dichloromethane (50 mL) was stirred at 45 °C overnight. The reaction was cooled to room temperature. Saturated sodium bicarbonate solution (5 mL) was added. The mixture was stirred for 30 minutes, and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:10) to give N-[3-(benzyloxy)cyclobutylidene]-2-methylpropane-2-sulfinamide (4.50 g, 57% yield) as a pale yellow oil.

[0127] To a stirred mixture of trimethylsilylacetylene (4.70 g, 47.8 mmol, 2.97 equiv) in diethyl ether (100 mL) was added n-BuLi (13.0 mL, 32.5 mmol, 2.02 equiv, 2.5 M in hexanes) dropwise at −78 °C under a N atmosphere. The mixture was stirred at −78 °C for 1 h. N-[3-(benzyloxy)cyclobutylidene]-2-methylpropane-2-sulfinamide (4.50 g, 16.1 mmol, 1.00 equiv) in EtO (10 mL) was added dropwise at −78 °C. The mixture was stirred at −78 °C for 2 h. The reaction was quenched with water (100 mL). The mixture was extracted with EA (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA:PE=1:3) to give N-[3-(benzyloxy)-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]-2-methylpropane-2-sulfinamide (950 mg, 16% yield) as a colorless oil.

[0128] To a stirred mixture of N-[3-(benzyloxy)-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]-2-methylpropane-2-sulfinamide (300 mg, 0.800 mmol, 1.00 equiv.) in chloromethane (5 mL), BBr3 (3.00 mL, 3.00 mmol, 3.70 equiv., 1 M in DCM) was added at room temperature. The mixture was stirred at room temperature for 2 hours. Water (0.1 mL) was added to the mixture and stirred for 0.5 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure to give 3-amino-3-((trimethylsilyl)ethynyl)cyclobutan-1-ol hydrobromide salt (130 mg, 62% yield) as a pale yellow solid. 1 H NMR (400MHz, methanol-d4) δ4.42-4.31(m,1H), 2.83(ddt,J=9.1,7.0,2.5Hz,2H), 2.37(ddt,J=11.6,7.6,2.2Hz,2H), 0.22(s,9H). LCMS(ESI,m / z):184[M+H-HBr] + . Example 3 Compound C [ka]

[0129] A mixture of 3-oxetanone (5.00 g, 69.4 mmol, 1.00 equiv.), tert-butanesulfinamide (9.20 g, 75.9 mmol, 1.10 equiv.), titanium isopropylate (21.6 g, 76.0 mmol, 1.10 equiv.), and dichloromethane (50.00 mL) was stirred at 45 °C overnight. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate solution (5.0 mL). The mixture was stirred for 30 minutes, and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:10) to give 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (5.00 g, 39% yield) as a pale yellow oil. LCMS (ESI, m / z): 176 [M+H] + .

[0130] To a stirred mixture of trimethylsilylacetylene (8.40 g, 85.5 mmol, 3.00 equiv) in THF (50.00 mL), n-BuLi (30.0 mL, 2.5 M in hexane, 75.0 mmol, 2.63 equiv) was added dropwise under atmospheric pressure at −78° C. The mixture was stirred at −78° C. for 1 h. A mixture of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (5.00 g, 28.5 mmol, 1.00 equiv) in THF (10 mL) was added dropwise at −78° C. The reaction was stirred at −78° C. for 2 h and then quenched with water (100 mL). The mixture was extracted with EA (3×100 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:10) to give 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]propane-2-sulfinamide (7.00 g, 88% yield) as a pale yellow oil. LCMS (ESI, m / z): 274 [M+H] + .

[0131] Hydrochloric acid (7.5 mL, 30.0 mmol, 2.05 equiv., 4 M in 1,4-dioxane) was added to a mixture of 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]propane-2-sulfinamide (4.00 g, 14.6 mmol, 1.00 equiv.) and 1,4-dioxane (50 mL). The mixture was stirred at room temperature for 2 hours. The solid was collected by filtration, washed with PE, and dried to give 3-[2-(trimethylsilyl)ethynyl]oxetan-3-amine hydrochloride (2.70 g, 89% yield) as a pale yellow solid. LCMS (ESI, m / z): 170 [M+H-HCl] + . Example 4 Compound D [ka]

[0132] A 250 mL round-bottom flask was charged with ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 equiv) and dimethyl sulfoxide (100 mL). KOH (5.03 g, 89.7 mmol, 1.50 equiv) was added portionwise at 0 °C. The mixture was stirred at room temperature for 30 min. Methyl iodide (10.2 g, 71.8 mmol, 1.20 equiv) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 4 h. The reaction was quenched with water (100 mL) and diluted with EA (500 mL). The mixture was washed with brine (200 mL) and water (5×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (10.1 g, 92% yield) as a white solid. LCMS (ESI, m / z): 182 [M+H] + .

[0133] Ethyl 1,3,5-trimethylpyrrole-2-carboxylate (2.00 g, 11.0 mmol, 1.00 equiv.), 5-amino-2-fluorobenzonitrile (3.00 g, 22.1 mmol, 2.00 equiv.), and tetrahydrofuran (20 mL) were added to a 100 mL three-necked round-bottom flask under N2. Lithium hexamethyldisilazide (33.0 mL, 33.0 mmol, 3.00 equiv., 1 M in THF) was added dropwise to the above mixture at 0 °C. The resulting solution was stirred at room temperature overnight, and the reaction was quenched with saturated ammonium chloride solution (50 mL). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by trituration with EA:hexane (1:1), and the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-1,3,5-trimethylpyrrole-2-carboxamide (2.50 g, 75% yield) as a white solid. LCMS (ESI, m / z): 272 [M+H] + .

[0134] A 50 mL three-necked round-bottom flask was charged with ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.50 g, 13.8 mmol, 1.00 equiv.) and dichloromethane (100 mL). Ethyl oxalochloridate (2.82 g, 20.0 mmol, 1.50 equiv.) in dichloromethane (20 mL) was added dropwise to the mixture at 0 °C. Aluminum chloride (4.23 g, 31.7 mmol, 2.50 equiv.) was added portionwise at 0 °C. The solution was stirred at room temperature overnight, and the reaction was quenched with water / ice. The solution was extracted with dichloromethane (3 × 100 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by trituration with EA:hexane (1:1), and the solid was collected by filtration and dried to give ethyl 4-(2-ethoxy-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.00 g, 56% yield) as a white solid. LCMS (ESI, m / z): 372 [M+H] + .

[0135] A 50 mL round-bottom flask was charged with ethyl 4-(2-ethoxy-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.00 g, 5.39 mmol, 1.00 equiv.), lithium hydroxide (21.6 mg, 10.8 mmol, 2.00 equiv.), methanol (50 mL), and water (10 mL). The resulting solution was stirred at room temperature overnight. The methanol was removed under reduced pressure. The residue was dissolved in water (50 mL) and extracted with EA (3 × 20 mL). The pH value of the aqueous layer was adjusted to 3 with hydrochloric acid (1 mol / L). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, dried over anhydrous sulfate, filtered, and concentrated under reduced pressure to give the desired product, 2-(5-((3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (1.50 g, 81% yield) as a white solid. LCMS (ESI, m / z): 344 [M+H] + . Example 5 Compound E [ka]

[0136] A 250 mL round-bottom flask was charged with ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 equiv) and dimethyl sulfoxide (100 mL). KOH (5.03 g, 89.7 mmol, 1.50 equiv) was added portionwise at 0 °C. The mixture was stirred at room temperature for 30 minutes. Methyl iodide (10.2 g, 71.8 mmol, 1.20 equiv) was added dropwise to the above mixture at room temperature. The resulting solution was stirred at room temperature for 4 hours. The reaction was quenched with water (100 mL) and diluted with EA (500 mL). The mixture was washed with brine (200 mL) and water (5×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (10.1 g, 92% yield) as a white solid. LCMS (ESI, m / z): 182 [M+H] + .

[0137] Ethyl 1,3,5-trimethylpyrrole-2-carboxylate (5.00 g, 27.6 mmol, 1.00 equiv.), 4-fluoro-3-(trifluoromethyl)aniline (7.40 g, 41.3 mmol, 1.50 equiv.), and tetrahydrofuran (50.00 mL) were placed in a 250 mL round-bottom flask purged and maintained with an inert N atmosphere. LiHMDS (80.0 mL, 80.0 mmol, 2.90 equiv., 1 mol / L in THF) was added dropwise to the mixture at 0 °C. The resulting solution was stirred overnight at room temperature and quenched with saturated ammonium chloride solution (100 mL). The solution was extracted with EA (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by trituration with EA:hexane (1:1). The solid was collected by filtration and dried to give N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethylpyrrole-2-carboxamide (9.00 g, 93% yield) as a white solid. LCMS (ESI, m / z): 315 [M+H] + .

[0138] In a 250 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of N2, N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethylpyrrole-2-carboxamide (3.00 g, 9.55 mmol, 1.00 equiv.) and dichloromethane (100 mL) were placed. A solution of ethyl chloroglyoxylate (1.56 g, 11.5 mmol, 1.20 equiv.) in dichloromethane (20 mL) was added dropwise to the mixture at 0 °C. Aluminum chloride (1.90 g, 14.3 mmol, 1.50 equiv.) was added portionwise to the above mixture at 0 °C. The resulting solution was stirred at room temperature overnight, and the reaction was quenched with ice / water (100 mL). The mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:2) to give ethyl 2-(5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrol-3-yl)-2-oxoacetate (2.00 g, 48% yield) as a white solid. LCMS (ESI, m / z): 415 [M+H] + .

[0139] A 100 mL round-bottom flask was charged with ethyl 2-(5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrol-3-yl)-2-oxoacetate (2.00 g, 4.83 mmol, 1.00 equiv), LiOH (0.231 g, 9.65 mmol, 2.00 equiv), methanol (50.00 mL), and water (10.00 mL). The resulting solution was stirred at room temperature overnight and diluted with water (100 mL). The pH of the mixture was adjusted to 3 with hydrochloric acid (1 mol / L). The mixture was extracted with EA (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrol-3-yl)(oxo)acetic acid (1.85 g, 94% yield) as a white solid. LCMS (ESI, m / z): 387 [M+H] + . Example 6 compound 26 [ka]

[0140] A mixture of compound D (1.00 g, 2.91 mmol, 1.00 equiv.), HATU (3.30 g, 8.68 mmol, 2.98 equiv.), 1,2-dichloromethane (50 mL), N,N-diisopropylethylamine (1.50 mL, 8.61 mmol, 2.96 equiv.), and compound C (0.900 g, 4.37 mmol, 1.50 equiv.) was stirred at room temperature overnight. The reaction was quenched with water (200 mL). The mixture was extracted with dichloromethane (3 x 200 mL). The combined organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with EA (50 mL), and the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-4-[([3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]carbamoyl)carbonyl]pyrrole-2-carboxamide (1.30 g, 90% yield) as a white solid. LCMS (ESI, m / z): 495 [M+H] + .

[0141] A mixture of N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-4-[([3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]carbamoyl)carbonyl]pyrrole-2-carboxamide (1.30 g, 2.63 mmol, 1.00 equiv.), potassium carbonate (1.10 g, 7.89 mmol, 3.00 equiv.), methanol (5 mL), and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was triturated with water (100 mL), and the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-4-[[(3-ethynyloxetan-3-yl)carbamoyl]carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (compound 26) (784.8 mg, 68% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H), 9.75(s,1H), 8.20(dd,J=5.8,2.7Hz,1H), 7.95(ddd,J=8.0,4.7,2.6 Hz,1H), 7.53(t,J=9.1Hz,1H), 4.72(d,J=6.6Hz,4H), 3.65(s,1H), 3.59(s,3H), 2.41(s,3H), 2.25(s,3H). LCMS(ESI,m / z):423[M+H] + . Example 7 Compounds 31a and 31b

change

[0142] A 40 mL vial was charged with compound A (240 mg, 1.97 mmol, 1.00 equiv.), 1,2-dichloroethane (10 mL), compound D (678 mg, 1.97 mmol, 1.00 equiv.), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (751 mg, 1.97 mmol, 1.00 equiv.), and N,N-diisopropylethylamine (766 mg, 5.92 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature overnight, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product mixture (360 mg) was separated by prechiral HPLC (Column: CHIRALPAK IG, 20 × 250 mm, 5 μm column; Mobile Phase A: Hex (8 mmol / L NH3, MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow Rate: 18 mL / min; Gradient: 50B to 50B in 22 min; 254 / 220 nm; RT1: 12.491; RT2: 17.162). The appropriate fractions were identified by UV absorbance (254 nm) to afford the pure first-eluting enantiomer, N-(3-cyano-4-fluorophenyl)-4-([[(2S)-1-hydroxybut-3-yn-2-yl]carbamoyl]carbonyl]carbonyl)-1,3,5-trimethylpyrrole-2-carboxamide (125.6 mg, 0.306 mmol), as a white solid. LCMS(ES)m / z=411(M+H) + . 1 H NMR(300MHz,DMSO-d6)δ10.52(s,1H), 9.05(d,J=8.2Hz,1H), 8.19(dd,J=5.8,2.7Hz,1H), 7.92-7.98(m,1H), 7.53(t,J=9 .2Hz,1H), 5.13(t,J=5.9Hz,1H), 4.58-4.65(m,1H), 3.66-3.46(m,5H), 3.22(d,J=2.3Hz,1H), 2.39(s,3H), 2.24(s,3H).

[0143] The second eluting enantiomer, N-(3-cyano-4-fluorophenyl)-4-([[(2R)-1-hydroxybut-3-yn-2-yl]carbamoyl]carbonyl)-1,3,5-trimethylpyrrole-2-carboxamide (133.5 mg, 0.326 mmol), was obtained as a white solid. LCMS (ES) m / z=411 (M+H). + . 1 H NMR(300MHz,DMSO-d6)δ10.52(d,J=3.5Hz,1H), 9.07(d,J=8.2Hz,1H), 8.28-8.11(m,1H), 7.92-7.98(m,1H), 7.60-7 .45(m,1H), 5.14(s,1H), 4.61(s,1H), 3.57(s,5H), 3.21-3.23(m,1H), 2.39(d,J=4.0Hz,3H), 2.24(d,J=4.1Hz,3H). Example 8 compound 32 [ka]

[0144] A mixture of compound B (200 mg, 1.10 mmol, 1.00 equiv.), compound D (250 mg, 0.700 mmol, 0.67 equiv.), ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg, 1.70 mmol, 1.50 equiv.), 1-hydroxy-7-azabenzotriazole (220 mg, 1.60 mmol, 1.50 equiv.), N,N-diisopropylethylamine (220 mg, 1.70 mmol, 1.56 equiv.), and 1,2-dichloroethane (10 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in EA (50 mL) and washed with water (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (EA:PE=2:1) ​​to give N-(3-cyano-4-fluorophenyl)-4-[([3-hydroxy-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]carbamoyl)carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (170 mg, 46% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ10.55(s,1H), 9.29(s,1H), 8.22(dd,J=5.8,2.7Hz,1H), 7.98(ddd,J=9.3,4.9,2.7Hz,1H), 7.56(t,J=9.1Hz,1H), 5.33(d ,J=6.7Hz,1H), 4.14(q,J=7.2Hz,1H), 3.60(s,3H), 2.77(ddd,J=9.5,6. 9,3.0Hz,2H), 2.43(s,3H), 2.28(s,3H), 2.22-2.10(m,2H), 0.14(s,9H). LCMS(ESI,m / z):509[M+H] + .

[0145] A mixture of N-(3-cyano-4-fluorophenyl)-4-[([3-hydroxy-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]carbamoyl)carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (170 mg, 0.30 mmol, 1.00 equiv.), methanol (5 mL), and potassium carbonate (150 mg, 1.10 mmol, 3.22 equiv.) was stirred at room temperature for 2 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: Column: XBridge C 18 OBD Prep column, 19 mm x 250 mm; mobile phase A: water (0.05% TFA), mobile phase B: THF - HPLC; flow rate: 25 mL / min; gradient: 25% to 55% in 7 min; 220 nm. Purification afforded N-(3-cyano-4-fluorophenyl)-4-[[(1-ethynyl-3-hydroxycyclobutyl)carbamoyl]carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (26.1 mg, 18% yield) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ10.50(s,1H), 9.26(s,1H), 8.20(dd,J=5.8,2.7Hz,1H), 8.03-7.91(m,1H), 7.53(t,J=9.2Hz,1H), 5.30(d,J =6.7Hz,1H), 4.15(q,J=7.3Hz,1H), 3.60(s,3H), 3.22(s,1H), 2.83-2.71(m,2H), 2.42(s,3H), 2.27(s,3H), 2.17(t,J=10.1Hz,2H). LCMS(ESI,m / z):437[M+H] + . Example 9 compound 54 [ka]

[0146] Cesium carbonate (9.78 g, 30 mmol, 3 equiv.) was added to a solution of compound 26 (4.22 g, 10 mmol), di-tert-butyl chloromethyl phosphate (3.89 g, 15 mmol, 1.5 equiv.), and tetrabutylammonium iodide (738 mg, 2 mmol, 0.2 equiv.) in anhydrous DMSO (40 mL). The mixture was stirred overnight at room temperature and then partitioned between water and ethyl acetate. The organic phase was separated and washed with dilute brine (2x). The aqueous phase was back-extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure to give a yellow-beige foam (9 g). The residue was purified by column chromatography using 40–100% ethyl acetate–hexane to give the bis-tert-butyl phosphate intermediate (1.72 g, 27%).

[0147] To a solution of the bis-tert-butyl phosphate intermediate from the previous step (1.7 g, 2.6 mmol) in IPA (10 mL) was added 0.2 M aqueous sodium acetate (6 mL, 1.2 mmol, 0.46 equiv.) and 0.2 M aqueous acetic acid (2 mL, 0.4 mmol, 0.15 equiv.). The mixture was heated at 55–60°C for 3 h. After cooling to room temperature, the mixture was made basic (pH 8.5) with 2 N aqueous NaOH (3.1 mL, 6.2 mmol). The resulting solution was concentrated under reduced pressure to ~8 mL. Some precipitate was filtered off and discarded. The filtrate was diluted with acetone (40 mL), and the resulting mixture was kept at 4°C overnight. A fine crystalline solid formed which was collected by filtration, rinsed with acetone and dried under vacuum to give sodium (2-(5-((3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-N-(3-ethynyloxetan-3-yl)-2-oxoacetamido)methyl phosphate (1.15 g, 76%). LC-MS: (ES, m / z): 531 [MH] - . 1 H NMR (400MHz,D2O), δ7.94(m,1H), 7.74(m,1H), 7.31(dd,1H), 5.16(d,2H), 5.0(d,2H), 4.82(d,2H), 3.56(s,3H), 2.45(s,3H), 2.28(s,3H). Example 10 compound 73 [ka]

[0148] To a stirred solution of compound 26 (844 mg, 2 mmol) and chloromethyl isobutyrate (0.379 mL, 3 mmol, 1.5 equiv.) in DMF (15 mL) at 0 °C was added sodium hydride (176 mg, 4.4 mmol, 2.2 equiv. as a 60% dispersion in mineral oil). The mixture was stirred at room temperature for 2 h and then partitioned between a half-saturated aqueous solution of ammonium chloride and ethyl acetate. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl 2-methylpropanoate (compound 73, 530 mg, 50.8%) was isolated by column chromatography (5-25% ethyl acetate in dichloromethane) followed by crystallization from isopropyl acetate. LC-MS: (ES, m / z): 523 [M+H] + . 1 H NMR (400MHz, DMSO-d6), δ10.6(bs,1H), 8.22(dd,1H), 7.98(m,1H), 7.55(dd,1H), 5.47(s,2H), 4.93 (d,2H), 4.65(d,2H), 3.71(s,1H), 3.62(s,3H), 2.48(m,1H), 2.45(s,3H), 2.28(s,3H), 1.05(d,6H). Example 11 compound 77 [ka]

[0149] [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl 2,2-dimethylpropanoate was synthesized as described in Example 10, using pivaloyl chloride instead of chloromethyl isobutyrate. Compound 77 (800 mg, 74.6%) was isolated by column chromatography (5-25% ethyl acetate in dichloromethane) followed by crystallization from ethyl acetate:hexane. LC-MS: (ES, m / z): 537 [M+H] + . 1 H NMR(400MHz,DMSO-d6), δ10.6(bs,1H), 8.21(dd,1H), 7.97(m,1H), 7.55(dd,1H), 5.46(s,2H) , 4.93(d,2H), 4.66(d,2H), 3.73(s,1H), 3.62(s,3H), 2.45(s,3H), 2.28(s,3H), 1.07(s,9H). Example 12 compound 78 [ka]

[0150] [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo-acetyl]-(3-ethynyloxetan-3-yl)amino]methyl isopropyl carbonate was synthesized as described in Example 10, using chloromethyl isopropyl carbonate instead of chloromethyl isobutyrate. Compound 78 (770 mg, 71.6%) was isolated by column chromatography (5-30% ethyl acetate in dichloromethane) followed by crystallization from ethyl acetate:hexane. LC-MS: (ES, m / z): 539 [M+H] + . 1H NMR (400MHz, DMSO-d6), δ10.6(bs,1H), 8.22(dd,1H), 7.98(m,1H), 7.56(dd,1H), 5.49(s,2H), 4.92 (d,2H), 4.71(m,1H), 4.65(d,2H), 3.71(s,1H), 3.62(s,3H), 2.44(s,3H), 2.27(s,3H), 1.20(d,6H). Example 13 Compound 66B [ka]

[0151] 90% hydroxyacetone (16.59 g) and 4-dimethylaminopyridine (1.37 g, 0.05 equiv.) were combined in a reactor and diluted with dichloromethane (100 mL). tert-Butyldiphenylsilyl chloride (63.40 g, 1.03 equiv.) was added, followed by a dichloromethane (230 mL) rinse. The solution was cooled in a room temperature water bath and stirred while triethylamine (36 mL, 1.15 equiv.) was added over 1 minute. After 3 minutes, a solid began to precipitate. After 18 hours, the mixture was concentrated, and hexane (350 mL) and water (200 mL) were added. The aqueous phase was removed using a separatory funnel. The organic phase was washed with water (2 × 150 mL), dried over sodium sulfate, and concentrated to give 1-((tert-butyldiphenylsilyl)oxy)propan-2-one (72.62 g). 1 H NMR (CDCl3,400MHz): δ7.70(4H,d), 7.47(6H,m), 4.20(2H,s), 2.22(3H,s), 1.13(9H,s).

[0152] (R)-(+)-2-Methyl-2-propanesulfinamide (18.47 g, 1.0 equiv.), 1-((tert-butyldiphenylsilyl)oxy)propan-2-one (47.62 g, 1.0 equiv.), and toluene (500 mL) were mixed in a reactor under Ar. Titanium tetraisopropanoate (75.8 g, 1.75 equiv.) was added, and the mixture was then rinsed with toluene (400 mL). The solution was heated at 100 °C for 23 h. After cooling to room temperature, saturated aqueous sodium bicarbonate (50 mL) was added, and the mixture was stirred for 2 min. The resulting slurry was filtered through Celite, and the organic phase was dried over sodium sulfate. The solution was concentrated to a brown liquid, which was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give the product sulfinimine as a red oil (13.8 g). The product was dissolved in toluene (90 mL) and placed on an addition funnel on top of the reaction flask. The reaction flask was charged with trimethylsilylacetylene (9.78 g, 3.0 equiv.) and toluene (230 mL). An Ar atmosphere was established, and the mixture was stirred and cooled in a dry ice-acetone bath. 2.5 M n-butyllithium in hexanes (33.1 mL, 2.5 equiv.) was added at an internal temperature below -61 °C. After stirring for 1 hour and 10 minutes, the sulfinimine solution was added over 1 hour, while maintaining the internal temperature below -67 °C. The mixture was stirred for 1.5 hours and then removed from the cooling bath. The mixture was allowed to warm to 0 °C by immersion in a room temperature water bath, at which point the mixture was slowly warmed to -20 °C by the action of ambient air. Water (20 mL) was added, and the mixture was stirred for 2 minutes. The mixture was then filtered through Celite. The organic phase was dried over sodium sulfate and concentrated to give a brown oil (16.8 g), which was purified by normal-phase silica gel chromatography using a dichloromethane-ethyl acetate gradient to give (R)-N-((S)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (6.00 g) as an orange oil. 1H NMR (CDCl3,400MHz): δ7.75(4H,m), 7.45(6H,m), 3.90(1H,s), 3.80(1H,d), 3.60(1H,d), 1.50(3H,s), 1.25(9H,s), 1.10(9H,s), 0.20(9H,s).

[0153] (R)—N-((S)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (6.00 g, 1.0 equiv.) was dissolved in 1,4-dioxane (70 mL) followed by 4.1 equiv. of 4 M HCl in 1,4-dioxane (12 mL). The solution was stirred for 1 hour and then concentrated. Toluene (75 mL) was added and the solution was concentrated. To the concentrate was added 2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (4.50 g, 1.0 equiv.), HATU (6.47 g, 1.46 equiv.), N,N-dimethylformamide (250 mL), and N,N-diisopropylethylamine (17.8 mL, 9.0 equiv.). The solution was stirred for 21 hours and then concentrated. Ethyl acetate (250 mL) was added. The resulting solution was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, concentrated, and mixed with dichloromethane (60 mL). The slurry was filtered. The filtrate was concentrated and purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give the product (7.58 g) as a yellow foam. 1 H NMR (CDCl3,400MHz): δ7.90(1H,m), 7.77(5H,m), 7.63(1H,s), 7.43(6H,m), 7.25(2H,m), 3 .91(1H,d), 3.85(1H,d), 3.71(3H,s), 2.41(6H,s), 1.71(3H,s), 1.12(9H,s), 0.20(9H,s). LC-MS:(ES,m / z):778[M+1].

[0154] The starting material (7.58 g) was dissolved in THF (75 mL) and 1.0 M tetrabutylammonium fluoride in THF (24 mL, 2.5 equiv.) was added. The solution was stirred for 2 hours and then concentrated. The concentrate was dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (3 × 50 mL) and brine (30 mL), dried over sodium sulfate, and concentrated to give a yellow oil (7.3 g). This oil was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give a yellow foam (4.11 g), which was dissolved in DMF (30 mL). The mixture was stirred while water (30 mL) was slowly added. Crystallization of a white solid began after 3 minutes. Stirring of the resulting slurry was continued for 1 hour and then cooled in an ice bath for 0.5 hours. The slurry was filtered and washed with 2:1 water:DMF (10 mL) followed by water (20 mL). The filter cake was dried under vacuum at 65°C to give (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (3.46 g) as a white powder. 1 H NMR (CDCl3,400MHz): δ10.50(1H,s), 8.47(1H,s), 8.22(1H,m), 7.99(1H,m), 7.51(1H,t), 5.20(1 H,t), 3.70(1H,m), 3.60(3H,s), 3.58(1H,m), 3.21(1H,s), 2.42(3H,s), 2.30(3H,s), 1.51(3H,s). LC-MS:(ES,m / z):468[M+1]. α D 20 20.6°C (c=1.03, MeOH). Example 14 Compound 66A [ka]

[0155] (S)-(+)-2-Methyl-2-propanesulfinamide (4.82 g, 1.0 equiv.), 1-((tert-butyldiphenylsilyl)oxy)propan-2-one (12.43 g, 1.0 equiv.), and toluene (310 mL) were mixed in a reactor under Ar. Titanium tetraisopropanoate (13.57 g, 1.20 equiv.) was added, and the residue was then rinsed with toluene (400 mL). The resulting solution was heated at 100 °C for 18 h. After cooling to room temperature, saturated aqueous sodium bicarbonate (13 mL) was added, and the mixture was stirred for 5 min. The resulting slurry was filtered through Celite, and the organic phase was dried over sodium sulfate. The solution was concentrated to give a brown liquid (16.5 g), which was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give the product sulfinimine (6.07 g) as an orange oil. The oil was dissolved in toluene (50 mL) and placed in an addition funnel on top of a reaction flask. The reaction flask was charged with trimethylsilylacetylene (4.30 g, 3.0 equiv.) and toluene (195 mL), and an argon atmosphere was established. The mixture was stirred and cooled in a dry ice-acetone bath. 2.5 M n-butyllithium in hexanes (14.6 mL, 2.5 equiv.) was added at an internal temperature below -63 °C. After stirring for 1 hour and 10 minutes, the solution was warmed to -20 °C for 2 minutes. The sulfinimine solution was added over 14 minutes while the mixture was cooled to below -67 °C. The mixture was stirred at -73 to (-67) °C for 1 hour and then removed from the cooling bath. The contents were allowed to warm slowly to -40 °C by ambient air, when the reaction was warmed to 0 °C by immersion in a room temperature water bath. Water (10 mL) was added. The mixture was stirred for 5 minutes and then filtered through Celite. The organic phase was dried over sodium sulfate and concentrated to give an orange oil (7.55 g) which was partially purified using normal phase silica gel chromatography and an ethyl acetate-hexane gradient to give an orange oil (4.10 g).This oil was further purified using normal phase silica gel chromatography and an ethyl acetate-dichloromethane gradient to give (S)-N-((R)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (1.93 g) as a yellow oil. 1 H NMR (CDCl3,400MHz): δ7.75(4H,m), 7.45(6H,m), 3.90(1H,s), 3.80(1H,d), 3.60(1H,d), 1.50(3H,s), 1.25(9H,s), 1.10(9H,s), 0.20(9H,s).

[0156] (S)—N—((R)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (1.93 g, 1.0 equiv.) was diluted with 1,4-dioxane (40 mL), followed by the addition of 4 M hydrogen chloride in 1,4-dioxane (4 mL, 4.3 equiv.). The solution was stirred for 3 h and then concentrated. To the concentrate was added 2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (1.21 g, 0.83 equiv.), HATU (1.79 g, 1.25 equiv.), N,N-dimethylformamide (75 mL), and N,N-diisopropylethylamine (4.2 mL, 6.42 equiv.). The solution was stirred for 16 hours and then concentrated. Ethyl acetate (75 mL) was added. The solution was washed with water (30 mL) and brine (25 mL), dried over sodium sulfate, and concentrated to a red solid (5.6 g), which was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give the product amide as a yellow foam (2.57 g). 1H NMR (CDCl3,400MHz): δ7.90(1H,m), 7.77(5H,m), 7.63(1H,s), 7.43(6H,m), 7.25(2H,m), 3 .91(1H,d), 3.85(1H,d), 3.71(3H,s), 2.41(6H,s), 1.71(3H,s), 1.12(9H,s), 0.20(9H,s). LC-MS:(ES,m / z):778[M+1].

[0157] The starting material (2.57 g) was dissolved in THF (25 mL) and 1.0 M tetrabutylammonium fluoride in THF (8.2 mL, 2.5 equiv.) was added. The solution was stirred for 1.5 hours and then concentrated. The concentrate was dissolved in ethyl acetate (30 mL). The solution was washed with water (3 × 20 mL) and then brine (15 mL). The solution was dried over sodium sulfate and concentrated to a yellow oil (2.6 g), which was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give a yellow wax (1.4 g). The wax was dissolved in dichloromethane (80 mL) and warmed to dissolve all solids. The mixture was removed from the heat, and the solution was stirred while slowly cooling. A slurry formed over 1.5 hours. The mixture was cooled in an ice bath for 1 hour and then filtered. The filter cake was washed with ice-cold dichloromethane and then dried under vacuum at 60°C to give (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (0.90 g) as a white powder. 1 H NMR (CDCl3,400MHz): δ10.50(1H,s), 8.47(1H,s), 8.22(1H,m), 7.99(1H,m), 7.51(1H,t), 5.20(1 H,t), 3.70(1H,m), 3.60(3H,s), 3.58(1H,m), 3.21(1H,s), 2.42(3H,s), 2.30(3H,s), 1.51(3H,s). LC-MS:(ES,m / z):468[M+1]. α D 20 -22.4°C (c=0.98, MeOH). Example 15 Compounds 165a and 165b [ka]

[0158] To a stirred solution of (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (233.5 mg, 0.5 mmol) and pyridine (0.2 mL) in DCM (3 mL) was added isobutyryl chloride (0.126 mL, 1.2 mmol). The reaction was warmed to 40 °C and stirred overnight. After quenching the reaction with methanol, the mixture was partitioned between isopropyl acetate and 1 M sodium dihydrogen phosphate. The organic layer was separated and the solvent was removed under reduced pressure. The residue was purified by column chromatography (20-50% ethyl acetate-hexane) to give 165a (192 mg, 71%) as a pale yellow foam. LC-MS: (ES, m / z): 538.4 [M+H]. 1 H NMR (CDCl3,400MHz): δ7.91(m,1H), 7.77(m,1H), 7.65(br.s,1H), 7.22(dd,1H), 7.17(br.s,1H), 4.46 (dd,2H), 3.73(s,3H), 2.65(m,1H), 2.46(s,1H), 2.42(s.,3H), 2.41(s,3H), 1.75(s,3H), 1.22(d,6H).

[0159] The (S)-enantiomer was synthesized as described for the (R)-enantiomer using (S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, m / z): 538.4 [M+H]. Example 16 Compounds 166a and 166b [ka]

[0160] Compounds 166a and 166b were synthesized from the parent alcohol (233 mg, 0.5 mmol) according to the procedure described in Example 15, using pivaloyl chloride instead of isobutyryl chloride. 166a (237 mg, 86%). LC-MS: (ES, m / z): 552.5 [M+H]. 1 H NMR (CDCl3,400MHz): δ7.91(m,1H), 7.77(m,1H), 7.65(br.s,1H), 7.23(dd,1H), 7.16(br.s,1H) ), 7.44(dd,2H), 3.72(s,3H), 2.45(s,1H), 2.42(s,3H), 2.40(s,3H), 1.75(s,3H), 1.26(s,9H). 166b LC-MS:(ES,m / z):552.5[M+H]. Example 17 Compounds 167a and 167b [ka]

[0161] To a stirred solution of Boc-L-valine (214 mg, 0.99 mmol) in acetonitrile (3 mL) was added carbonyldiimidazole (160 mg, 0.99 mmol). After 1 h, the imidazolide solution was added to a solution of (S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (307 mg, 0.66 mmol), DIPEA (0.343 mL, 1.97 mmol), and DMAP (16 mg, 0.13 mmol) in acetonitrile (2 mL). The reaction was allowed to proceed at room temperature for 1 h before being quenched with water. The solution was taken up in isopropyl acetate and 1 M sodium dihydrogen phosphate. The organic phase was separated, washed with sodium bicarbonate, and concentrated under reduced pressure. The residue was purified by column chromatography (20–50% ethyl acetate–hexane) to give the Boc-protected intermediate as a yellowish foam, which was dissolved in ethyl acetate (4 mL). The solution was treated with a 4 M solution of hydrogen chloride in dioxane (1.9 mL, 7.6 mmol). After 3.5 h, the mixture was concentrated under reduced pressure, and the residue was triturated with MTBE (5 mL). The resulting solid was isolated by filtration. The filter cake was rinsed with MTBE, and the product (370 mg, 93%) was dried under vacuum. LC-MS: (ES, m / z): 567.7 [M-HCl+H]. 1 H NMR(400MHz,DMSO-d6)δ:10.58(s,1H), 9.00(s,1H), 8.45(br.s,3H), 8.23(m,1H), 7.98(m,1H), 7.53(dd ,1H), 4.53(dd,2H), 3.53(s,3H), 3.48(s,1H), 2.43(s,3H), 2.26(s,3H), 1.60(s,3H), 1.03-0.93(m,7H).

[0162] The (R)-enantiomer was obtained as described for the (S)-enantiomer using (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, m / z): 567.7 [M-HCl+H]. Example 18 Compounds 168a and 168b [ka]

[0163] To a stirred solution of (S)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (4.82 g, 10.4 mmol) in THF (100 mL) and pyridine (2.44 mL, 31 mmol) at 0° C. was added phosphorus oxychloride (2.88 mL, 31 mmol). The mixture was stirred at 0° C. for 1 h, after which the reaction was quenched with water (30 mL). The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with ethyl acetate, and the solution was washed with water (3×). The organic phase was concentrated to dryness, and the residue was dissolved in isopropanol (100 mL). Aqueous NaOH (2 M) was added slowly (9.7 mL) until the pH was ∼8.5. Addition of NaOH formed a precipitate, which was isolated by filtration. The filter cake was rinsed with isopropanol and dried under vacuum to give the product (5.19 g, 83%). LC-MS: (ES, m / z): 548.1 [M-2Na+3H]. 1 H NMR(400MHz,D2O)δ:7.83(m,H), 7.66(m,1H), 7.31(dd,1H), 3.91(split dd,2H), 3.54(s,3H), 2.80(s,1H), 2.40(s,3H), 2.29(s,3H), 1.61(s,3H). 31 P NMR(162MHz,D2O)δ:4.08(s).

[0164] The (R)-enantiomer was obtained as described for the (S)-enantiomer using (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, m / z): 548.1 [M-2Na+3H]. Example 19

[0165] Following procedures and starting materials similar to those described in the above examples, the following compounds were made. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] Example 20 Additional compounds

[0166] The above synthesis is illustrative and can be used as a starting point for preparing many additional compounds. Provided below are examples of compounds of formula (I) that can be prepared by various methods, including those synthetic schemes shown and described herein. Those skilled in the art will recognize modifications of the disclosed synthesis and will be able to devise routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] Example A HBV-DNA antiviral assay using HepG2.2.15 cells

[0167] The following assay procedure describes an HBV antiviral assay. This assay uses HepG2.2.15 cells transfected with the HBV genome and quantification of extracellular HBV DNA as the endpoint. Cell viability is assessed in parallel by measuring intracellular ATP content using CellTiter-Glo® reagent from Promega.

[0168] On day 0, HepG2.2.15 cells were plated in a 96-well plate at 6.0x10 4 Cells were seeded at a density of 100 cells / well (0.1 mL / well). Cells were incubated at 37°C and 5% CO2.

[0169] On day 1, the test articles were diluted and added to cell culture wells (in duplicate, eight concentrations, 4-fold dilutions). GLS4, tenofovir, and sorafenib were used as reference compounds. 100 μL of culture medium containing the compounds was added to the plate, giving a final total volume of 200 μL per well. The final concentration of DMSO in the culture medium was 0.5%. A plate map of compound treatment is shown below. Cells were cultured at 37°C and 5% CO2 for 3 days. [ka]

[0170] On day 4, plates were refreshed with compound-containing culture medium.

[0171] On day 7, cell viability was assessed using CellTiter-Glo® and cell culture supernatants were collected for determination of HBV DNA by qPCR. HBV DNA quantification by qPCR

[0172] Extracellular DNA was isolated using a QIAamp 96 DNA Blood Kit according to the manufacturer's instructions. HBV DNA was then quantified by qPCR using the HBV-specific primers and probes specified in Table 1 on an ABI-7900HT using the FastStart Universal MasterMix from Roche. The PCR cycle program consisted of 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 1 minute. [Table 3]

[0173] DNA standards were prepared by diluting the pAAV2 HBV1.3 plasmid at concentrations ranging from 10 to 1 x 10 copies / µL and used to generate a standard curve by plotting the Ct value versus the concentration of the HBV plasmid DNA standard. The amount of HBV DNA in each sample was determined by interpolation from the standard curve. Cell viability

[0174] After collecting the supernatant, cell viability was assessed. 、 Detection was performed using CellTiter-Glo® according to the manufacturer's manual. Briefly, 50 μL of fresh cell culture medium was added to the culture plate, followed by the addition of 50 μL of CellTiter-Glo to each well. The plate was incubated at room temperature for 10 minutes. Luminescence signals were collected on a BioTek Synergy 2 plate reader. Data analysis

[0175] Cell viability was calculated as follows: % cell viability = (luminescence value of test sample - mean luminescence value of blank) / (mean luminescence value of 0.5% DMSO control - mean luminescence of blank) x 100%. HBV DNA inhibition was calculated as follows: 100 - (HBV DNA copy number of test sample - HBV DNA copy number of ETV) / HBV DNA copy number of 0.5% DMSO control - HBV DNA copy number of ETV) x 100%. CC 50 , E.C. 50, and E.C. 90 Values ​​were determined by dose-response curves fitted by GraphPad Prism using "log(agonist) vs. response-variable slope".

[0176] The compounds of formula (I) are active against HBV as shown in Table 2, where "A" indicates EC 50 "B" indicates EC <1 nM 50 ≥ 1 nM and < 10 nM, "C" indicates EC 50 ≥ 10 nM and < 100 nM, "D" indicates EC 50 ≥ 100 nM and < 1000 nM, "E" indicates EC 50 >1000nM. [Table 4-1] [Table 4-2]

[0177] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternatives consistent with the true scope and spirit of the present invention. Another aspect of the present invention may be as follows. [1] A compound of formula (I) having the following structure: [C1] JPEG0007811768000090.jpg37128 During the ceremony, R 1 is unsubstituted or substituted C 2 Alkenyl, unsubstituted or substituted C 2 alkynyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl, 2 Alkenyl, 2 Alkynyl, unsubstituted C 1-4 When the haloalkyl and the monocyclic heteroaryl are substituted, the C 2 Alkenyl, 2 The alkynyl and the monocyclic heteroaryl are independently selected from halogen, unsubstituted C 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, unsubstituted monocyclic C 3-6 Cycloalkyl- and hydroxy-substituted monocyclic C 3-6 cycloalkyl; R 2 and R 3 are independently hydrogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl; 3-6 When the cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C 3-6 The cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy, and the C 1-4 When alkyl is substituted, the C 1-4 The alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, provided that R 2 and R 3 at least one of which is not hydrogen, or R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3-6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3-6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, 3-6 The cycloalkyl and the 3- to 6-membered heterocyclyl are independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy; R 4 and R 5 are independently hydrogen, halogen, unsubstituted C 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 2-4 is alkenyl, R 6 is hydrogen, unsubstituted C 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 3-4 is alkenyl, However, R4 、R 5 and R 6 at least one of which is not hydrogen, or R 5 is hydrogen, halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 2-4 alkenyl, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring, X 1 is CR A or N, R 7a 、R 7b 、R 7c and R 7d are independently hydrogen, halogen, unsubstituted C 1-4 Haloalkyl, cyano, or unsubstituted C 1-4 is an alkoxy, R 8 is hydrogen, -CH 2 OC(=O)-(unsubstituted C 1-4 alkyl), -CH 2 OC(=O)-O(unsubstituted C 1-4 alkyl), -CH 2 -(α-amino acid) or -CH 2 -phosphate, R A is hydrogen, halogen, unsubstituted C 1-4 haloalkyl, or cyano; The compound, or a pharmaceutically acceptable salt thereof. 〔2〕R 2 and R 3 are independently hydrogen, unsubstituted C 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl; 3-6 When the cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C 3-6 The compound according to [1] above, wherein the cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen and hydroxy. 〔3〕R 2 and R 3 are unsubstituted C 1-4 The compound according to [2] above, wherein the aryl group is alkyl. 〔4〕R 2 and R 3 are independently hydrogen, substituted C 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl, wherein C 1-4 The compound according to [1] above, wherein the alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy. 〔5〕R 2 and R 3 The compound according to any one of the above [1] to [4], wherein one of is hydrogen. 〔6〕R 2 and R 3 The other of these is unsubstituted C 1-4 The compound according to [5] above, wherein the aryl group is alkyl. 〔7〕R 2 and R 3 The other of these is substitution C 1-4 alkyl, 1-4 When alkyl is substituted, the C 1-4 The compound according to [5] above, wherein the alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy. 〔8〕R 2 and R 3 The other of these is unsubstituted C 1-4 The compound according to [5] above, which is haloalkyl. 〔9〕R 2 and R 3 The other of these is an unsubstituted monocyclic C 3-6 The compound according to [5] above, which is cycloalkyl. 〔10〕R 2 and R 3 The other of the two is a substituted monocyclic C 3-6 The compound according to [5] above, which is cycloalkyl. 〔11〕R 2 and R 3 The compound according to the above [5], wherein the other of the above is an unsubstituted monocyclic 3- to 6-membered heterocyclyl. 〔12〕R 2 and R 3 and the other of the above is a substituted monocyclic 3- to 6-membered heterocyclyl. 〔13〕R 2 and R 3 The other of these is unsubstituted C 1-4 The compound according to [5] above, which is hydroxyalkyl. 〔14〕R 2 and R 3 The other of these is unsubstituted C 1-5 The compound according to [5] above, which is alkoxyalkyl. 〔15〕R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted or substituted monocyclic C 3-6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, 3-6 When cycloalkyl and 3- to 6-membered heterocyclyl are substituted, 3-6 The compound according to [1] above, wherein the cycloalkyl and the 3- to 6-membered heterocyclyl are independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy. 〔16〕R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form an unsubstituted monocyclic C 3-6 The compound according to

[15] above, which forms a cycloalkyl. 〔17〕R 2 and R 3 is R 2 and R 3 together with the carbon to which it is attached to form a substituted monocyclic C 3-6 The compound according to

[15] above, which forms a cycloalkyl. 〔18〕R 2 and R 3 is R 2 and R 3 together with the carbon to which it is bonded to form an unsubstituted monocyclic 3- to 6-membered heterocyclyl. 〔19〕R 2 and R 3 is R 2 and R 3 together with the carbon to which it is bonded to form a substituted monocyclic 3- to 6-membered heterocyclyl.

[20] The monocyclic 3- to 6-membered heterocyclyl is an unsubstituted or substituted oxetane, an unsubstituted or substituted thietane, an unsubstituted or substituted [Case 2] JPEG0007811768000091.jpg16128 , unsubstituted or substituted [C3] JPEG0007811768000092.jpg17128 , unsubstituted or substituted [C4] JPEG0007811768000093.jpg14128 , unsubstituted or substituted [5] JPEG0007811768000094.jpg18128 , unsubstituted or substituted [6] JPEG0007811768000095.jpg15128 , and unsubstituted or substituted [7] JPEG0007811768000096.jpg23128 The compound according to

[18] or

[19] above, selected from the group consisting of: 〔21〕R 4 The compound according to any one of the above [1] to

[20] , wherein is hydrogen. 〔22〕R 4 The compound according to any one of the above [1] to

[20] , wherein is a halogen. 〔23〕R 4 is unsubstituted C 1-4 The compound according to any one of [1] to

[20] above, which is alkyl. 〔24〕R 4 is deuterated C 1-4 The compound according to any one of [1] to

[20] above, which is alkyl. 〔25〕R 5 The compound according to any one of the above [1] to

[24] , wherein is hydrogen. 〔26〕R5 The compound according to any one of the above [1] to

[24] , wherein is a halogen. 〔27〕R 5 is unsubstituted C 1-4 The compound according to any one of the above [1] to

[24] , which is alkyl. 〔28〕R 6 is unsubstituted C 1-4 The compound according to any one of [1] to

[27] above, which is alkyl. 〔29〕R 6 is unsubstituted C 3-4 The compound according to any one of the above [1] to

[27] , which is alkenyl. 〔30〕R 5 is hydrogen and R 4 and R 6 and R are taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring. 〔31〕R 5 is a halogen and R 4 and R 6 and R are taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring. 〔32〕R 5 is unsubstituted C 1-4 alkyl, and R 4 and R 6 and R are taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring. 〔33〕R 5 is unsubstituted C 2-4 alkenyl, and R 4 and R 6 and R are taken together to form an unsubstituted or substituted 5- or 6-membered heterocyclic ring. 〔34〕X 1 is N. The compound according to any one of [1] to

[33] above. 〔35〕X 1 is CR A The compound according to any one of [1] to

[33] above, 〔36〕R A The compound according to

[35] above, wherein is hydrogen. 〔37〕R A The compound according to

[35] above, wherein is a halogen. 〔38〕R A is unsubstituted C 1-4 The compound according to

[35] above, which is haloalkyl. 〔39〕R A The compound according to

[35] above, wherein is cyano. 〔40〕R A is unsubstituted C 1-4 The compound according to

[35] above, which is alkoxy. 〔41〕R 7a The compound according to any one of the above [1] to

[40] , wherein is hydrogen. 〔42〕R 7a The compound according to any one of the above [1] to

[40] , wherein is a halogen. 〔43〕R 7a is unsubstituted C 1-4 The compound according to any one of the above [1] to

[40] , which is haloalkyl. 〔44〕R 7a The compound according to any one of the above [1] to

[40] , wherein is cyano. 〔45〕R 7a is unsubstituted C 1-4 The compound according to any one of the above [1] to

[40] , which is alkoxy. 〔46〕R 7b The compound according to any one of the above [1] to

[45] , wherein is hydrogen. 〔47〕R 7b The compound according to any one of the above [1] to

[45] , wherein is a halogen. 〔48〕R 7b is unsubstituted C 1-4 The compound according to any one of the above [1] to

[45] , which is haloalkyl. 〔49〕R 7b The compound according to any one of the above [1] to

[45] , wherein is cyano. 〔50〕R 7b is unsubstituted C 1-4 The compound according to any one of [1] to

[45] above, which is alkoxy. 〔51〕R 7c The compound according to any one of the above [1] to

[50] , wherein is hydrogen. 〔52〕R 7c The compound according to any one of the above [1] to

[50] , wherein is a halogen. 〔53〕R 7c is unsubstituted C 1-4 The compound according to any one of the above [1] to

[50] , which is haloalkyl. 〔54〕R7c The compound according to any one of the above [1] to

[50] , wherein is cyano. 〔55〕R 7c is unsubstituted C 1-4 The compound according to any one of [1] to

[50] above, which is alkoxy. 〔56〕R 7d The compound according to any one of the above [1] to

[55] , wherein is hydrogen. 〔57〕R 7d The compound according to any one of the above [1] to

[55] , wherein is a halogen. 〔58〕R 7d is unsubstituted C 1-4 The compound according to any one of the above [1] to

[55] , which is haloalkyl. 〔59〕R 7d The compound according to any one of the above [1] to

[55] , wherein is cyano. 〔60〕R 7d is unsubstituted C 1-4 The compound according to any one of the above [1] to

[55] , which is alkoxy. 〔61〕R 1 is unsubstituted C 2 The compound according to any one of the above [1] to

[60] , which is alkenyl. 〔62〕R 1 is a substitution C 2 The compound according to any one of the above [1] to

[60] , which is alkenyl. 〔63〕R 1 is unsubstituted C 2 The compound according to any one of the above [1] to

[60] , which is alkynyl. 〔64〕R 1 is a substitution C 2 The compound according to any one of the above [1] to

[60] , which is alkynyl. 〔65〕R 1 is unsubstituted C 1-4 The compound according to any one of the above [1] to

[60] , which is haloalkyl. 〔66〕R 1 is an unsubstituted monocyclic heteroaryl. 〔67〕R 1 is a substituted monocyclic heteroaryl. 〔68〕R 1 is an unsubstituted bicyclic heteroaryl. 〔69〕R 1 is a substituted bicyclic heteroaryl. 〔70〕R 1 The compound according to any one of the above [1] to

[60] , wherein is unsubstituted monocyclic heterocyclyl. 〔71〕R 1 is a substituted monocyclic heterocyclyl. 〔72〕R 8 The compound according to any one of the above [1] to

[71] , wherein is hydrogen. 〔73〕R 8 Ha-CH 2 OC(=O)-(unsubstituted C 1-4 The compound according to any one of the above [1] to

[71] , wherein R is 1 or 2; 〔74〕R 8 Ha-CH 2 OC(=O)-O(unsubstituted C 1-4 The compound according to any one of the above [1] to

[71] , wherein R is 1 or 2; 〔75〕R 8 Ha-CH 2 -(α-amino acid). 〔76〕R 8 Ha-CH 2 -phosphate.

[77] The compound is [8] JPEG0007811768000097.jpg216153 [9] JPEG0007811768000098.jpg217152 [C10] JPEG0007811768000099.jpg216152 [C11] JPEG0007811768000100.jpg221152 [C12] JPEG0007811768000101.jpg192152 [C13] JPEG0007811768000102.jpg62141 The compound according to [1] above, or any pharmaceutically acceptable salt thereof, selected from the group consisting of:

[78] The compound is [C14] JPEG0007811768000103.jpg216152 [C15] JPEG0007811768000104.jpg233152 [C16] JPEG0007811768000105.jpg235152 [C17] JPEG0007811768000106.jpg237152 [C18] JPEG0007811768000107.jpg55150 The compound according to [1] above, or any pharmaceutically acceptable salt thereof, selected from the group consisting of:

[79] The compound is [C19] JPEG0007811768000108.jpg216152

[20] JPEG0007811768000109.jpg217152

[21] JPEG0007811768000110.jpg224152 [C22] JPEG0007811768000111.jpg160157 The compound according to

[78] or

[79] above, or a pharmaceutically acceptable salt of any of the above, selected from the group consisting of:

[80] [C23] JPEG0007811768000112.jpg216153

[24] JPEG0007811768000113.jpg153157 or a pharmaceutically acceptable salt of any of the above.

[81] A pharmaceutical composition comprising an effective amount of the compound according to any one of [1] to

[80] above or a pharmaceutically acceptable salt thereof, and an excipient.

[82] Use of the compound according to any one of [1] to

[80] above in the preparation of a medicament for the treatment of hepatitis B.

[83] Use of the compound according to any one of [1] to

[80] above in the preparation of a medicament for the treatment of hepatitis D.

[84] The use of any one of

[82] to

[83] , wherein the use comprises the use of one or more additional agents selected from the group consisting of interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors, and small molecule immunomodulators.

[85] The use of

[84] , wherein the one or more additional drugs are selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil.

[86] The compound according to any one of [1] to

[80] above for use in the treatment of hepatitis B.

[87] The compound according to any one of [1] to

[80] above for use in the treatment of hepatitis D.

[88] The compound according to any one of

[86] to

[87] , wherein the compound is used in combination with one or more additional agents selected from the group consisting of interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors, and small molecule immunomodulators.

[89] The compound described in

[88] , wherein the one or more additional drugs are selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil.

[90] A method for treating hepatitis B in a subject, comprising administering an effective amount of a compound according to any one of [1] to

[80] to the subject suffering from hepatitis B and in need of treatment.

[91] A method for treating hepatitis D in a subject, comprising administering an effective amount of a compound described in any one of [1] to

[80] to the subject suffering from hepatitis D and in need of treatment.

[92] The method of any one of

[90] to

[91] , further comprising administering an additional agent selected from the group consisting of interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors, and small molecule immunomodulators.

[93] The method of

[92] , wherein the additional drug is selected from the group consisting of recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil.

Claims

1. The following structure A compound having the formula:

2. The following structure A compound having the formula:

3. and di-tert-butyl chloromethyl phosphate providing a method for producing ... A method for preparing a compound having the formula:

4. by removing the t-butyl group of providing a method for producing ... A method for preparing a compound having the formula:

5. A method for producing a compound having the following structure, comprising reacting a compound having the following structure with sodium hydroxide, sodium acetate, or a combination thereof: A method for preparing a compound having the formula:

6. 6. The method of claim 5, wherein the reacting step is carried out with sodium hydroxide.

7. The method of claim 5, wherein the reacting step is carried out with sodium acetate.

8. The method of claim 5, wherein the reacting step is carried out with a combination of sodium hydroxide and sodium acetate.

Images