Pyrrole compound

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 to any priority application) For example, in the application data sheet or claims filed together with the present application, any and all applications in which the claim of foreign or domestic priority is confirmed, including U.S. Provisional Patent Application No. 62 / 828,919 filed on April 3, 2019, and No. 62 / 932,686 filed on November 8, 2019, are incorporated herein by reference in accordance with 37 CFR 1.57 and Rules 4.18 and 20.6. Background

[0002] (Field of the Invention) The present application relates to the fields of chemistry, biochemistry, and medicine. 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 are disclosed herein. Also disclosed herein are methods for treating diseases and / or conditions with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Background Art

[0003] Hepatitis B virus (HBV) is a DNA virus and a member of the Hepadnaviridae family. HBV infects more than 300 million people worldwide and is the causative pathogen of liver cancers and liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. There are approved drugs for treating HBV either by enhancing the immune system or by delaying the replication of the HBV virus, but HBV poses problems due to the drawbacks associated with each of the approved drugs.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[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 a pharmaceutical composition that may contain an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments described herein relate to a method for treating HBV and / or HDV infection, which may include administering to a subject identified as suffering from 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 the treatment of HBV and / or HDV infection.

[0008] Some embodiments disclosed herein relate to a method for inhibiting the replication of HBV and / or HDV, which may include contacting cells 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 the replication of HBV and / or HDV. These and other embodiments are described in more detail below.

Modes for Carrying Out the Invention

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

[0010] HBV can be transmitted by blood, semen, and / or other body fluids. This can occur through direct blood-to-blood contact, unprotected sexual intercourse, sharing of needles, and from an infected mother to her infant during the birth process. Hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available drugs do not cure HBV and / or HDV infection. Rather, the drugs suppress virus replication.

[0011] Hepatitis D virus (HDV) is a DNA virus even among the viruses of the Hepadnaviridae family. HDV can only spread in the presence of HBV. The transmission route of HDV is the same as that of HBV. The transmission of HDV can occur either through co-infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV lead to more serious complications compared to infection by HBV alone. These complications include a high likelihood of experiencing liver damage in acute infections, rapid progression to cirrhosis, and an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B, hepatitis D has the highest fatality rate of 20% among all hepatitis infections. Currently, there is no cure or vaccine for hepatitis D. Definition

[0012] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications referenced in this specification are incorporated by reference in their entirety unless specifically noted otherwise. If there are multiple definitions for a term in this specification, the definitions in this section shall prevail unless specifically noted 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", in the case of substitution, the substituent may be selected from one or more of the indicated substituents. When no substituents are indicated, an "optionally substituted" or "substituted" group as indicated may be substituted with one or more groups independently selected individually 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-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, nitro, azide, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino, monosubstituted amino group, and disubstituted amino group.

[0014] As used herein, "C" where "a" and "b" are integers a ~C b"a" and "b" refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" carbon atoms (including both end values). Thus, for example, the "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-. For alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl groups, when "a" and "b" are not specified, the broadest scope described in these definitions is assumed.

[0015] As used herein, "alkyl" refers to a straight-chain 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 it appears in this specification, a numerical range such as "1 to 20" always 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 a maximum of 20 carbon atoms, but this definition also encompasses the term "alkyl" when no numerical range is specified). The alkyl group may also be an intermediate-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 represented by "C1-C4 alkyl" or a similar notation. By way of example only, "C1-C4 alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, 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. The alkyl group may be substituted or unsubstituted.

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

[0018] As used herein, "cycloalkyl" refers to a completely saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When consisting of two or more rings, the rings may be joined by fusion. The cycloalkyl group can contain 3 to 10 atoms in the ring. 3 to 8 atoms in the ring or 3 to 6 atoms in the ring. The cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not 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, but when two or more are present, the double bonds cannot form a completely delocalized π - electron system over all the rings (otherwise, the group is an "aryl" as defined herein). When consisting of two or more rings, the rings may be joined by fusion. The cycloalkenyl group can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. The cycloalkenyl group may 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 where two carbocyclic rings share a chemical bond) having a completely delocalized π - electron system over all the rings. The number of carbon atoms in the aryl group can vary. For example, the aryl group is C6 - C 14 aryl group, C6 - C 10It 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 a monocyclic, bicyclic, and tricyclic aromatic ring system (a ring system 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 ring of the heteroaryl group can vary. For example, the 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. Further, 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. The heteroaryl group may be substituted or unsubstituted.

[0022] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms together with 1 to 5 heteroatoms constitute the ring system. The heterocyclic ring may optionally contain one or more unsaturated bonds so positioned, but a completely delocalized π - electron system does not occur over the entire ring. The number of atoms in the ring of the heterocyclyl group can be different. For example, the heterocyclyl 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. The heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. The heterocyclic ring may further contain one or more carbonyl or thiocarbonyl functional groups to be defined to include oxo - and thio - based systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When consisting of two or more rings, the rings may be joined by fusion. In addition, any nitrogen in the heterocyclyl may be quaternized. The heterocyclyl group may be substituted or unsubstituted.Examples of such "heterocyclyl" groups include, but are not limited to, 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, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and their benzofused analogs (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 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 attached as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaryl(alkyl) may 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 their benzo-fused analogs.

[0025] "(heterocyclyl)alkyl" refers to a heterocyclic group attached as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of heteroarysicyclic(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] "Lower alkylene group" is a straight-chain -CH2- linking group that forms a bond to connect molecular fragments via their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). The lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group with substituents enumerated 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 alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzyloxy. Alkoxy may be substituted or unsubstituted.

[0028] As used herein, "acyl" refers to 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 acrylyl. Acyl may be substituted or unsubstituted.

[0029] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are substituted 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 are replaced by 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 may 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 may be substituted or unsubstituted.

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

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

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

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

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

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

[0038] The "trihalomethanesulfonyl" group refers to the "X3CSO2-" group, where each X is halogen.

[0039] The "trihalomethanesulfonamide" group refers to the "X3CS(O)2N(R A )-" group, where each X is 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 -NH2 group.

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

[0042] The "cyano" group refers to the "-CN" group.

[0043] As used herein, the term "azido" refers to the -N3 group.

[0044] The "isocyanato" group refers to the "-NCO" group.

[0045] The "thiocyanato" group refers to the "-CNS" group.

[0046] The "isothiocyanato" group refers to the "-NCS" group.

[0047] The "mercapto" group refers to the "-SH" group.

[0048] The "carbonyl" group refers to the C=O group.

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

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

[0051] The "O-carbamyl" group refers to the "-OC(=O)N(R A R B )" group, where R A and R Bmay independently be 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 refers to the "[ROC(=O)N(R A )-" group, wherein R and R A may independently be 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 refers to the "-OC(=S)-N(R A R B )" group, wherein R A and R B may independently be 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 refers to the "[ROC(=S)N(R A )-" group, wherein R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0055] The "C-amide" group refers to the "-C(=O)N(R A R B) refers to the "base", where R in the formula A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The C-amide may be substituted or unsubstituted.

[0056] The "N-amide" group refers to the "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). The N-amide may be substituted or unsubstituted.

[0057] As used herein, the term "halogen atom" or "halogen" means any one of the radiation-stable atoms in Group 7 of the periodic table of 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 amino acids). 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 meaning as understood by those skilled in the art, [Chemical formula] in its protonated form (e.g., [Chemical formula] is included together with

[0060] When the number of substituents is not specified (for example, haloalkyl), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may contain 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, unless otherwise stated, are consistent with their general use, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11: 942-944 (1972)).

[0062] The term "pharmaceutically acceptable salt" refers to salts of a compound that do not provide a significant irritation to the organism to which it is administered and do not inactivate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutically acceptable salts can be obtained by reacting the compound with an inorganic acid, such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutically acceptable salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as 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. Pharmaceutically acceptable salts can also be obtained by reacting the compound with a base to form salts, such as ammonium salts, alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, salts of organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts having amino acids such as arginine and lysine.

[0063] The terms and phrases used in this application, and variations thereof, particularly those in the appended claims, should be construed as non-limiting and non-exclusive unless otherwise expressly stated. By way of example, 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 "including", "containing", or "characterized by", and is inclusive or non-exclusive and does not exclude additional, unrecited elements or method steps. The term "having" should be construed to mean "having at least". The term "including" should be construed to mean "including but not limited to". The term "example" is used to provide an illustrative example of an item in the description and is not an exhaustive or limiting list. Additionally, the term "comprising" shall be construed as a synonym for 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] Regarding the use of substantially any plural and / or singular terms in this specification, one of ordinary skill in the art can appropriately convert from plural to singular and / or from singular to plural depending on the context and / or use. Various singular / plural exchanges may be explicitly described herein for clarity. The indefinite articles "a" or "an" do not exclude a plurality.

[0065] In any of the compounds described herein that have one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in the R configuration, the S configuration, or a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any of the compounds described herein that have one or more double bonds that can give rise to geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E, Z, or a mixture thereof. Similarly, it is understood that all tautomeric forms are also intended to be included in any of the compounds described.

[0066] It is to be understood that when a compound disclosed herein has a valence that is unfilled, that valence will be 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 may be labeled with isotopes. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as an increase in in vivo half-life or a reduction in the required dosage. Each chemical element represented in a compound structure may include any isotope of the foregoing elements. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein include all possible isotopic forms thereof, unless the context clearly indicates otherwise.

[0068] It is understood that when a range of values is provided, the upper and lower limits thereof, as well as each value intervening between the upper and lower limits of that range, are included within the embodiments. Compound

[0069] Some embodiments disclosed herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

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

[0071] In some embodiments, R 4 may be hydrogen, R 5 may be hydrogen, R 6 may be unsubstituted C 1~4 alkyl. In other embodiments, R 4 may be halogen, R 5 may be hydrogen, R 6 may be unsubstituted C 1~4 alkyl. In still other embodiments, R 4 may be hydrogen, R 5 may be halogen, R 6 may be unsubstituted C 1~4 alkyl. In still other embodiments, R 4 may be hydrogen, R 5 may be unsubstituted C 1~4 alkyl, and R 6 may be unsubstituted C 3~4 alkenyl.

[0072] In some embodiments, R 4 may be hydrogen, R 5 may be halogen, and R 6 may be hydrogen. In other embodiments,4 may be hydrogen, and R 5 may be halogen, and R 6 may be hydrogen. In still other embodiments, R 4 may be halogen, and R 5 may be halogen, and R 6 may be hydrogen. In yet still other embodiments, R 4 may be unsubstituted C 1~4 alkyl, and R 5 may be hydrogen, and R 6 may be unsubstituted C 1~4 alkyl. In some embodiments, R 4 may be unsubstituted C 1~4 alkyl, and R 5 may be halogen, and R 6 may be unsubstituted C 1~4 alkyl. In other embodiments, R 4 may be unsubstituted C 1~4 alkyl, and R 5 may be unsubstituted C 1~4 alkyl, and R 6 may be unsubstituted C 1~4 alkyl. In still other embodiments, R 4 , R 5 and / or R 6 when is unsubstituted C 1~4 alkyl, the unsubstituted C 1~4 alkyl may be methyl. For example, R 4 , R 5 and R 6 may each be methyl. In still other embodiments, R 4 may be hydrogen, and R 5 and R 6 may each be unsubstituted C 1~4 alkyl. In some embodiments, R 4 may be halogen, and R 5 and R 6 may each be unsubstituted C 1~4 alkyl. In other embodiments, R 5 may be halogen, and R 4 and R6 is each unsubstituted C 1~4 alkyl may also be. In yet other embodiments, R 4 and R 5 may each be hydrogen, and R 6 is unsubstituted C 1~4 alkyl may also be. In still yet other embodiments, R 4 may be hydrogen, R 5 may be halogen, R 6 is unsubstituted C 1~4 alkyl may also be. In some embodiments, R 4 and R 5 may each be halogen, and R 6 is unsubstituted C 1~4 alkyl may also be. In other embodiments, R 4 and R 5 may each be unsubstituted C 1~4 alkyl, and R 6 may be deuterated C 1~4 alkyl, such as CD3.

[0073] As provided herein, in some embodiments, R 5 may be hydrogen, halogen, unsubstituted C 1~4 alkyl, or unsubstituted C 2~4 alkenyl, and R 4 and R 6 together may form an unsubstituted or substituted 5- to 6-membered heterocyclic ring. For example, R 4 and R 6 together may form an unsubstituted or substituted

Chemical formula

Chemical formula

[0074] The 6-membered aromatic ring containing X 1 may be optionally substituted phenyl or optionally substituted pyridine. When X 1 is CR A , the 6-membered ring may be optionally substituted phenyl. When X 1 is N (nitrogen), the 6-membered aromatic ring may be optionally substituted pyridine. As provided herein, the 6-membered aromatic ring containing X 1 can be substituted. When substituted, phenyl and / or pyridine may be substituted one, two, or more than three 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 may be CR A . When X 1 is CR A , R Amay be a non-hydrogen group. For example, in some embodiments, R A may be a halogen (e.g., F, Cl, or Br). In other embodiments, R A may be unsubstituted C 1~4 haloalkyl. Suitable C 1~4 haloalkyls include, but are not limited to, -CHF2, -CF3, CH2F, CHClF, and CCl3. In still other embodiments, R A may be cyano. In yet other embodiments, R A may be unsubstituted C 1~4 alkoxy. Exemplary C 1~4 alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0076] As described herein, R 7b and / R 7c may be hydrogen. Similarly to R A , R 7b and / R 7c may be a non-hydrogen group, such as a halogen, unsubstituted C 1~4 haloalkyl, cyano, and unsubstituted C 1~4 alkoxy. In some embodiments, R 7b may be hydrogen. In other embodiments, R 7b may be a halogen (e.g., F, Cl, or Br). In still other embodiments, R 7b may be unsubstituted C 1~4 haloalkyl, such as those described herein, including -CHF2, -CF3, and -CH2F. In yet other embodiments, R 7b may be cyano. In some embodiments, R 7b may be unsubstituted C 1~4 alkoxy, such as those described herein. In some embodiments, R 7c may be hydrogen. In other embodiments, R 7c may be a halogen such as F, Cl, or Br. In still other embodiments, R7c is unsubstituted C 1~4 haloalkyl, for example, -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In still other embodiments, R 7c may be cyano. In some embodiments, R 7c is unsubstituted C 1~4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0077] X 1 Similar to other positions on the 6-membered aromatic ring containing, 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 still other embodiments, R 7a is unsubstituted C 1~4 haloalkyl, for example, -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In still other embodiments, R 7a may be cyano. In some embodiments, R 7a is unsubstituted C 1~4 alkoxy, which may include, but is not limited to, those described herein. In some embodiments, R 7d may be hydrogen. In other embodiments, R 7d may be a halogen (e.g., F, Cl, or Br). In still other embodiments, R 7d is unsubstituted C 1~4 haloalkyl (including, but not limited to, -CHF2, -CF3, -CH2F, -CHClF, and -CCl3). In still other embodiments, R 7d may be cyano. In some embodiments, R 7d is unsubstituted C 1~4 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 may be a non-hydrogen group as described herein. R 7b or R 7c may be a non-hydrogen group as described herein, and R 7a and R 7d are each hydrogen. In still other embodiments, R A may be a non-hydrogen group as described herein. One of R 7b and R 7c may be a non-hydrogen group as described herein, the other of R 7b and R 7c may be hydrogen, and R 7a and R 7d are each hydrogen. The following is a 6-membered aromatic ring containing X 1 :

Chemical formula

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

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

[0081] As described herein, R 2 and R3 may be different. As an example, R 2 and R 3 of which one may be hydrogen, and R 2 and R 3 the other may be 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. In some embodiments, R 2 and R 3 of which one may be hydrogen, and R 2 and R 3 the other may be unsubstituted C 1~4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, R 2 and R 3 of which one may be hydrogen, and R 2 and R 3 the other may be unsubstituted C 1~4 haloalkyl. Exemplary C 1~4 haloalkyls are described herein and include, but are not limited to, -CHF2, -CF3, CH2F, CHClF and CCl3. In yet another embodiment, R 2 and R 3 of which one may be hydrogen, and R 2 and R 3 the other may be unsubstituted or substituted monocyclic C 3~6 cycloalkyl. For example, R 2 and R 3 of which one may be hydrogen, and R 2 and R 3 the other may be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, and unsubstituted cyclohexyl, or R 2 and R 3 of which one may be hydrogen, and R 2 and R3 The other one of them may be a substituted cyclopropyl, a substituted cyclobutyl, a substituted cyclopentyl, or a substituted cyclohexyl. When substituted, the substituted monocyclic C 3~6 The cycloalkyl may be substituted with a substituent independently selected from halogen (F, Cl or Br) and hydroxy, and may be substituted 1, 2 or 3 times. In some embodiments, the substituted monocyclic C 3~6 The cycloalkyl may be substituted with one or two halogens. For example, R 2 and R 3 One of them may be hydrogen, and R 2 and R 3 The other one of them may be

Chemical formula

[0082] The prodrug moiety may be present in one of R 2 and R 3 In some embodiments, one of R 2 and R 3 may be unsubstituted C 1~4 alkyl (e.g., methyl), and the other of R 2 and R 3 may be substituted C 1~4 alkyl, where the C 1~4 alkyl is substituted with one or more substituents selected from phosphate, O-linked α-amino acids, 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 hydroxy from its backbone carboxylic acid group. When an α-amino acid is attached as an -O-linked α-amino acid, the hydrogen that is part of the hydroxy from its backbone carboxylic acid group is absent, and the α-amino acid is attached via oxygen. In some embodiments, the -O-linked α-amino acid substituted on the C 2 of R 3 or R 1~4 may be an -O-linked -L-α-amino acid. In other embodiments, the -O-linked α-amino acid substituted on the C 2 of R 3 or R 1~4 may be an -O-linked -D-α-amino acid. Examples of -O-linked α-amino acids are shown here with respect to R 8 R 2 or R 3Replacement C 1~4 Another example of a prodrug moiety that may be present on the alkyl is O-carboxy. In some embodiments, R 2 and R 3 one of may be unsubstituted C 1~4 alkyl (e.g., methyl), and R 2 and R 3 the other of may be O-carboxy-substituted C 1~4 alkyl. For example, the O-carboxy-substituted C 1~4 alkyl may have the structure -(CH2)4-OC(=O)(unsubstituted C 1~4 alkyl). As described herein, the C 2 or R 3 alkyl of may be substituted with phosphate. For example, when R 1~4 or R 2 is substituted C 3 alkyl having phosphate, R 1~4 or R 2 or R 3 may be -CH2-O-P(=O)(O - )2 or -CH2-O-P(=O)(OH)2.

[0083] As provided herein, R 2 and R 3 together with the carbon to which R 2 and R 3 are attached may form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, and the C 3~6 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 together with the carbon to which R 2 and R 3 are attached may form an unsubstituted monocyclic C 3~6 cycloalkyl. In other embodiments, R 2 and R 3 together with the carbon to which R 2 and R3 together with the carbon to which it is attached, forms a substituted monocyclic C 3~6 cycloalkyl. The C 3~6 cycloalkyl may be unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl. The C 3~6 When the cycloalkyl is substituted, the C 3~6 cycloalkyl may be substituted one, two or more times. When two or more substituents are present, the substituents may all be the same or at least different substituents may be present. For example, in some embodiments, the C 3~6 cycloalkyl may be substituted with one or two halogens (e.g., one or two fluoro substituents). In other embodiments, the C 3~6 cycloalkyl may be substituted with hydroxy. Exemplary C 3~6 cycloalkyls 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,

Chemical formula

[0084] In some embodiments, R 2 and R 3 are such that R 2 and R 3 together with the carbon to which they are attached, can form an unsubstituted monocyclic 3- to 6-membered heterocyclyl. In some embodiments, R 2 and R 3 are such that R 2 and R 3 together with the carbon to which they are attached, can form a substituted monocyclic 3- to 6-membered heterocyclyl. For example, R 2 and R 3 are such that R2 and R 3 together with the carbon to which they are attached can form an unsubstituted or substituted monocyclic 3-membered heterocyclyl, unsubstituted or substituted monocyclic 4-membered heterocyclyl, unsubstituted or substituted monocyclic 5-membered heterocyclyl, or unsubstituted or substituted monocyclic 6-membered heterocyclyl. In some embodiments, R 2 and R 3 are such that R 2 and R 3 together with the carbon to which they are attached can form an unsubstituted monocyclic oxygen-containing 3- to 6-membered heterocyclyl. In other embodiments, R 2 and R 3 are such that R 2 and R 3 together with the carbon to which they are attached can 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

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0085] Various unsaturated substituents may be present in R 1 As described herein, R 1 may be substituted or unsubstituted. In some embodiments, R 1 may be unsubstituted C2 alkenyl. In other embodiments, R 1 is a substituted C2 alkenyl that may be substituted with one or more substituents independently selected from halogen, unsubstituted C 1~4 haloalkyl, unsubstituted C 1~4 hydroxyalkyl, unsubstituted monocyclic C 3~6 cycloalkyl, and hydroxy-substituted monocyclic C 3~6 cycloalkyl. In some embodiments, R 1 may be unsubstituted C2 alkynyl. In other embodiments, R 1 may be substituted C2 alkynyl. C2 alkynyl may be substituted one or more times with substituents independently selected from halogen, unsubstituted C 1~4 haloalkyl, unsubstituted C 1~4 hydroxyalkyl, unsubstituted monocyclic C 3~6 cycloalkyl, and hydroxy-substituted monocyclic C 3~6 cycloalkyl. For example, C2 alkynyl may be substituted once with unsubstituted monocyclic C 3~6 cycloalkyl, or C2 alkynyl may be substituted once with unsubstituted C 1~4 haloalkyl. In some embodiments, R 1 may be unsubstituted C 1~4 haloalkyl, for example CF3.

[0086] As described herein, some cyclic moieties may be present in 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 may be an unsubstituted or substituted 1,2,3-triazole (e.g.,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] Various substituents may be present on R 8 . In some embodiments, R 8 may be hydrogen. In other embodiments, R 8 may be -CH2OC(=O)-(unsubstituted C 1~4 alkyl). For example, R 8 may be pivaloyloxymethyl (POM). In still other embodiments, R 8 may be -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), for example, isopropyloxycarbonyloxymethyl (POC). In yet 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. When R 8 contains an α-amino acid, the carboxylic acid moiety is the portion linked to the -CH2- of -CH2-(α-amino acid), and the hydrogen of the carboxylic acid is absent. As some examples, R 8is [Chem.] may also be. In some embodiments, the α-amino acid of R 8 -CH2-(α-amino acid) may be an L-α-amino acid. In other embodiments, the α-amino acid of R 8 -CH2-(α-amino acid) may be a D-α-amino acid. In some embodiments, R 8 is -CH2-phosphate ( [Chem.] ) may also be.

[0088] The compounds of formula (I) and their pharmaceutically acceptable salts can have various 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 when C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are substituted, C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are independently substituted with one or more substituents selected from halogen, unsubstituted C 1~4 alkyl, unsubstituted C 1~4 haloalkyl, unsubstituted C 1~4 hydroxyalkyl, unsubstituted monocyclic C 1~4 cycloalkyl, and hydroxy-substituted monocyclic C 3~6 cycloalkyl, and R 3~6 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 1~5may be selected from alkoxyalkyl, and when monocyclic C 3~6 cycloalkyl and monocyclic 3-6 heterocyclyl are substituted, monocyclic C 3~6 cycloalkyl and monocyclic 3-6 heterocyclyl are each independently substituted with one or more substituents selected from halogen or hydroxy, and when C 1~4 alkyl is substituted, C 1~4 alkyl is substituted with one or more substituents selected from phosphate, O-linked α-amino acid, and O-carboxy, provided that at least one of R 2 and R 3 is not hydrogen, and R 4 and R 5 are each independently hydrogen, halogen, unsubstituted C 1~4 alkyl, deuterated C 1~4 alkyl, or unsubstituted C 2~4 alkenyl, and R 6 is hydrogen, unsubstituted C 1~4 alkyl, deuterated C 1~4 alkyl, or unsubstituted C 3~4 alkenyl, provided that at least one of R 4 , R 5 and R 6 is not hydrogen, X 1 is CR A or N, and R 7a , R 7b , R 7c and R 7d are each independently hydrogen, halogen, unsubstituted C 1~4 haloalkyl, cyano, or unsubstituted C 1~4 alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH2-(α-amino acid) or -CH2-phosphate, and R A is hydrogen, halogen, unsubstituted C 1~4 haloalkyl, or cyano. In this paragraph, R 2 and R 3When at least one of them is not hydrogen, R 2 and R 3 are such that (1) R 2 and R 3 are each unsubstituted C 1~4 alkyl, such as methyl, (2) phosphate, O - linked α - amino acid, or C 1~4 alkyl substituted with O - carboxy (e.g., - O(C = O)(unsubstituted C 1~4 alkyl)), (3) unsubstituted C 1~4 haloalkyl (e.g., CF3), (4) unsubstituted cyclopropyl, and (5) unsubstituted C 1~4 hydroxyalkyl (e.g., - CH2OH), provided that this is possible.

[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 when C2 alkenyl, C2 alkynyl, and unsubstituted C 1~4 haloalkyl, and monocyclic heteroaryl are substituted, C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are each independently substituted with one or more substituents 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 together with the carbon to which R 2 and R 3 are attached may form an unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or an unsubstituted or substituted monocyclic 3 - to 6 - membered heterocyclyl, and when C 3~6 cycloalkyl and 3 - to 6 - membered heterocyclyl are substituted, C 3~6The cycloalkyl and 3- to 6-membered heterocyclyl are each independently substituted with one or two substituents selected from halogen and hydroxy, R 4 and R 5 are each independently hydrogen, halogen, unsubstituted C 1~4 alkyl, deuterated C 1~4 alkyl, or unsubstituted C 2~4 alkenyl, and R 6 is hydrogen, unsubstituted C 1~4 alkyl, deuterated C 1~4 alkyl, or unsubstituted C 3~4 alkenyl, provided that at least one of R 4 , R 5 and R 6 is not hydrogen, X 1 may be CR A or N, and R 7a , R 7b , R 7c and R 7d are each independently hydrogen, halogen, unsubstituted C 1~4 haloalkyl, cyano, or unsubstituted C 1~4 alkoxy, and R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH2-(α-amino acid) or -CH2-phosphate, and R A is hydrogen, halogen, unsubstituted C 1~4 haloalkyl, or cyano. As provided herein, R 2 and R 3 together with the carbon to which R 2 and R 3 are attached can form unsubstituted cyclobutyl, fluorine-substituted cyclobutyl, hydroxy-substituted cyclobutyl, or unsubstituted oxetane.

[0090] In yet other embodiments, R 1 is unsubstituted or substituted C2 alkenyl, unsubstituted or substituted C2 alkynyl, unsubstituted C 1~4It may be haloalkyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclyl. When C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are substituted, C2 alkenyl, C2 alkynyl, and monocyclic heteroaryl are each independently 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 may be substituted with one or more substituents selected from, R 2 and R 3 are each 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 when monocyclic C 3~6 cycloalkyl and monocyclic 3- to 6 heterocyclyl are substituted, monocyclic C 3~6 cycloalkyl and monocyclic 3- to 6 heterocyclyl may each independently be substituted with one or more substituents selected from halogen or hydroxy, and when C 1~4 alkyl is substituted, C 1~4 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 are, together with the carbon to which R 2 and R 3 is attached, may form unsubstituted or substituted monocyclic C 3~6 cycloalkyl, or unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, and when C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl are substituted, C 3~6The cycloalkyl and 3- to 6-membered heterocyclyl may each independently be substituted with one or two substituents selected from halogen and hydroxy, R 5 may be hydrogen, halogen, unsubstituted C 1~4 alkyl, or unsubstituted C 2~4 alkenyl, R 4 and R 6 may together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring, X 1 may be CR A or N (nitrogen), R 7a , R 7b , R 7c and R 7d are each independently hydrogen, halogen, unsubstituted C 1~4 haloalkyl, cyano, or unsubstituted C 1~4 alkoxy, R 8 is hydrogen, -CH2OC(=O)-(unsubstituted C 1~4 alkyl), -CH2OC(=O)-O(unsubstituted C 1~4 alkyl), -CH2-(α-amino acid) or -CH2-phosphate, R A is hydrogen, halogen, unsubstituted C 1~4 haloalkyl, or cyano.

[0091] Examples of the compounds of formula (I), or pharmaceutically acceptable salts thereof, include the following.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0092] Further examples of the compound of formula (I), or pharmaceutically acceptable salts thereof, include the following. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] or any pharmaceutically acceptable salt of the above.

[0093] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, cannot be one or more of the following compounds. [Chemical formula] or any pharmaceutically acceptable salt of the above. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, cannot be the compounds provided in International Publication No. WO2017 / 156255. In some embodiments, R 1It cannot be a difluorophenyl-substituted phenyl. In some embodiments, R 1 cannot be an unsubstituted or substituted tetrazole, an unsubstituted or substituted 1,2,3-triazole, and / or an unsubstituted or substituted imidazole. In some embodiments, X 1 is not CR A and R A is a halogen (such as 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 an unsubstituted C 1~4 haloalkyl, such as CF3. In some embodiments, at least one of R 4 and R 5 is a halogen. In some embodiments, at least one of R 4 R 5 and R 6 is a halogen. Synthesis

[0094] The compounds of formula (I) together with the compounds described herein may be prepared in various ways. General synthetic routes for preparing the compounds of formula (I) are shown and described herein together with some examples of starting materials used for synthesizing the compounds described herein. The routes shown and described herein are merely illustrative and are not intended to limit the claims in any way and should not be so construed. Those skilled in the art can recognize variations of the disclosed syntheses and devise alternative routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims.

Chemical formula

[0095] The synthesis of the compound of formula (I) can be carried out as outlined in Scheme 1. An ester of general formula (Ia) can be coupled with an amine of general formula (Ib) in a suitable solvent (such as THF) in the presence of a base, such as LiHMDS, to obtain an amide of general formula (Ic). A ketoester of general formula (Id) can be obtained by reaction of the compound of general formula (Ic) with ethyl 2-chloro-2-oxoacetate in the presence of aluminum chloride in a suitable solvent (such as DCM). Subsequently, the compound of general formula (Id) can be saponified under basic conditions using lithium hydroxide in a mixture of, for example, methanol and water to obtain a keto acid derivative of general formula (Ie). The coupling of the compound of general formula (Ie) with a substituted amine of general formula (If) is carried out in a suitable solvent (such as DCM) in the presence of a peptide coupling agent, such as HATU or EDCI / HOAT, and in the presence of an organic amine base (such as Et3N or DIPEA) to obtain the compound of formula (I) and its pharmaceutically acceptable salts. Pharmaceutical composition

[0096] Some embodiments described herein relate to pharmaceutical compositions that 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, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0098] As used herein, "diluent" refers to a component in a pharmaceutical composition that has no pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to bulk up a potent drug that is too small in mass for manufacture and / or administration. It may also be a liquid for dissolving a drug administered by injection, ingestion, or inhalation. Common forms of diluents in the art include, but are not limited to, buffered aqueous solutions such as phosphate buffered saline that mimics the composition of human blood.

[0099] As used herein, "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, among other things, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. A "diluent" is a type of excipient.

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

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

[0102] The pharmaceutical compositions disclosed herein can be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, sugar coating, levigating, emulsifying, encapsulating, entrapping, or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts having pharmaceutically compatible counterions. Method of Use

[0103] Some embodiments described herein relate to methods of treating HBV and / or HDV infection that may include administering to a subject identified as having 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 an effective amount of 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 that may include contacting HBV- and / or HDV-infected cells 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 of inhibiting the replication of HBV and / or HDV, which may include contacting cells 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 the replication of HBV and / or HDV. 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 the replication of HBV and / or HDV.

[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 of treating cirrhosis developed due to 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 cells infected with HBV and / or HDV in a subject suffering from cirrhosis with them. 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, for treating cirrhosis.

[0108] Some embodiments disclosed herein relate to a method for treating liver cancer (such as hepatocellular carcinoma), 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, and / or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting cells infected with HBV and / or HDV in a subject suffering from liver cancer with them. 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. 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 treating liver cancer.

[0109] Some embodiments disclosed herein relate to a method for treating liver disorders, which may include administering to a subject suffering from liver disorders an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting cells infected with HBV and / or HDV in a subject suffering from liver disorders with them. 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 disorders. 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 treating liver disorders.

[0110] Various indicators for determining the effectiveness of methods 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 reduction of HBV DNA (e.g., reduction to < 10 5 copies / mL in serum), reduction of HBV surface antigen (HBsAg) and HBV e-antigen (HBeAg), reduction of plasma viral load, reduction of viral replication, shortening of time to seroconversion (undetectable virus in patient serum), increased rate of sustained viral response to therapy, improvement of liver function, and / or decrease in morbidity or mortality in clinical outcome, but are not limited thereto.

[0111] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean complete cure or elimination of a disease or condition. Any degree of any alleviation of any undesirable sign or symptom of a disease or condition can be considered treatment and / or therapy. Further, treatment can include actions that can worsen the overall sense of a subject's health or appearance.

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

[0113] The term "effective amount" is used to indicate the amount of an active compound or agent that elicits the indicated biological or medical response. For example, the effective amount of a compound can be the amount necessary to alleviate or improve the symptoms of a disease or to extend the survival of a subject being treated. This response can occur in a tissue, system, animal, or human and can include the alleviation of the signs or symptoms of the disease being treated. Determination of the effective amount is within the ability of a person of ordinary skill in the art considering the disclosure provided herein. The effective amount of a compound disclosed herein required as a dosage is determined by the route of administration, the type of animal, including the human being treated, and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect but is determined by factors such as body weight, diet, concurrent medication, and other factors that would be recognized by a person of ordinary skill in the medical arts.

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

[0115] Subjects clinically diagnosed with HBV and / or HDV infection include "naïve" subjects (e.g., subjects not previously treated for HBV and / or HDV) and subjects who have failed previous treatment for HBV and / or HDV ("treatment non-successful" subjects). Treatment non-successful subjects include "non-responders" (subjects who did not achieve a sufficient reduction in ALT (alanine aminotransferase) levels, e.g., subjects who could not achieve a greater than 1 log10 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 in whom ALT levels increased, e.g., ALT > 2 times the upper normal limit and detectable serum HBV DNA by hybridization assay). Further examples of subjects include those with asymptomatic HBV and / or HDV infection.

[0116] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be provided to treatment-naive subjects suffering from HBV and / or HDV. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be provided to non-responder subjects suffering from HBV and / or HDV. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be provided to relapsing subjects suffering from HBV and / or HDV. In some embodiments, the subject can have HBeAg-positive chronic hepatitis B. In some embodiments, the subject can have HBeAg-negative chronic hepatitis B. In some embodiments, the subject can have cirrhosis. In some embodiments, the subject may be asymptomatic; for example, the subject may be infected with HBV and / or HDV but exhibit no symptoms of viral infection. In some embodiments, the subject can be immunocompromised. In some embodiments, the subject may be undergoing chemotherapy.

[0117] Examples of agents used to treat HBV and / or HDV include immunomodulators and nucleosides / nucleotides. Examples of immunomodulators include interferons (including 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 are adverse side effects, the need for subcutaneous administration, and high cost. Potential advantages of the compounds of formula (I) or any of the foregoing pharmaceutically acceptable salts may be fewer adverse side effects, a delay in the occurrence of adverse side effects, and / or a reduction in the severity of adverse side effects. Drawbacks of nucleoside / nucleotide therapy can 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 viral strains that exhibit a delay, attenuation, and / or lack of response to antiviral agents. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be provided to a subject infected with HBV and / or HDV strains that are resistant to one or more anti-HBV and / or anti-HDV agents. Examples of antiviral agents against which resistance can develop include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. In some embodiments, the development of resistant HBV and / or HDV strains when a subject is treated with the compounds described herein or pharmaceutically acceptable salts thereof is delayed compared to the development of HBV and / or HDV strain resistance 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 the compound may induce liver injury. Thus, the formation of glutathione adducts can be used as an indicator for safety prediction. Unexpectedly, many of the compounds of formula (I) and the compounds described herein, such as 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 shown efficacy in HepG2.2.15 cell line assays with an EC 50 > 1000 pM. Many of the compounds described herein, such as the compounds of formula (I) and pharmaceutically acceptable salts thereof, unexpectedly have an EC 50Shows improved potency in the HepG2.2.15 cell line assay that is in the range of <1000 pM. Thus, the compounds described herein, including the compounds of formula (I) and their pharmaceutically acceptable salts, can have at least 16-fold higher potency than known compounds. In some embodiments, the improved potency results in a significantly reduced dosing requirement, and thus, the burden of the daily dose is improved and the safety margin can be improved. Combination therapy

[0120] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts 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, interferons, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (such as antisense oligonucleotides and siRNA), 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 / 757632, filed November 8, 2018 (incorporated herein by reference for the purposes of the NAPs described herein).

[0121] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts can be administered with one or more additional agents in a single pharmaceutical composition. In some embodiments, the compound or its pharmaceutically acceptable salt can be administered with one or more additional agents as two or more separate pharmaceutical compositions. Further, the order of administration of the compounds described herein or their pharmaceutically acceptable salts with one or more additional agents can be different.

Example

[0122] Further embodiments, which do not in any way limit the scope of the claims, are disclosed in more detail in the following examples. Example 1 Compound A [Chemical formula]

[0123] A 250 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of N2 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), 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 the internal temperature below -65 °C. The resulting solution was stirred at -78 °C for 2 h and the reaction was quenched by slowly adding cold CH3OH (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 under vacuum to give tert-butyl 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.20 g, crude) as a colorless oil.

[0124] To a 40 mL vial were added 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 using 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), 4M hydrochloric acid in 1,4-dioxane, and ethanol (10 mL) was stirred at 60 °C overnight. 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

Chemical formula

[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 mixture 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 and eluted 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), n-BuLi (13.0 mL, 32.5 mmol, 2.02 equiv, 2.5 M in hexane) was added dropwise at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 hour. N-[3-(benzyloxy)cyclobutylidene]-2-methylpropane-2-sulfinamide (4.50 g, 16.1 mmol, 1.00 equiv) in Et2O (10 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hours. 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) was added BBr3 (3.00 mL, 3.00 mmol, 3.70 equiv, 1 M in DCM) at room temperature. The mixture was stirred at room temperature for 2 h. Water (0.1 mL) was added to the mixture and stirred for 0.5 h. 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, yield 62%) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ 4.42 - 4.31 (m, 1H), 2.83 (ddt, J = 9.1, 7.0, 2.5 Hz, 2H), 2.37 (ddt, J = 11.6, 7.6, 2.2 Hz, 2H), 0.22 (s, 9H). LCMS (ESI, m / z): 184 [M + H - HBr] + 。 Example 3 Compound C

Chemical formula

[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 min and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA:PE (1:10) to give 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (5.00 g, yield 39%) 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 eq) in THF (50.00 mL), n-BuLi (30.0 mL, 2.5 M in hexanes, 75.0 mmol, 2.63 eq) was added dropwise at -78 °C under an atmosphere. The mixture was stirred at -78 °C for 1 h. A mixture of 2-methyl-N-(oxetan-3-ylidene)propan-2-sulfinamide (5.00 g, 28.5 mmol, 1.00 eq) 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 and eluted with EA:PE (1:10) to give 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]propan-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 eq, 4 M in 1,4-dioxane) was added to a mixture of 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetan-3-yl]propan-2-sulfinamide (4.00 g, 14.6 mmol, 1.00 eq) and 1,4-dioxane (50 mL). The mixture was stirred at room temperature for 2 h. 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

Chemical Structure

[0132] To a 250 mL round-bottom flask, ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 equiv) and dimethyl sulfoxide (100 mL) were added. 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 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] + .

[0133] To a 100 mL three-necked round-bottom flask, 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 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 under vacuum. The residue was purified by trituration with EA:hexane (1:1), and the solid was recovered 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] Into a 50 mL three-necked round-bottom flask, ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.50 g, 13.8 mmol, 1.00 equiv) and dichloromethane (100 mL) were added. Ethyl oxalyl chloride (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 under vacuum. The residue was purified by trituration with EA:hexane (1:1), and the solid was recovered 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] Into a 50 mL round-bottom flask, 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) were charged. The resulting solution was stirred at room temperature overnight. 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-pyrrole-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 [Chemical formula]

[0136] Ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 eq) and dimethyl sulfoxide (100 mL) were placed in a 250 mL round-bottom flask. KOH (5.03 g, 89.7 mmol, 1.50 eq) 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 eq) 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] The inert atmosphere of N2 was purged and maintained. 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 into a 250 mL round-bottom flask. 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 at room temperature overnight and the reaction was 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 under vacuum. 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 added. 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 overnight at room temperature 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 and eluted 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, yield 48%) as a white solid. LCMS (ESI, m / z): 415 [M+H] + .

[0139] Into a 100 mL round-bottom flask, 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 eq), LiOH (0.231 g, 9.65 mmol, 2.00 eq), methanol (50.00 mL), and water (10.00 mL) were added. The resulting solution was stirred overnight at room temperature and diluted with water (100 mL). The pH value 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 obtain (5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrol-3-yl)(oxo)acetic acid (1.85 g, yield 94%) as a white solid. LCMS (ESI, m / z): 387 [M+H] + . Example 6 Compound 26 [Chemical formula]

[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 × 200 mL). The combined organic layers were 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 recovered 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 recovered 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. 11H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.75 (s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.95 (ddd, J = 8.0, 4.7, 2.6 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 4.72 (d, J = 6.6 Hz, 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 [Chemical formula]

[0142] Into a 40 mL vial were added compound A (240 mg, 1.97 mmol, 1.00 equivalent), 1,2-dichloroethane (10 mL), compound D (678 mg, 1.97 mmol, 1.00 equivalent), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (751 mg, 1.97 mmol, 1.00 equivalent), and N,N-diisopropylethylamine (766 mg, 5.92 mmol, 3.00 equivalents). 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 mixture of products (360 mg) was separated by preparative chiral HPLC (column: CHIRALPAK IG, 20 × 250 mm, 5 μm, mobile phase A: Hex(8 mmol / L NH3.MeOH)-HPLC, mobile phase B: EtOH--HPLC; flow rate: 18 mL / min; gradient: 50B~50B in 22 min; 254 / 220 nm; RT1: 12.491; RT2: 17.162). Appropriate fractions were identified by UV absorbance (254 nm), and N-(3-cyano-4-fluorophenyl)-4-([[(2S)-1-hydroxybut-3-yn-2-yl]carbamoyl]carbonyl)-1,3,5-trimethylpyrrole-2-carboxamide (125.6 mg, 0.306 mmol), the pure first-eluting enantiomer, was obtained as a white solid. LCMS (ES) m / z = 411 (M+H) + 。 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.92 - 7.98 (m, 1H), 7.53 (t, J = 9.2 Hz, 1H), 5.13 (t, J = 5.9 Hz, 1H), 4.58 - 4.65 (m, 1H), 3.66 - 3.46 (m, 5H), 3.22 (d, J = 2.3 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H).

[0143] The enantiomer that elutes second, 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 (300 MHz, DMSO-d6) δ 10.52 (d, J = 3.5 Hz, 1H), 9.07 (d, J = 8.2 Hz, 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 = 4.0 Hz, 3H), 2.24 (d, J = 4.1 Hz, 3H). Example 8 Compound 32

Chemical formula

[0144] A mixture of Compound B (200 mg, 1.10 mmol, 1.00 equivalent), Compound D (250 mg, 0.700 mmol, 0.67 equivalent), ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg, 1.70 mmol, 1.50 equivalents), 1-hydroxy-7-azabenzotriazole (220 mg, 1.60 mmol, 1.50 equivalents), N,N-diisopropylethylamine (220 mg, 1.70 mmol, 1.56 equivalents), 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, yield 46%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.29 (s, 1H), 8.22 (dd, J = 5.8, 2.7 Hz, 1H), 7.98 (ddd, J = 9.3, 4.9, 2.7 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 5.33 (d, J = 6.7 Hz, 1H), 4.14 (q, J = 7.2 Hz, 1H), 3.60 (s, 3H), 2.77 (ddd, J = 9.5, 6.9, 3.0 Hz, 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 h. 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 × 250 mm; mobile phase A: water (0.05% TFA), mobile phase B: THF - HPLC; flow rate: 25 mL / min; gradient: 25% - 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, yield 18%) as a yellow solid. 11H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.26 (s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 8.03 - 7.91 (m, 1H), 7.53 (t, J = 9.2 Hz, 1H), 5.30 (d, J = 6.7 Hz, 1H), 4.15 (q, J = 7.3 Hz, 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 = 10.1 Hz, 2H). LCMS (ESI, m / z): 437 [M + H] + 。 Example 9 Compound 54

Chem.

[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 (2×). The aqueous phase was back-extracted with ethyl acetate. The combined organic solutions were dried over sodium sulfate and concentrated under reduced pressure to give a yellow-beige foam (9 g). The residue was purified by column chromatography on 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), 0.2 M aqueous sodium acetate solution (6 mL, 1.2 mmol, 0.46 equiv) and 0.2 M aqueous acetic acid solution (2 mL, 0.4 mmol, 0.15 equiv) were added. The mixture was heated at 55 - 60 °C for 3 hours. After cooling to room temperature, the mixture was made basic (pH 8.5) using 2 N aqueous NaOH solution (3.1 mL, 6.2 mmol). The resulting solution was concentrated to ~8 mL under reduced pressure. Some precipitate was filtered off and discarded. The filtrate was diluted with acetone (40 mL), and the resulting mixture was maintained at 4 °C overnight. A fine crystalline solid was formed, which was collected by filtration, rinsed with acetone, and dried under vacuum to obtain 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[M - H] - . 1 H NMR (400 MHz, D2O), δ 7.94 (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

Chemical Structure

[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 half-saturated aqueous ammonium chloride solution 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) and subsequently crystallized from isopropyl acetate. LC-MS: (ES, m / z): 523 [M + H]] + . 1 H NMR (400 MHz, DMSO-d6), δ 10.6 (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 [Chemical formula]

[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) and subsequently crystallized from ethyl acetate:hexane. LC-MS: (ES, m / z): 537 [M+H]] + 。 1 H NMR (400 MHz, DMSO-d6), δ 10.6 (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

Chemical Structure

[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) and subsequently crystallized from ethyl acetate:hexane. LC-MS: (ES, m / z): 539 [M+H]] + 。 11H NMR (400 MHz, DMSO-d6), δ 10.6 (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 [Chemical formula]

[0151] 90% hydroxyacetone (16.59 g) and 4-dimethylaminopyridine (1.37 g, 0.05 equivalent) were combined in a reactor and diluted with dichloromethane (100 mL). tert-Butyldiphenylsilyl chloride (63.40 g, 1.03 equivalents) was added, followed by a rinse with dichloromethane (230 mL). The solution was cooled in a water bath at room temperature and stirred while triethylamine (36 mL, 1.15 equivalents) was added over 1 minute. After 3 minutes, solids 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 by means of a separatory funnel. The organic phase was washed with water (2 × 150 mL), dried over sodium sulfate, and concentrated to obtain 1-((tert-butyldiphenylsilyl)oxy)propan-2-one (72.62 g). 1 1H NMR (CDCl3, 400 MHz): δ 7.70 (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 tetraisopropoxide (75.8 g, 1.75 equiv) was added, and then the mixture was 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 in an addition funnel above the reaction flask. Trimethylsilylacetylene (9.78 g, 3.0 equiv) and toluene (230 mL) were placed in the reaction flask. An Ar atmosphere was established, 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 h 10 min, the sulfinimine solution was added over 1 h while maintaining the internal temperature below -67 °C. The mixture was stirred for 1.5 h and then removed from the cooling bath. When the reaction mixture was warmed to 0 °C by immersion in a room temperature water bath, the mixture was slowly warmed to -20 °C by the action of the ambient air. Water (20 mL) was added, and the mixture was stirred for 2 min. Subsequently, the mixture was filtered through Celite. Drying and concentration of the organic phase over sodium sulfate gave 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-methylpropan-2-sulfinamide (6.00 g) as an orange oil. 11H NMR (CDCl3, 400 MHz): δ 7.75 (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-methylpropan-2-sulfinamide (6.00 g, 1.0 eq) was dissolved in 1,4-dioxane (70 mL), followed by 4 M HCl in 1,4-dioxane (12 mL) (4.1 eq). The solution was stirred for 1 h and then concentrated. Toluene (75 mL) was added and the solution was concentrated. To the concentrate were 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 eq), HATU (6.47 g, 1.46 eq), N,N-dimethylformamide (250 mL), and N,N-diisopropylethylamine (17.8 mL, 9.0 eq). The solution was stirred for 21 h 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 1H NMR (CDCl3, 400 MHz): δ 7.90 (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 tetrabutylammonium fluoride 1.0 M in THF (24 mL, 2.5 eq) was added. The solution was stirred for 2 h 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 slowly adding water (30 mL). Crystallization of the white solid started after 3 min. Stirring of the resulting slurry was continued for 1 h and then cooled in an ice bath for 0.5 h. 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 1H NMR (CDCl3, 400 MHz): δ 10.50 (1H, s), 8.47 (1H, s), 8.22 (1H, m), 7.99 (1H, m), 7.51 (1H, t), 5.20 (1H, 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 [Chemical formula]

[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 tetraisopropoxide (13.57 g, 1.20 equiv) was added, and then the residue was 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 solution (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. This oil was dissolved in toluene (50 mL) and placed in an addition funnel above the reaction flask. Trimethylsilylacetylene (4.30 g, 3.0 equiv) and toluene (195 mL) were placed in the reaction flask 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 h 10 min, the solution was warmed to -20 °C for 2 min. While cooling the mixture below -67 °C, the sulfinimine solution was added over 14 min. The mixture was stirred at -73 to (-67) °C for 1 h and then removed from the cooling bath. When the reaction mixture was warmed to 0 °C using immersion in a room temperature water bath, the contents were slowly warmed to -40 °C by the action of the ambient air. Water (10 mL) was added. The mixture was stirred for 5 min 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 by normal-phase silica gel chromatography and using an ethyl acetate-dichloromethane gradient to give (S)-N-((R)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropan-2-sulfinamide (1.93 g) as a yellow oil. 1 1H NMR (CDCl3, 400 MHz): δ 7.75 (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-methylpropan-2-sulfinamide (1.93 g, 1.0 equiv) was diluted with 1,4-dioxane (40 mL), and then 4 M hydrogen chloride in 1,4-dioxane (4 mL, 4.3 equiv) was added. After stirring this solution for 3 h, it was concentrated. To the concentrate were 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). After stirring this solution for 16 h, it was 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). 11H NMR (CDCl3, 400 MHz): δ 7.90 (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 tetrabutylammonium fluoride 1.0 M in THF (8.2 mL, 2.5 eq) was added. The solution was stirred for 1.5 h 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). This wax was dissolved in dichloromethane (80 mL), warmed to dissolve all the solids, removed from the heat, and then stirred while cooling slowly. A slurry formed over 1.5 h. The mixture was cooled in an ice bath for 1 h and then filtered. The filter cake was washed with ice-cold dichloromethane and 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 1H NMR (CDCl3, 400 MHz): δ 10.50 (1H, s), 8.47 (1H, s), 8.22 (1H, m), 7.99 (1H, m), 7.51 (1H, t), 5.20 (1H, 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 [Chemical formula]

[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 mixture was warmed to 40 °C and stirred overnight. The reaction was quenched with methanol, and 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 afford 165a (192 mg, 71%) as a pale yellow foam. LC-MS: (ES, m / z): 538.4 [M+H]. 1 1H NMR (CDCl3, 400 MHz): δ 7.91 (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] (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 was used to synthesize the (S)-enantiomer as described for the (R)-enantiomer. LC-MS: (ES, m / z): 538.4 [M+H]. Example 16 Compounds 166a and 166b [Chemical formula]

[0160] Using pivaloyl chloride instead of isobutyryl chloride, compounds 166a and 166b were synthesized from the parent alcohol (233 mg, 0.5 mmol) according to the procedure described in Example 15. 166a (237 mg, 86%). LC-MS: (ES, m / z): 552.5 [M+H]. 1 1H NMR (CDCl3, 400 MHz): δ 7.91 (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

Chemical Structure

[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 hour, the solution of imidazolide 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). After the reaction was allowed to proceed at room temperature for 1 hour, the reaction was 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 4 M hydrogen chloride solution in dioxane (1.9 mL, 7.6 mmol). After 3.5 hours, 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 (400 MHz, 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] (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 was used to obtain the (R)-enantiomer as described for the (S)-enantiomer. LC-MS: (ES, m / z): 567.7 [M-HCl+H]. Example 18 Compounds 168a and 168b

Chemical formula

[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 and then the reaction was quenched with water (30 mL). The mixture was warmed 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 solution (2 M) was slowly added until pH~8.5 (9.7 mL). The 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 1H NMR (400 MHz, 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 31P NMR (162 MHz, D2O) δ: 4.08 (s).

[0164] (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 was used to obtain the (R)-enantiomer as described for the (S)-enantiomer. LC-MS: (ES, m / z): 548.1 [M - 2Na + 3H]. Example 19

[0165] Following the same procedures and starting materials as described in the above examples, the following compounds were prepared.

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

[0166] The foregoing syntheses are illustrative and can be used as starting points for preparing numerous additional compounds. Examples of compounds of formula (I) that can be prepared in various ways including these synthetic schemes shown and described herein are provided below. Those skilled in the art will recognize modifications of the disclosed syntheses 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

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

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

[0169] On day 1, the test article was diluted and added to the cell culture wells (in duplicate, 8 concentrations, 4-fold dilutions). GLS4, tenofovir, and sorafenib were used as reference compounds. 100 μL of culture medium containing the compound was added to the plate, and the final total volume per well was 200 μL. The final concentration of DMSO in the culture medium was 0.5%. The plate map for compound treatment is shown below. The cells were cultured at 37 °C and 5% CO2 for 3 days.

Chemical formula

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

[0171] On day 7, cell viability was evaluated using CellTiter-Glo® and the supernatant of the cell culture was collected for determination of HBV DNA by qPCR. Quantification of HBV DNA by qPCR

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

Table 3

[0173] DNA standards were prepared by diluting the pAAV2 HBV1.3 plasmid at concentrations ranging from 10 to 1×107 copies / μL, and were used to generate a standard curve by plotting the Ct value against 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 、 detected using CellTiter-Glo (registered trademark) according to the manufacturer's manual. Briefly, 50 μL of fresh cell culture medium was added to the culture plate, followed by 50 μL of CellTiter-Glo to each well. The plate was incubated at room temperature for 10 minutes. The luminescence signal was collected on a BioTek Synergy 2 plate reader. Data analysis

[0175] Cell viability was calculated as follows: % cell viability = (luminescence value of the test sample - average luminescence value of the blank) / (average luminescence value of the 0.5% DMSO control - average luminescence of the blank) × 100%. HBV DNA inhibition was calculated as follows: 100 - (HBV DNA copies in the test sample - HBV DNA copies of ETV) / (HBV DNA copies of the 0.5% DMSO control - HBV DNA copies of ETV) × 100%. CC 50 、EC 50and EC 90 The value was determined by a dose - response curve fitted by GraphPad Prism using "log(agonist) vs. response - variable slope".

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

Table 4 - 1

Table 4 - 2

[0177] The above has been described in some detail as figures and examples for clarity and understanding, but it will be understood by those skilled in the art that numerous various modifications can be made without departing from the spirit of the present disclosure. Therefore, the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure. On the contrary, it should be clearly understood that all modifications and alternatives in line with the true scope and spirit of the present invention are included. Another aspect of the present invention may be as follows. [1] A compound of formula (I) having the following structure: [Chemical formula 1] JPEG0007710215000090.jpg37128 In the formula: 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, and when the C 2 alkenyl, the C 2 alkynyl, unsubstituted C 1-4 haloalkyl, and the monocyclic heteroaryl are substituted, the C 2 alkenyl, the C 2 alkynyl, and the monocyclic heteroaryl are each independently substituted with one or more substituents selected from the group consisting of 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 each independently selected from the group consisting of 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. When the monocyclic C 3-6 cycloalkyl and the monocyclic 3- to 6-membered heterocyclyl are substituted, the monocyclic C 3-6 cycloalkyl and the monocyclic 3- to 6-membered heterocyclyl are each independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy. When the C 1-4 alkyl is substituted, the C 1-4 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 at least one of R 2 and R 3 is not hydrogen, or R 2 and R 3 together with the carbon to which R 2 and R 3 are attached form an unsubstituted or substituted monocyclic C 3-6 cycloalkyl or an unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl. When the C 3-6 cycloalkyl and the 3- to 6-membered heterocyclyl are substituted, the C 3-6 cycloalkyl and the 3- to 6-membered heterocyclyl are each independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy; R 4 and R 5 are each independently hydrogen, halogen, unsubstituted C 1-4 alkyl, deuterated C 1-4 alkyl, or unsubstituted C 2-4 alkenyl; 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 which is not hydrogen, or R 5 is hydrogen, halogen, unsubstituted C 1-4 alkyl, or unsubstituted C 2-4 alkenyl, 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 independently are hydrogen, halogen, unsubstituted C 1-4 haloalkyl, cyano, or unsubstituted C 1-4 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 -phosphoric acid, R A is hydrogen, halogen, unsubstituted C 1-4 haloalkyl, or cyano, a compound, or a pharmaceutically acceptable salt thereof. 〔2〕R 2 and R 3 independently are 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, selected from the group consisting of, when the monocyclic C 3-6 cycloalkyl and the monocyclic 3- to 6 heterocyclyl are substituted, the monocyclic C 3-6cycloalkyl and the monocyclic 3- to 6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy, the compound according to [1] above. 〔3〕R 2 and R 3 each are unsubstituted C 1-4 alkyl, the compound according to [2] above. 〔4〕R 2 and R 3 independently are 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, selected from the group consisting of, when the C 1-4 alkyl is substituted, the C 〔5〕R 2 alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, the compound according to [1] above. 3 and R 〔6〕R 2 one of which is hydrogen, the compound according to any one of [1] to [4] above. 3 and R 1-4 the other of which is unsubstituted C 〔7〕R 2 alkyl, the compound according to [5] above. 3 and R 1-4 the other of which is substituted C 1-4 alkyl, when the C 1-4 alkyl is substituted, the C 〔8〕R 2 alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid and O-carboxy, the compound according to [5] above. 3 and R 1-4 the other of which is unsubstituted C 〔9〕R 2 haloalkyl, the compound according to [5] above. and R 3 The other of which is unsubstituted monocyclic C 3-6 cycloalkyl, the compound according to [5] above. 〔10〕R 2 And R 3 The other of which is substituted monocyclic C 3-6 cycloalkyl, the compound according to [5] above. 〔11〕R 2 And R 3 The other of which is unsubstituted monocyclic 3- to 6-membered heterocyclyl, the compound according to [5] above. 〔12〕R 2 And R 3 The other of which is substituted monocyclic 3- to 6-membered heterocyclyl, the compound according to [5] above. 〔13〕R 2 And R 3 The other of which is unsubstituted C 1-4 hydroxyalkyl, the compound according to [5] above. 〔14〕R 2 And R 3 The other of which is unsubstituted C 1-5 alkoxyalkyl, the compound according to [5] above. 〔15〕R 2 And R 3 are, together with the carbon to which R 2 and R 3 are attached, form an unsubstituted or substituted monocyclic C 3-6 cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 6-membered heterocyclyl, and when the C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are substituted, the C 3-6 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, the compound according to [1] above. 〔16〕R 2 And R 3 are, together with the carbon to which R 2 and R 3 are attached, form an unsubstituted monocyclic C 3-6 cycloalkyl, the compound according to

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

[15] above. 〔18〕R 2 And R 3 are, together with the carbon to which R 2 and R 3are attached, form an unsubstituted monocyclic 3- to 6-membered heterocyclyl, the compound according to

[55] above. 〔19〕R 2 And R 3 are, together with the carbon to which R 2 and R 3 are attached, form a substituted monocyclic 3- to 6-membered heterocyclyl, the compound according to

[15] above.

[20] The monocyclic 3- to 6-membered heterocyclyl is unsubstituted or substituted oxetane, unsubstituted or substituted thietane, unsubstituted or substituted [Chemical Formula 2] JPEG0007710215000091.jpg16128 , unsubstituted or substituted [Chemical Formula 3] JPEG0007710215000092.jpg17128 , unsubstituted or substituted [Chemical Formula 4] JPEG0007710215000093.jpg14128 , unsubstituted or substituted [Chemical Formula 5] JPEG0007710215000094.jpg18128 , unsubstituted or substituted [Chemical Formula 6] JPEG0007710215000095.jpg15128 , and unsubstituted or substituted [Chemical Formula 7] JPEG0007710215000096.jpg23128 selected from the group consisting of, the compound according to

[18] or

[19] above. 〔21〕R 4 is hydrogen, the compound according to any one of [1] to

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

[20] above. 〔23〕R 4 is unsubstituted C 1-4 alkyl, the compound according to any one of [1] to

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

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

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

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

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

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

[27] , wherein it is alkenyl. 〔30〕R 5 is hydrogen, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring. The compound according to any one of [1] to

[20] . 〔31〕R 5 is halogen, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring. The compound according to any one of [1] to

[20] . 〔32〕R 5 is unsubstituted C 1-4 alkyl, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring. The compound according to any one of [1] to

[20] . 〔33〕R 5 is unsubstituted C 2-4 alkenyl, and R 4 and R 6 together form an unsubstituted or substituted 5- to 6-membered heterocyclic ring. The compound according to any one of [1] to

[20] . 〔34〕X 1 is N. The compound according to any one of [1] to

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

[33] . 〔36〕R A is hydrogen. The compound according to

[35] . 〔37〕R A is halogen. The compound according to

[35] . 〔38〕R Ais unsubstituted C 1-4 haloalkyl. The compound according to

[35] . 〔39〕R A is cyano. The compound according to

[35] . 〔40〕R A is unsubstituted C 1-4 alkoxy. The compound according to

[35] . 〔41〕R 7a is hydrogen. The compound according to any one of [1] to

[40] . 〔42〕R 7a is halogen. The compound according to any one of [1] to

[40] . 〔43〕R 7a is unsubstituted C 1-4 haloalkyl. The compound according to any one of [1] to

[40] . 〔44〕R 7a is cyano. The compound according to any one of [1] to

[40] . 〔45〕R 7a is unsubstituted C 1-4 alkoxy. The compound according to any one of [1] to

[40] . 〔46〕R 7b is hydrogen. The compound according to any one of [1] to

[45] . 〔47〕R 7b is halogen. The compound according to any one of [1] to

[45] . 〔48〕R 7b is unsubstituted C 1-4 haloalkyl. The compound according to any one of [1] to

[45] . 〔49〕R 7b The compound according to any one of [1] to

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

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

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

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

[50] , wherein it is haloalkyl. 〔54〕R7c The compound according to any one of [1] to

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

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

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

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

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

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

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

[60] , wherein it is alkenyl. 〔62〕R 1 is substituted C 2 The compound according to any one of [1] to

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

[60] , wherein it is alkynyl. 〔64〕R 1 is substituted C 2 The compound according to any one of [1] to

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

[60] , wherein it is haloalkyl. 〔66〕R 1 The compound according to any one of [1] to

[60] , wherein it is unsubstituted monocyclic heteroaryl. 〔67〕R 1 The compound according to any one of [1] to

[60] , wherein it is substituted monocyclic heteroaryl. 〔68〕R 1 The compound according to any one of [1] to

[60] , wherein it is unsubstituted bicyclic heteroaryl. 〔69〕R 1 The compound according to any one of [1] to

[60] , wherein it is substituted bicyclic heteroaryl. 〔70〕R 1The compound according to any one of [1] to

[60] , wherein it is unsubstituted monocyclic heterocyclyl. 〔71〕R 1 The compound according to any one of [1] to

[60] , wherein it is substituted monocyclic heterocyclyl. 〔72〕R 8 The compound according to any one of [1] to

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

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

[71] , wherein it is (alkyl). 〔75〕R 8 is -CH 2 The compound according to any one of the above [1] to

[71] , wherein it is -(α-amino acid). 〔76〕R 8 is -CH 2 The compound according to any one of the above [1] to

[71] , wherein it is -phosphate.

[77] The compound is [Chemical Formula 8] JPEG0007710215000097.jpg216153 [Chemical Formula 9] JPEG0007710215000098.jpg217152 [Chemical Formula 10] JPEG0007710215000099.jpg216152 [Chemical Formula 11] JPEG0007710215000100.jpg221152 [Chemical Formula 12] JPEG0007710215000101.jpg192152 [Chemical Formula 13] JPEG0007710215000102.jpg62141 The compound according to the above [1], or a pharmaceutically acceptable salt of any of the above, which is selected from the group consisting of.

[78] The compound is [Chemical Formula 14] JPEG0007710215000103.jpg216152 [Chemical Formula 15] JPEG0007710215000104.jpg233152 [Chemical Formula 16] JPEG0007710215000105.jpg235152 [Chemical Formula 17] JPEG0007710215000106.jpg237152 [Chemical Formula 18] JPEG0007710215000107.jpg55150 The compound according to the above [1], or a pharmaceutically acceptable salt of any of the above, which is selected from the group consisting of.

[79] The compound is [Chemical Formula 19] JPEG0007710215000108.jpg216152 [Chemical Formula 20] JPEG0007710215000109.jpg217152 [Chemical Formula 21] JPEG0007710215000110.jpg224152 [Chemical Formula 22] JPEG0007710215000111.jpg160157 The compound according to the above

[78] or

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

[80] [Chemical Formula 23] JPEG0007710215000112.jpg216153 [Chemical Formula 24] JPEG0007710215000113.jpg153157 The compound, or a pharmaceutically acceptable salt of any of the above, which is selected from the group consisting of.

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

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

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

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

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

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

[84] The use according to any one of the above

[82] to

[83] , wherein the use comprises the use of one or more additional medicaments 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 according to the above

[84] , wherein the one or more additional medicaments 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 the above [1] to

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

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

[80] for use in the treatment of hepatitis D. 〔88〕The compound according to any one of 〔86〕 to 〔87〕 above, which 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 according to 〔88〕 above, wherein the one or more additional agents 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 to the subject in need of treatment suffering from hepatitis B an effective amount of the compound according to any one of 〔1〕 to 〔80〕 above. 〔91〕A method for treating hepatitis D in a subject, comprising administering to the subject in need of treatment suffering from hepatitis D an effective amount of the compound according to any one of 〔1〕 to 〔80〕 above. 〔92〕The method according to any one of 〔90〕 to 〔91〕 above, 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 according to 〔92〕 above, wherein the additional agent 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. A compound of formula (I) having the following structure, wherein, R 1 is unsubstituted C 2 alkynyl and R 2 is an unsubstituted C 1-4 alkyl, R 3 is selected from the group consisting of substituted C 1-4 alkyl and unsubstituted C 1-4 hydroxyalkyl, and the substituted C 1-4 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 1 is unsubstituted C 2 alkenyl or unsubstituted C 2 alkynyl, and R 2 and R 3 are, together with the carbon to which R 2 and R 3 are attached, forming an unsubstituted or substituted monocyclic C 3-4 cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 4-membered heterocyclyl, and when the C 3-4 cycloalkyl and the 3- to 4-membered heterocyclyl are substituted, the C 3-4 cycloalkyl and the 3- to 4-membered heterocyclyl are each independently substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, R 4 and R 5 are each unsubstituted C 1-4 alkyl, R 6 is unsubstituted C 1-4 alkyl, and X 1 is CR A and R A is a halogen, and R 7a 、R 7c and R 7d are each hydrogen, R 7b is unsubstituted C 1-4 haloalkyl or cyano, and R 8 is hydrogen, the compound, or a pharmaceutically acceptable salt thereof.

2. R 2 is unsubstituted C 1-4 alkyl, R 3 is substituted C 1-4 alkyl and unsubstituted C 1-4 hydroxyalkyl, and is selected from the group consisting of, said substituted C 1-4 alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O - linked α - amino acid, and O - carboxy, the compound according to claim 1.

3. R 2 is unsubstituted C 1-4 alkyl, and R 3 is unsubstituted C 1-4 hydroxyalkyl, the compound according to claim 1.

4. R 1 is an unsubstituted C 2 alkenyl, and R 2 and R 3 are such that R 2 and R 3 together with the carbon to which they are attached form an unsubstituted or substituted monocyclic C 3-4 cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 4-membered heterocyclyl, and when the C 3-4 cycloalkyl and 3- to 4-membered heterocyclyl are substituted, the C 3-4 cycloalkyl and the 3- to 4-membered heterocyclyl are each independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy, the compound according to claim 1.

5. R 1 is unsubstituted C 2 alkynyl, and R 2 and R 3 are such that, together with the carbon to which R 2 and R 3 is attached, form an unsubstituted or substituted monocyclic C 3-4 cycloalkyl, or an unsubstituted or substituted monocyclic 3- to 4-membered heterocyclyl, and when the C 3-4 cycloalkyl and the 3- to 4-membered heterocyclyl are substituted, the C 3-4 cycloalkyl and the 3- to 4-membered heterocyclyl are each independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy. The compound according to claim 1.

6. R 2 and R 3 are, together with the carbon to which R 2 and R 3 is attached, forming an unsubstituted or substituted monocyclic C 3-4 cycloalkyl, and when the C 3-4 cycloalkyl is substituted, the C 3-4 cycloalkyl is independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy. The compound according to any one of claims 4 to 5

7. R 2 and R 3 are combined with the carbon to which R 2 and R 3 is attached to form an unsubstituted or substituted monocyclic 3- to 4-membered heterocyclyl, and when the 3- to 4-membered heterocyclyl is substituted, the 3- to 4-membered heterocyclyl is independently substituted with one or two substituents selected from the group consisting of halogen and hydroxy. The compound according to any one of claims 4 to 5.

8. The monocyclic 3- to 4-membered heterocyclyl is unsubstituted or substituted oxetane, unsubstituted or substituted thietane, unsubstituted or substituted , and unsubstituted or substituted and is selected from the group consisting of, the compound according to claim 7.

9. R 4 is methyl, R 5 is methyl, and R 6 is methyl, the compound according to any one of claims 1 to 8.

10. R A The compound according to any one of claims 1 to 9, wherein R is fluorine.

11. R 7b is unsubstituted C 1-4 haloalkyl, and the compound according to any one of claims 1 to 10.

12. R 7b is cyano, the compound according to any one of claims 1 to 10.

13. R 1 is unsubstituted C 2 alkynyl, and R 2 is an unsubstituted C 1-4 alkyl, and R 3 is selected from the group consisting of substituted C 1-4 alkyl and unsubstituted C 1-4 hydroxyalkyl, and when the C 1-4 alkyl is substituted, the C 1-4 alkyl is substituted with one or more substituents selected from the group consisting of phosphate, O-linked α-amino acid, and O-carboxy, the compound according to claim 1.

14. R 1 is unsubstituted C 2 alkynyl, and R 2 and R 3 are taken together with the carbon to which R 2 and R 3 is attached to form an unsubstituted or substituted monocyclic 3- to 4-membered heterocyclyl, and when the 3- to 4-membered heterocyclyl is substituted, the 3- to 4-membered heterocyclyl is substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy. The compound according to claim 1.

15. R 2 and R 3 are, together with the carbon to which R 2 and R 3 is attached, form an unsubstituted or substituted oxetane, a compound according to claim 14.

16. R 7b is cyano, and R A is F, the compound according to any one of claims 13 to 15.

17. R 7b is -CF 3 and R A is F, the compound according to any one of claims 13 to 15.

18. The following structure, a compound having, or a pharmaceutically acceptable salt thereof.

19. The following structure, a compound having.

20. The following structure, a compound having, or a pharmaceutically acceptable salt thereof.

21. The following structure, a compound having, or a pharmaceutically acceptable salt thereof.

22. The following structure, a compound having, or a pharmaceutically acceptable salt thereof.

23. The following structure, a compound having, or a pharmaceutically acceptable salt thereof.

24. The following structure, a compound having, or a pharmaceutically acceptable salt or stereoisomer thereof.

25. A compound selected from the group consisting of, or a pharmaceutically acceptable salt of any of the above.

26. The compound according to claim 25 selected from the group consisting of, or a pharmaceutically acceptable salt of any of the above.

27. selected from the group consisting of, or a pharmaceutically acceptable salt of any of the above.

28. A pharmaceutical composition for the treatment of hepatitis B, comprising an effective amount of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition for the treatment of hepatitis D, comprising an effective amount of the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition according to claim 28 or 29, wherein the pharmaceutical composition can be used in combination with 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.

31. The pharmaceutical composition according to claim 30, wherein the additional agent 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.

Images