Pyrrole compounds

Abstract

Provided herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising compounds described herein, including pharmaceutically acceptable salts of compounds described herein, and methods of synthesis thereof. Also provided herein are methods of treating diseases and / or conditions with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of the Chinese Patent Application No. 202080028131.4 filed on April 01, 2020, having the title of “Pyrrole Compounds”.

[0002] Incorporation by Reference of Any Priority Application

[0003] Any or all of the patent applications to which priority is claimed in the patent application data sheet or request filed, e.g., with the present patent application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Patent Application 62 / 828919 filed April 3, 2019 and 62 / 932686 filed November 8, 2019. BACKGROUND TECHNICAL FIELD

[0005] The present application relates to the fields of chemistry, biochemistry, and medicine. Disclosed herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharmaceutically acceptable salts of the compounds described herein), and methods of synthesis thereof. Also disclosed herein are methods of treating diseases and / or disorders with the compounds of Formula (I) or pharmaceutically acceptable salts thereof.

[0006] DESCRIPTON

[0007] Hepatitis B virus (HBV) is a DNA virus and a member of the Hepadnaviridae Hepadnaviridae ) family. HBV infects over 300 million worldwide and is the causative agent of liver cancer and liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. While there are approved drugs for treating HBV by enhancing the immune system or slowing the replication of the HBV virus, HBV remains a problem due to the drawbacks associated with each of the approved drugs. SUMMARY

[0008] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments disclosed herein relate to a pharmaceutical composition that can comprise an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as having HBV and / or HDV infection an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for treating HBV and / or HDV infection.

[0011] Some embodiments disclosed herein relate to methods for inhibiting the replication of HBV and / or HDV, which may include contacting HBV- and / or HDV-infected cells with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for inhibiting the replication of HBV and / or HDV.

[0012] These are other implementation schemes described in more detail below. Detailed Implementation

[0013] HBV is a partially double-stranded circular DNA of approximately 3.2 kilobase pairs and is classified into eight genotypes, A through H. The HBV replication pathway has been studied in more detail. (TJ Liang, Hepatology (2009), Vol. 49 (Supplement 5): pp. S13–S21). Part of replication involves the formation of a covalently closed circular form (cccDNA). The presence of cccDNA increases the risk of viral reactivation throughout the host organism's lifespan. HBV carriers can transmit the disease for many years. An estimated 300 million people are infected with hepatitis B virus, and an estimated 750,000 people die from hepatitis B worldwide each year. Furthermore, immunosuppressed individuals or those undergoing chemotherapy are particularly at risk of HBV reactivation. HBV can be acute and / or chronic. Acute HBV infection can be asymptomatic or present with symptomatic acute hepatitis.

[0014] HBV can be transmitted through blood, semen, and / or other bodily fluids. This can occur through direct blood-to-blood contact, unprotected sex, sharing needles, and from an infected mother to her baby during childbirth. HBV surface antigen (HBsAg) is most commonly used to screen for the presence of this infection. Currently available medications do not cure HBV and / or HDV infection. Instead, medications suppress viral replication.

[0015] Hepatitis D virus (HDV) is also a DNA virus belonging to the Hepatoviridae family. HDV can only replicate in the presence of HBV. The transmission routes of HDV are similar to those of HBV. HDV transmission can occur through co-infection with HBV (co-infection) or in addition to chronic hepatitis B or a hepatitis B carrier state (over-infection). Both HDV over-infection and co-infection lead to more severe complications compared to HBV infection alone. These complications include a greater likelihood of experiencing liver failure and rapid progression of cirrhosis in acute infection, and an increased risk of developing liver cancer in chronic infection. In combination with hepatitis B, hepatitis D has the highest mortality rate of all hepatitis infections, at 20%. Currently, there is no treatment or vaccine available for hepatitis D.

[0016] definition

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, publications, and other publications cited herein are incorporated herein by reference in their entirety unless otherwise stated. Where multiple definitions exist for terms herein, the terminology used in that section shall prevail unless otherwise stated.

[0018] Whenever a group is described as “optionally substituted,” the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as “unsubstituted or substituted,” if substituted, the one or more substituents may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" group may be substituted by one or more groups selected individually and independently from: deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), (heterocyclic)alkyl, hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, isocyanate, thiocyanate, nitro, azide, silyl, sulfinyl, sulfonyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amino, monosubstituted amino group and disubstituted amino group.

[0019] As used in this article, where "a" and "b" are integers, "C" represents the integers. a To C bThe term "C1 to C4 alkyl" refers 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 heterocyclic group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic group may contain "a" to "b" carbon atoms (inclusive of the endpoints). Therefore, for example, "C1 to C4 alkyl" groups refer to all alkyl groups having 1 to 4 carbons, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic group, the widest range described in these definitions should be assumed.

[0020] As used herein, “alkyl” refers to a straight-chain or branched hydrocarbon chain containing a fully saturated (without double or triple bonds) hydrocarbon group. An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as “1 to 20” refer to every integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition of this invention also covers the term “alkyl” when no numerical range is specified). An alkyl group may also be a medium-sized alkyl group having 1 to 10 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of a compound may be named “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates the presence of one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0021] 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 group can vary. For example, the alkenyl group can be C10-C20. 2-4 alkenyl, C 2-6 alkenyl or C 2-8 Alkenyl groups. Examples of alkenyl groups include allenyl, vinylmethyl, and vinyl. Alkenyl groups can be unsubstituted or substituted.

[0022] 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 group can vary. For example, the alkynyl group can be C10-2000. 2-4 alkynyl group, C 2-6 alkynyl or C 2-8Alkynyl group. Examples of alkynyl groups include ethynyl and propynyl. The alkynyl group can be unsubstituted or substituted.

[0023] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings may be joined together in a fused manner. A cycloalkyl group may contain 3 to 10 atoms, 3 to 8 atoms, 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.

[0024] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bond cannot form a fully delocalized π-electron system throughout all rings (otherwise the group would be “aryl” as defined herein). When composed of two or more rings, the rings may be fused together. A cycloalkenyl group may contain 3 to 10 atoms or 3 to 8 atoms in the ring. The cycloalkenyl group may be unsubstituted or substituted.

[0025] As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a chemical bond) with a fully delocalized π-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C4. 14 aryl group, C6 to C 10 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 can be substituted or unsubstituted.

[0026] As used herein, “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), which are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term “heteroaryl” includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazolidone, 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, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, and triazine. The heteroaryl group can be substituted or unsubstituted.

[0027] As used herein, a "heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic ring system in which a carbon atom, along with 1 to 5 heteroatoms, constitutes the ring system. The heterocycle may optionally contain one or more unsaturated bonds positioned in such a manner that a fully delocalized π-electron system does not occur throughout all rings. The number of atoms in the ring of the heterocyclic group can vary. For example, the heterocyclic group may contain 4 to 14 atoms, 5 to 10 atoms, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. The heterocycle may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, these rings may be joined together in a fused form. Additionally, any nitrogen in the heterocyclic group may be quaternized. The heterocyclic group may be unsubstituted or substituted. Examples of such "heterocyclic" groups include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxopentane, 1,3-dioxopentane, 1,4-dioxopentane, 1,3-oxothiocyclohexane, 1,4-oxothiocyclohexadiene, 1,3-oxothiocyclopentane, 1,3-dithiocyclopentadiene, 1,3-dithiopentane, 1,4-oxothiocyclohexadiene, 1,3-oxothiocyclo ... Thioxacyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxacyclohexane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazolidinone, thiazoline, thiazoline, morpholine, ethylene oxide, piperidine N -Oxides, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidone-dione, 4-piperidinone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone and their benzo[a]-fused analogues (e.g., benzimidazolinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

[0028] As used herein, “aryl(alkyl)” means an aryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and the aryl group of an aryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0029] As used herein, “heteroaryl(alkyl)” means a heteroaryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and the heteroaryl group of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furanyl(alkyl), thienyl(alkyl), pyrroleyl(alkyl), pyridinyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo[a]-fused analogs.

[0030] "Heterocyclic (alkyl)" refers to a heterocyclic group that is substituent via a lower alkylene group. The lower alkylene group and the heterocyclic group of the heterocyclic (alkyl) group can 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-thiaran-4-yl (methyl), and 1,3-thiazin-4-yl (methyl).

[0031] A “lower alkylene group” is a straight-chain -CH2- group that forms a bond to connect a molecular segment via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen atoms of the lower alkylene group with one or more substituents listed in accordance with the definition of “substituted”.

[0032] As used herein, “alkoxy” refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0033] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl) group connected as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. The acyl group may be substituted or unsubstituted.

[0034] As used herein, “haloalkyl” means an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. The hydroxyalkyl group may be substituted or unsubstituted.

[0035] As used herein, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

[0036] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy groups may be substituted or unsubstituted.

[0037] The "sulfonyl" group refers to a "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). The sulfonyl group can be substituted or unsubstituted.

[0038] The "sulfinyl" group refers to a group in which R can be the same "-S(=O)-R" group as defined relative to the sulfoxide group. The sulfinyl group can be substituted or unsubstituted.

[0039] A "sulfonyl" group is one in which R can be the same "SO2R" group as defined relative to the sulfoxide group. The sulfonyl group can be substituted or unsubstituted.

[0040] The “O-carboxyl” group refers to an “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl) as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0041] The terms "ester" and "C-carboxyl" refer to groups in which the R group can be the same "-C(=O)OR" group as defined relative to the O-carboxyl group. Esters and C-carboxyl groups can be substituted or unsubstituted.

[0042] A "thiocarbonyl" group is one in which R can be the same "-C(=S)R" group as defined relative to the O-carboxyl group. Thiocarbonyl groups can be substituted or unsubstituted.

[0043] The “trihalomethanesulfonyl” group refers to the “X3CSO2-” group where each X is a halogen.

[0044] The "trihalomethanesulfonylamino" group refers to a group in which each X is a halogen and R is a halogen. AThe "X3CS(O)2N(R" is a group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A )-” group.

[0045] As used in this article, the term "amino" refers to the -NH2 group.

[0046] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0047] The "cyano" group refers to the "-CN" group.

[0048] As used in this article, the term "azido" refers to the -N3 group.

[0049] The "isocyanate" group refers to the "-NCO" group.

[0050] The "thiocyanate" group refers to the "-CNS" group.

[0051] The "isothiocyanate" group refers to the "-NCS" group.

[0052] The "thiol" group refers to the "-SH" group.

[0053] The "carbonyl" group refers to the C=O group.

[0054] The "S-sulfonamide" group refers to the R group within it. A and R B "-SO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A R B The S-sulfonamide group can be substituted or unsubstituted.

[0055] The "N-sulfonamide" group refers to the combination of R and R... A "RSO2N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl) A The N-sulfonamide group can be substituted or unsubstituted.

[0056] The "O-carbamoyl" group refers to the R group in the carbamoyl group. A and R B "-OC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A R BThe O-carbamoyl group can be substituted or unsubstituted.

[0057] The "N-carbamoyl" group refers to the combination of R and R... A "ROC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A The N-carbamoyl group can be substituted or unsubstituted.

[0058] The "O-thiocarbamoyl" group refers to the R group in the R group. A and R B "-OC(=S)-N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A R B The O-thiocarbamoyl group can be substituted or unsubstituted.

[0059] The "N-thiocarbamoyl" group refers to the group containing R and R. A "ROC(=S)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A The N-thiocarbamoyl group can be substituted or unsubstituted.

[0060] The "C-amide" group refers to the R group in the C-amide group. A and R B "-C(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A R B The C-amide group can be substituted or unsubstituted.

[0061] The "N-acylamino" group refers to the combination of R and R... A "RC(=O)N(R)" can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A The N-amino group can be substituted or unsubstituted.

[0062] As used herein, the term "halogen atom" or "halogen" refers to any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0063] 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, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

[0064] As used herein, the term "phosphate" is used in its ordinary sense as understood by those skilled in the art, and includes Together with its protonated form (e.g.) and ).

[0065] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1 to C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two, or three atoms.

[0066] As used herein, unless otherwise specified, abbreviations for any protecting groups, amino acids and other compounds conform to their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Committee (see Biochem. 11:942-944 (1972)).

[0067] The term "pharmaceutically acceptable salt" refers to a salt of a compound that will not cause significant irritation to the organism to which it is applied and will not eliminate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Drug salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Drug salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids (e.g., 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). Drug salts can also be obtained by reacting the compound with a base to form salts such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reacting with amino acids (e.g., arginine and lysine).

[0068] The terms and phrases and their variations used in this application, particularly in the appended claims, should be understood as open-ended rather than restrictive, unless otherwise expressly stated. For the foregoing examples, the term "comprising" should be understood as "including but not limited to," "including but not limited to," etc.; as used herein, the term "comprising" is synonymous with "containing," "comprising," or "characterized as" and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term "having" should be interpreted as "having at least"; the term "comprising" should be interpreted as "including but not limited to"; the term "example" is used to provide exemplary instances of the items under discussion, not an exhaustive or restrictive list thereof. Furthermore, the term "comprising" should be interpreted as synonymous with the phrase "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 at least includes the stated features or components, but may also include additional features or components.

[0069] For virtually any plural and / or singular term used herein, those skilled in the art can convert from plural to singular and / or from singular to plural, as appropriate to the context and / or application. For clarity, various singular / plural substitutions may be explicitly stated herein. The indefinite articles “a” or “an” do not exclude multiples.

[0070] It should be understood that in any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly specified, each center may independently be an (R) configuration or an (S) configuration or a mixture thereof. Therefore, the compounds presented herein may be enantiomerically pure, enantiomerically enriched racemic mixtures or diastereomeric pure, diastereomeric enriched stereoisomers. Furthermore, it should be understood that in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond may independently be E or Z or a mixture thereof. Likewise, it should be understood that all tautomeric forms are intended to be included in any of the compounds described herein.

[0071] It should be understood that in cases where the compounds disclosed herein have unfilled valences, they are filled with hydrogen or its isotopes (e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0072] It should be understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to increased metabolic stability, such as, for example, an increased in vivo half-life or a reduced dose requirement. Each chemical element represented in the compound structure may include any isotope of that element. For example, in the compound structure, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position in the 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). Therefore, unless the context clearly specifies otherwise, the compounds mentioned herein encompass all possible isotopic forms.

[0073] Regarding the range values ​​provided, it should be understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are covered within the implementation scheme.

[0074] compound

[0075] Some of the embodiments disclosed herein involve compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) Where: R 1 It can be an unsubstituted or substituted C2 alkenyl group, an unsubstituted or substituted C2 alkynyl group, or an unsubstituted C2 alkenyl group. 1-4 Halogenated alkyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclic group, wherein when the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl are substituted, the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl can be independently substituted by 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 hydroxylated monocyclic C 3-6 cycloalkyl; R 2 and R 3 It can be independently selected from hydrogen, unsubstituted or substituted C. 1-4 Alkyl, unsubstituted C 1-4 Halogenated alkyl groups, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 When cycloalkyl groups and monocyclic 3-6 heterocyclic groups are substituted, the monocyclic C 3-6 Cycloalkyl and monocyclic 3-6 heterocyclic groups can be independently substituted by one or more substituents selected from halogens or hydroxyl groups, and wherein when C 1-4When alkyl groups are substituted, C 1-4 The alkyl group is substituted by one or more substituents selected from the following: phosphate group, O-linked α-amino acid group, and O-carboxyl group; or R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6-membered heterocyclic groups, wherein when C 3-6 When cycloalkyl groups and 3-6 membered heterocyclic groups are substituted, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups can be independently substituted by one or two substituents selected from halogens and hydroxyl groups; R 4 and R 5 It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 2-4 alkenyl; R 6 It can be hydrogen or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 3-4 alkenyl; and the prerequisite is R 4 R 5 and R 6 At least one of them is not hydrogen; or R 5 It can be hydrogen, halogen, or unsubstituted C. 1-4 Alkyl or unsubstituted C 2-4 alkenyl; and R 4 and R 6 They can combine to form unsubstituted or substituted 5-6 membered heterocycles; Y 1 CR A Or N (nitrogen); R 7a R 7b R 7c and R 7d It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl, cyano or unsubstituted C 1-4 Alkoxy; R 8 It can be hydrogen, -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), -CH2OC(=O)-O- (unsubstituted C) 1-4 Alkyl group, -CH2-(α-amino acid) or -CH2-phosphate group; and R A It can be hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl or cyano groups.

[0076] Various groups can be attached to the pyrrole ring of formula (I). As provided herein, the pyrrole ring can be attached with hydrogen, halogen, or unsubstituted C.1-4 Alkyl, deuterated C 1-4 Alkyl and / or unsubstituted C 2-4 Alkenyl, provided that R 4 R 5 and R 6 At least one of them is not hydrogen. C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R 4 and R 5 One of them can be a halogen or an unsubstituted C. 1-4 Alkyl, and / or R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 and / or R 5 Each can be an independent halogen or unsubstituted C. 1-4 Alkyl, and / or R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 and R 5 Each can be an independent halogen or unsubstituted C. 1-4 Alkyl, and R 6 Can be unreplaced C 1-4 Alkyl group. In another embodiment, R 4 R 5 and R 6 One of them could be the unreplaced C. 1-4 Alkyl, and R 4 R 5 and R 6 One of them could be the unreplaced C. 3-4 Alkenyl. When R 4 R 5 and R 6 One of them is deuterated C 1-4 In the case of alkyl groups, C 1-4 One or more hydrogen atoms in an alkyl group can be replaced by deuterium. For example, R 4 R 5 and R 6 One of them can be CH2D, CHD2, CD3, CH2CD3, CD2CD3, CH2CH2CD3, or CH(CD3)2. In some implementations, R 4 R 5 and R 6 One of them could be deuterated C 1-4 Alkyl, and R 4 R 5 and R 6 The other two in the equation can be unsubstituted C. 1-4 alkyl.

[0077] In some implementation schemes, R 4 It can be hydrogen; R 5 It can be hydrogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 It can be halogen; R 5 It can be hydrogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 It can be hydrogen; R 5 It can be halogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 It can be hydrogen; R 5 Can be unreplaced C 1-4 Alkyl; and R 6 Can be unreplaced C 3-4 Alkenyl group.

[0078] In some implementation schemes, R 4 It can be hydrogen; R 5 It can be halogen; and R 6 It can be hydrogen. In other embodiments, R 4 It can be hydrogen; R 5 It can be halogen; and R 6 It can be hydrogen. In other embodiments, R 4 It can be halogen; R 5 It can be halogen; and R 6 It can be hydrogen. In another embodiment, R 4 Can be unreplaced C 1-4 Alkyl; R 5 It can be hydrogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In some embodiments, R 4 Can be unreplaced C 1-4 Alkyl; R 5 It can be halogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 Can be unreplaced C 1-4 Alkyl; R 5 Can be unreplaced C 1-4 Alkyl; and R 6 Can be unreplaced C 1-4 Alkyl. In other embodiments, when R 4 R 5 and / or R 6 For unreplaced C1-4 When alkyl, the unsubstituted C 1-4 Alkyl groups can be methyl groups. For example, R 4 R 5 and R 6 Each of them can be methyl. In another embodiment, R 4 It can be hydrogen; and R 5 and R 6 Each can be an unreplaced C 1-4 Alkyl group. In some embodiments, R 4 It can be halogen; and R 5 and R 6 Each can be an unreplaced C 1-4 Alkyl group. In other embodiments, R 5 It can be halogen; and R 4 and R 6 Each can be an unreplaced C 1-4 Alkyl group. In other embodiments, R 4 and R 5 Each can be hydrogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In another embodiment, R 4 It can be hydrogen; R 5 It can be halogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In some embodiments, R 4 and R 5 Each can be a halogen; and R 6 Can be unreplaced C 1-4 Alkyl group. In other embodiments, R 4 and R 5 Each can be an unreplaced C 1-4 Alkyl; and R 6 Can be deuterated C 1-4 Alkyl groups, such as CD3.

[0079] As provided herein, in some implementations, R 5 It can be hydrogen, halogen, or unsubstituted C. 1-4 Alkyl or unsubstituted C 2-4 alkenyl; and R 4 and R 6 They can combine to form unsubstituted or substituted 5-6 membered heterocycles. For example, R 4 and R 6 They can be combined to form unsubstituted or substituted compounds. or not replaced or replaced , where N The nitrogen of the pyrrole group in formula (I). In some embodiments, R 5It can be hydrogen; and R 4 and R 6 They can be combined to form unsubstituted or substituted 5-6 membered heterocycles, such as those described herein. In other embodiments, R 5 It can be halogen; and R 4 and R 6 They can be combined to form unsubstituted or substituted 5-6 membered heterocycles, such as those described herein. In other embodiments, R 5 Can be unreplaced C 1-4 Alkyl; and R 4 and R 6 They can be combined to form unsubstituted or substituted 5-6 membered heterocycles, such as those described herein. In another embodiment, R 5 Can be unreplaced C 2-4 alkenyl; and R 4 and R 6 They can combine to form unsubstituted or substituted 5-6 membered heterocycles, such as those described herein.

[0080] Including X 1 The 6-membered aromatic ring can be optionally substituted phenyl or optionally substituted pyridine. When X 1 For CR A In this case, the 6-membered ring can be an optionally substituted phenyl group. When X 1 When the nitrogen atom is N, the 6-membered aromatic ring can be optionally substituted pyridine. As provided herein, including X 1 The 6-membered aromatic ring can be substituted. When substituted, the phenyl and / or pyridine can be substituted once, twice, three times, or more. The substituted benzene ring can be substituted at the para position. Alternatively, the benzene ring can be substituted at the meta position. In some embodiments, the benzene ring can be substituted at the ortho position.

[0081] In some implementation schemes, X 1 It can be CH. In other implementations, X 1 CR A When X 1 For CR A At that time, R A It can be a non-hydrogen group. For example, in some embodiments, R A It can be a halogen (such as F, Cl, or Br). In other embodiments, R A Can be unreplaced C 1-4 Haloalkyl. Suitable C 1-4 Halogenated alkyl groups include, but are not limited to, -CHF2, -CF3, CH2F, CHClF, and CCl3. In other embodiments, R A It can be cyano. In another embodiment, R A Can be unreplaced C1-4 Alkyl groups. Example C 1-4 Alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0082] As described in this article, R 7b and / or R 7c It can be hydrogen. (And R) A Similarly, R 7b and / or R 7c It can be a non-hydrogen group, such as halogens or unsubstituted C. 1-4 Halogenated alkyl, cyano and unsubstituted C 1-4 Alkyl group. In some embodiments, R 7b It can be hydrogen. In other embodiments, R 7b It can be a halogen (e.g., F, Cl, or Br). In other embodiments, R 7b Can be unreplaced C 1-4 Halogenated alkyl groups, such as those described herein and including -CHF2, -CF3, and -CH2F. In another embodiment, R 7b It can be cyano. In some embodiments, R 7b Can be unreplaced C 1-4 Alkyl groups, such as those described herein. In some embodiments, R 7c It can be hydrogen. In other embodiments, R 7c It can be a halogen, such as F, Cl, or Br. In other embodiments, R 7c Can be unreplaced C 1-4 Halogenated alkyl groups, such as -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In another embodiment, R 7c It can be cyano. In some embodiments, R 7c Can be unreplaced C 1-4 Alkyl groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0083] With including X 1 The other positions on the 6-membered aromatic ring are the same, R 7a and / or R 7d It can be a hydrogen or non-hydrogen group. In some embodiments, R 7a It can be hydrogen. In other embodiments, R 7a It can be a halogen, such as F, Cl, or Br. In other embodiments, R 7a Can be unreplaced C 1-4 Halogenated alkyl groups, such as -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In another embodiment, R 7aIt can be cyano. In some embodiments, R 7a Can be unreplaced C 1-4 Alkyl groups, including but not limited to those described herein. In some embodiments, R 7d It can be hydrogen. In other embodiments, R 7d It can be a halogen (e.g., F, Cl, or Br). In other embodiments, R 7d Can be unreplaced C 1-4 Halogenated alkyl groups, including but not limited to -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In another embodiment, R 7d It can be cyano. In some embodiments, R 7d Can be unreplaced C 1-4 Alkyl groups. For example, R 7d It can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0084] In some implementation schemes, R A It can be a non-hydrogen group as described herein; and R 7b Or R 7c It can be a non-hydrogen group as described herein. In other embodiments, R A It can be a non-hydrogen group as described herein; R 7b Or R 7c It can be a non-hydrogen group as described herein; and R 7a and R 7d Each is hydrogen. In other embodiments, R A It can be a non-hydrogen group as described herein; R 7b and R 7c One of them can be a non-hydrogen group as described herein, and R 7b and R 7c The other one in R can be hydrogen; and R 7a and R 7d Each is hydrogen. The following includes X. 1 Examples of 6-membered aromatic rings: , , , and .

[0085] In some implementation schemes, R 2 and R 3 It can be independently selected from hydrogen, unsubstituted or substituted C. 1-4 Alkyl, unsubstituted C 1-4 Halogenated alkyl groups, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, unsubstituted C1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 When cycloalkyl groups and monocyclic 3-6 heterocyclic groups are substituted, the monocyclic C 3-6 Cycloalkyl and monocyclic 3-6 heterocyclic groups can be independently substituted by one or more substituents selected from halogens or hydroxyl groups, and wherein when C 1-4 When alkyl groups are substituted, C 1-4 The alkyl group is substituted by one or more substituents selected from: phosphate, O-linked α-amino acid, and O-carboxyl. In other embodiments, R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6-membered heterocyclic groups, wherein when C 3-6 When cycloalkyl groups and 3-6 membered heterocyclic groups are substituted, C 3-6 The cycloalkyl and 3-6-membered heterocyclic groups are independently substituted by one or two substituents selected from halogens and hydroxyl groups.

[0086] R 2 and R 3 The substituents can be the same or different, or R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6-membered heterocyclic groups. In some embodiments, R 2 and R 3 Each can be hydrogen. In other embodiments, R 2 and R 3 Each can be an unreplaced C 1-4 Alkyl group. Suitable unsubstituted C 1-4 Examples of alkyl groups are described in this article. For example, R 2 and R 3 Each can be a methyl group.

[0087] As described in this article, R 2 and R 3 They can be different. For example, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be the unsubstituted C. 1-4 Alkyl, unsubstituted C 1-4 Halogenated alkyl groups, unsubstituted or substituted monocyclic C 3-6Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 Alkoxyalkyl. In some embodiments, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be the unsubstituted C. 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In other embodiments, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be the unsubstituted C. 1-4 Haloalkyl. Exemplary C 1-4 Halogenated alkyl groups are described herein and include, but are not limited to, -CHF2, -CF3, -CH2F, -CHClF, and -CCl3. In other embodiments, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one can be an unsubstituted or substituted monocyclic C 3-6 Cycloalkyl groups. For example, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one can be an unsubstituted cyclopropyl, an unsubstituted cyclobutyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl; or, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one can be a substituted cyclopropyl, a substituted cyclobutyl, a substituted cyclopentyl, or a substituted cyclohexyl. When substituted, the substituted monocyclic C 3-6 The cycloalkyl group can be substituted once, twice, or three times independently by a halogen (F, Cl, or Br) and a hydroxyl group. In some embodiments, the substituted monocyclic C 3-6 Cycloalkyl groups can be substituted with one or two halogens. For example, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be In another implementation, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3The other component can be an unsubstituted or substituted monocyclic 3-6 membered heterocyclic group. Various monocyclic 3-6 membered heterocyclic groups are suitable for R... 2 / R 3 In some implementations, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be the unsubstituted C. 1-4 Hydroxyalkyl. For example, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one can be -CH2OH. In other embodiments, R 2 and R 3 One of them can be hydrogen; and R 2 and R 3 The other one could be the unsubstituted C. 1-5 Alkoxyalkyl. Unsubstituted C 1-5 Examples of alkoxyalkyl groups include -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2OCH(CH3)2, -CH2OCH2CH(CH3)2 and -CH2CH2OCH(CH3)2.

[0088] The prodrug fraction may be present in R 2 and R 3 One of them. In some implementations, R 2 and R 3 One of them could be the unreplaced C. 1-4 Alkyl (e.g., methyl); and R 2 and R 3 The other one in the list can be replaced by C. 1-4 Alkyl, wherein C 1-4 The alkyl group is substituted with one or more substituents selected from phosphate, O-linked α-amino acids, and O-carboxyl groups. Suitable α-amino acids are described herein and include, but are not limited to, alanine, asparagine, aspartic acid, cysteine, glutamic acid, 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 attached to the indicated moiety via a hydroxyl group from its main chain carboxylic acid group. When an α-amino acid is attached as an -O-linked α-amino acid, there is no hydrogen as part of the hydroxyl group from its main chain carboxylic acid group, and the α-amino acid is attached via oxygen. In some embodiments, in R 2 Or R 3C 1-4 The -O-linked α-amino acid substituted on the alkyl group can be an -O-linked -L-α-amino acid. In other embodiments, in R... 2 Or R 3 C 1-4 An α-amino acid with an alkyl substituent and an O-linked structure can be an O-linked -D-α-amino acid. Examples of -O-linked -α-amino acids are given here relative to R. 8 As shown. It can exist in R. 2 Or R 3 The replacement of C 1-4 Another example of a prodrug moiety on an alkyl group is an O-carboxyl group. In some embodiments, R 2 and R 3 One of them could be the unreplaced C. 1-4 Alkyl groups (such as methyl); and R 2 and R 3 The other one can be an O-carboxyl-substituted C. 1-4 Alkyl groups. For example, O-carboxyl-substituted C groups. 1-4 Alkyl groups can have the structure -(CH2)4-OC(=O) (unsubstituted C) 1-4 Alkyl group). As described herein, R 2 Or R 3 C 1-4 Alkyl groups can be substituted with phosphate groups. For example, when R... 2 Or R 3 It is a C that has been replaced by phosphate. 1-4 When alkyl, R 2 Or R 3 It can be -CH2-OP(=O)(O) - )2 or -CH2-OP(=O)(OH)2.

[0089] As provided in this article, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, when C 3-6 When cycloalkyl and 3-6 membered heterocyclic groups are substituted, they are independently substituted by one or two substituents selected from halogens and hydroxyl groups. In some embodiments, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted monocyclic C atoms. 3-6 Cycloalkyl. In other embodiments, R 2 and R 3 Can be combined with R2 and R 3 The attached carbon atoms combine to form substituted monocyclic carbon atoms. 3-6 Cycloalkyl. C 3-6 The cycloalkyl group can be unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl. When C 3-6 When cycloalkyl groups are substituted, C 3-6 The cycloalkyl group may be substituted once, twice, three times, or more. When two or more substituents are present, these substituents may be all identical or may contain at least different substituents. For example, in some embodiments, C 3-6 The cycloalkyl group may be substituted with one or two halogens (such as one or two fluorine substituents). In other embodiments, C 3-6 Cycloalkyl groups can be substituted with hydroxyl groups. Example C 3-6 Cycloalkyl groups include unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, fluorinated cyclopropyl, fluorinated cyclobutyl, fluorinated cyclopentyl, fluorinated cyclohexyl, hydroxylated cyclopropyl, hydroxylated cyclobutyl, hydroxylated cyclopentyl, and hydroxylated cyclohexyl. and .

[0090] In some implementation schemes, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted monocyclic 3-6-membered heterocyclic groups. In some embodiments, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form substituted monocyclic 3-6-membered heterocyclic groups. For example, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic 3-membered heterocyclic groups, unsubstituted or substituted monocyclic 4-membered heterocyclic groups, unsubstituted or substituted monocyclic 5-membered heterocyclic groups, or unsubstituted or substituted monocyclic 6-membered heterocyclic groups. In some embodiments, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted oxygen-containing monocyclic 3-6-membered heterocyclic groups. In other embodiments, R 2 and R 3 Can be combined with R 2 and R 3The attached carbon atoms combine to form an unsubstituted nitrogen-containing monocyclic 3-6 membered heterocyclic group. Suitable monocyclic 3-6 membered heterocyclic groups include, but are not limited to, unsubstituted or substituted oxetanes, unsubstituted or substituted cyclopropane sulfides, and unsubstituted or substituted... Unreplaced or replaced Unreplaced or replaced Unreplaced or replaced Unreplaced or replaced and unreplaced or replaced In some implementations, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form .

[0091] Various unsaturated substituents can exist in R 1 As described in this article, R 1 It may be substituted or not substituted. In some implementations, R 1 It can be an unsubstituted C2-olefin. In other embodiments, R 1 It can be a substituted C2 alkenyl group, which can be substituted by one or more substituents independently selected from the following: halogen, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, unsubstituted monocyclic C 3-6 Cycloalkyl and hydroxylated monocyclic C 3-6 Cycloalkyl. In some embodiments, R 1 It can be an unsubstituted C2 acetylene group. In other embodiments, R 1 The C2 ynyl group can be substituted. The C2 ynyl group can be substituted once or multiple times independently by a substituent selected from the following: halogen, unsubstituted C... 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, unsubstituted monocyclic C 3-6 Cycloalkyl and hydroxylated monocyclic C 3-6 Cycloalkyl. For example, the C2 alkynyl group can be an unsubstituted monocyclic C... 3-6 The cycloalkyl group is substituted once, or the C2 alkynyl group can be replaced by an unsubstituted C2 alkynyl group. 1-4 The alkyl halide is substituted once. In some embodiments, R 1 Can be unreplaced C 1-4 Halogenated alkyl groups, such as CF3.

[0092] As described in this article, several annular portions may exist in R. 1 In some implementation schemes, R 1 It can be an unsubstituted monocyclic heteroaryl group. In other embodiments, R 1Substituted monocyclic heteroaryl groups are possible. Several suitable monocyclic heteroaryl groups are described herein. In some embodiments, R... 1 It can be an unsubstituted or substituted nitrogen-containing monocyclic heteroaryl group, such as R 1 It can be unsubstituted or substituted 1,2,3-triazoles (such as...) and ), unsubstituted or substituted thiazoles (e.g.) and ), unsubstituted or substituted pyridyl groups (such as , and ), unsubstituted or substituted conpyrimidines (e.g. and ), unsubstituted or substituted pyrazoles (e.g.) , and ), unsubstituted or substituted imidazoles (such as and ), or unsubstituted or substituted oxadiazoles (e.g. Each of the structures shown can be unsubstituted or substituted (including cases where the hydrogen on the nitrogen can be replaced by a non-hydrogen substituent). In some embodiments, R 1 It can be an unsubstituted bicyclic heteroaryl group. In other embodiments, R 1 The substituted bicyclic heteroaryl group can be used. Exemplary bicyclic heteroaryl groups are provided herein, and include benzimidazole. In some embodiments, R... 1 It can be an unsubstituted monocyclic heterocyclic group. In other embodiments, R 1 It can be a substituted monocyclic heterocyclic group. Several examples of suitable monocyclic heterocyclic groups are described herein. In some embodiments, R 1 It can be unsubstituted or substituted 2-oxo-1H-pyridyl. When R 1 When the cyclic portion is replaced, various substituents can exist. It can exist in R. 1 Examples of substituents on a monocyclic heteroaryl group include the following substituents: unsubstituted C 1-4 Alkyl, unsubstituted cyclopropyl, and unsubstituted cyclobutyl.

[0093] Several substituents may exist in R 8 In some implementation schemes, R 8 It can be hydrogen. In other embodiments, R 8 It can be -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl group). For example, R 8 It can be neopentanoyloxymethyl (POM). In other embodiments, R 8 It can be -CH2OC(=O)-O (unsubstituted C)1-4 Alkyl groups, such as isopropoxycarbonyloxymethyl (POC). In another embodiment, R 8 It can be -CH2- (α-amino acid). Suitable α-amino acids include, but are not limited to, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. When R 8 When α-amino acids are included, the carboxylic acid moiety is the -CH2 portion attached to -CH2- (α-amino acid), and the hydrogen atom in the carboxylic acid is absent. As some examples, R... 8 Can be , , , , , , , , , , , , , , , , , and In some implementations, R 8 The -α-amino acid in -CH2-(α-amino acid) can be an L-α-amino acid. In other embodiments, R 8 The -α-amino acid in -CH2-(α-amino acid) can be a D-α-amino acid. In some embodiments, R 8 It can be -CH2-phosphate ( ).

[0094] Compounds of formula (I), together with their pharmaceutically acceptable salts, can have a variety of structures. In some embodiments, R 1 It can be an unsubstituted or substituted C2-alkenyl group, an unsubstituted or substituted C2-alkynyl group, an unsubstituted or substituted monocyclic heteroaryl group, an unsubstituted or substituted bicyclic heteroaryl group, or an unsubstituted or substituted monocyclic heterocyclic group, wherein when the C2-alkenyl group, C2-alkynyl group, or unsubstituted C2-alkynyl group is present, the C2-alkynyl group is present. 1-4 When the haloalkyl and monocyclic heteroaryl groups are substituted, the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl groups are independently substituted by one or more substituents selected from the following: halogen, unsubstituted C2 alkenyl, C2 ynyl, and C2 heteroaryl groups. 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, unsubstituted monocyclic C 3-6Cycloalkyl and hydroxylated monocyclic C 3-6 cycloalkyl; R 2 and R 3 It can be independently selected from hydrogen, unsubstituted or substituted C. 1-4 Alkyl, unsubstituted C 1-4 Halogenated alkyl groups, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 When cycloalkyl groups and monocyclic 3-6 heterocyclic groups are substituted, the monocyclic C 3-6 Cycloalkyl and monocyclic 3-6 heterocyclic groups are independently substituted by one or more substituents selected from halogens or hydroxyl groups, and wherein when C 1-4 When alkyl groups are substituted, C 1-4 The alkyl group is substituted by one or more substituents selected from: phosphate, O-linked α-amino acid, and O-carboxyl group, provided that R is present. 2 and R 3 At least one of them is not hydrogen; R 4 and R 5 It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 2-4 alkenyl; R 6 It can be hydrogen or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 3-4 alkenyl; and the prerequisite is R 4 R 5 and R 6 At least one of them is not hydrogen; Y 1 CR A Or N; R 7a R 7b R 7c and R 7d It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl, cyano or unsubstituted C 1-4 Alkoxy; R 8 It can be hydrogen, -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), -CH2OC(=O)-O- (unsubstituted C) 1-4 Alkyl group, -CH2-(α-amino acid) or -CH2-phosphate group; and R A It can be hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl or cyano. For the purposes of this paragraph, when R... 2 and R 3If at least one of them is not hydrogen, assume R 2 and R 3 The following situations: R 2 and R 3 Each can be (1) unsubstituted C 1-4 Alkyl groups, such as methyl groups; (2) C groups substituted with phosphate, O-linked α-amino acids, or O-carboxyl groups. 1-4 Alkyl groups, for example, -O (C=O) (unsubstituted C) 1-4 Alkyl); (3) Unsubstituted C 1-4 (4) Unsubstituted cyclopropyl and (5) Unsubstituted C 1-4 Hydroxyalkyl groups (such as -CH2OH).

[0095] In other implementations, R 1 It can be an unsubstituted or substituted C2-alkenyl group, an unsubstituted or substituted C2-alkynyl group, an unsubstituted or substituted monocyclic heteroaryl group, an unsubstituted or substituted bicyclic heteroaryl group, or an unsubstituted or substituted monocyclic heterocyclic group, wherein when the C2-alkenyl group, C2-alkynyl group, or unsubstituted C2-alkynyl group is present, the C2-alkynyl group is present. 1-4 When the haloalkyl and monocyclic heteroaryl groups are substituted, the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl groups are independently substituted by one or more substituents selected from the following: halogen, unsubstituted C2 alkenyl, C2 ynyl, and C2 heteroaryl groups. 1-4 Alkyl, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, unsubstituted monocyclic C 3-6 Cycloalkyl and hydroxylated monocyclic C 3-6 cycloalkyl; R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6-membered heterocyclic groups, wherein when C 3-6 When cycloalkyl groups and 3-6 membered heterocyclic groups are substituted, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are independently substituted by one or two substituents selected from halogens and hydroxyl groups; R 4 and R 5 It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 2-4 alkenyl; R 6 It can be hydrogen or unsubstituted C. 1-4 Alkyl, deuterated C 1-4 Alkyl or unsubstituted C 3-4 alkenyl; and the prerequisite is R 4 R 5 and R6 At least one of them is not hydrogen; Y 1 CR A Or N; R 7a R 7b R 7c and R 7d It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl, cyano or unsubstituted C 1-4 Alkoxy; R 8 It can be hydrogen, -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), -CH2OC(=O)-O- (unsubstituted C) 1-4 Alkyl group, -CH2-(α-amino acid) or -CH2-phosphate group; and R A It can be hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl or cyano groups. As provided herein, R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted cyclobutyl, fluorinated cyclobutyl, hydroxylated cyclobutyl, or unsubstituted oxetane.

[0096] In other implementations, R 1 It can be an unsubstituted or substituted C2 alkenyl group, an unsubstituted or substituted C2 alkynyl group, or an unsubstituted C2 alkenyl group. 1-4 Halogenated alkyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, or unsubstituted or substituted monocyclic heterocyclic group, wherein when the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl are substituted, the C2 alkenyl, C2 ynyl, and monocyclic heteroaryl can be independently substituted by 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 hydroxylated monocyclic C 3-6 cycloalkyl; R 2 and R 3 It can be independently selected from hydrogen, unsubstituted or substituted C. 1-4 Alkyl, unsubstituted C 1-4 Halogenated alkyl groups, unsubstituted or substituted monocyclic C 3-6 Cycloalkyl, unsubstituted or substituted monocyclic 3-6 membered heterocyclic groups, unsubstituted C 1-4 Hydroxyalkyl and unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 When cycloalkyl groups and monocyclic 3-6 heterocyclic groups are substituted, the monocyclic C 3-6Cycloalkyl and monocyclic 3-6 heterocyclic groups can be independently substituted by one or more substituents selected from halogens or hydroxyl groups, and wherein when C 1-4 When alkyl groups are substituted, C 1-4 The alkyl group is substituted by one or more substituents selected from the following: phosphate group, O-linked α-amino acid group, and O-carboxyl group; or R 2 and R 3 Can be combined with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-6 Cycloalkyl, or unsubstituted or substituted monocyclic 3-6-membered heterocyclic groups, wherein when C 3-6 When cycloalkyl groups and 3-6 membered heterocyclic groups are substituted, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups can be independently substituted by one or two substituents selected from halogens and hydroxyl groups; R 5 It can be hydrogen, halogen, or unsubstituted C. 1-4 Alkyl or unsubstituted C 2-4 alkenyl; and R 4 and R 6 They can combine to form unsubstituted or substituted 5-6 membered heterocycles; Y 1 CR A Or N (nitrogen); R 7a R 7b R 7c and R 7d It can be independently hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl, cyano or unsubstituted C 1-4 Alkoxy; R 8 It can be hydrogen, -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), -CH2OC(=O)-O- (unsubstituted C) 1-4 Alkyl group, -CH2-(α-amino acid) or -CH2-phosphate group; and R A It can be hydrogen, halogen, or unsubstituted C. 1-4 Halogenated alkyl or cyano groups.

[0097] Examples of compounds of formula (I) or pharmaceutically acceptable salts thereof include the following compounds: , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

[0098] Other examples of compounds of formula (I) or pharmaceutically acceptable salts thereof include the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

[0099] In some implementations, the compound of formula (I) or a pharmaceutically acceptable salt cannot be one or more of the following compounds: , , , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt cannot be a compound provided in WO 2017 / 156255. In other embodiments, R 1 It cannot be a difluorosubstituted phenyl. In some embodiments, R 1 It cannot be an unsubstituted or substituted tetrazolium, an unsubstituted or substituted 1,2,3-triazole, and / or an unsubstituted or substituted imidazole. In some embodiments, X 1 It cannot be CR A , where R A For halogens (such as F); and R 7B It cannot be a halogen (such as F or Cl). In some implementations, R A R 7a R 7b R 7c and R 7d At least one of them is unsubstituted C 1-4 Halogenated alkyl groups, such as CF3. In some embodiments, R 4 and R 5 At least one of them is a halogen. In some implementations, R 4 R 5 and R 6 At least one of them is hydrogen.

[0100] synthesis

[0101] Compounds of formula (I) and those described herein can be prepared in various ways. General synthetic routes for the preparation of compounds of formula (I) are shown and described herein, along with some examples of starting materials for the synthesis of the compounds described herein. The routes shown and described herein are merely illustrative and are not intended, nor should they be construed, as limiting the scope of the claims in any way. Those skilled in the art will be able to identify modifications to the disclosed syntheses and to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0102] Option 1

[0103] The synthesis of compounds 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 give an amide of general formula (Ic). The reaction of general formula (Ic) with ethyl 2-chloro-2-oxoacetate in a suitable solvent (such as DCM) in the presence of aluminum chloride gives a ketone ester of general formula (Id). Subsequently, general formula (Id) can be saponified under alkaline conditions in a mixture of methanol and water, for example, with lithium hydroxide, to give a keto acid derivative of general formula (Ie). The coupling of a substituted amine of general formula (If) with general formula (Ie) can be carried out in a suitable solvent (such as DCM) in the presence of a peptide coupling agent such as HATU or EDCI / HOAT in the presence of an organic amine base (such as Et3N or DIPEA) to give compounds of formula (I) and their pharmaceutically acceptable salts.

[0104] Pharmaceutical Composition

[0105] Some embodiments described herein relate to pharmaceutical compositions that may comprise an effective amount of the compound described herein (e.g., a compound as 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.

[0106] As used herein, "carrier" refers to a compound that facilitates the binding of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0107] As used herein, a "diluent" refers to a component in a pharmaceutical composition that does not possess pharmaceutical activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the volume of a potent pharmaceutical product whose mass is too small to manufacture and / or administer. It may also be a liquid used to dissolve a pharmaceutical product intended for administration by injection, ingestion, or inhalation. Common forms of diluents in the art are buffered aqueous solutions, such as, but not limited to, phosphate-buffered saline solutions that mimic the composition of human blood.

[0108] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc. "Diluent" is a type of excipient.

[0109] The correct formulation depends on the chosen route of administration. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Various techniques exist in the art for administering compounds, including but not limited to oral, rectal, topical, aerosol, injection, and parenteral delivery (including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, and intraocular injection). Pharmaceutical compositions are typically formulated according to a specific intended route of administration.

[0110] The compound can also be administered locally rather than systemically, for example, by injecting it directly into the infected area in the form of a reservoir or sustained-release formulation. Furthermore, the compound can be administered in targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. Liposomes can target organs and be selectively taken up by them.

[0111] The pharmaceutical compositions disclosed herein can be manufactured in ways known per se, such as by conventional mixing, dissolving, granulation, pill preparation, grinding, emulsification, encapsulation, embedding, or tableting processes. As described herein, compounds used in pharmaceutical compositions may be provided as salts having pharmaceutically compatible counterions.

[0112] How to use

[0113] Some embodiments described herein relate to methods of treating HBV and / or HDV infection, which may include administering to a subject identified as having HBV and / or HDV infection an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the manufacture of a medicament for treating HBV and / or HDV infection using a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, for treating HBV and / or HDV infection.

[0114] Some embodiments disclosed herein relate to methods for treating HBV and / or HDV infection, which may include contacting HBV and / or HDV-infected cells with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the manufacture of medicaments for treating HBV and / or HDV infection using a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for treating HBV and / or HDV infection.

[0115] Some embodiments disclosed herein relate to methods for inhibiting the replication of HBV and / or HDV, which may include contacting HBV- and / or HDV-infected cells with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the manufacture of medicaments for inhibiting the replication of HBV and / or HDV using a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for inhibiting the replication of HBV and / or HDV.

[0116] In some implementations, HBV infection can be acute HBV infection. In some implementations, HBV infection can be chronic HBV infection.

[0117] Some embodiments disclosed herein relate to methods for treating cirrhosis developed due to HBV and / or HDV infection, which may include administering to a subject with cirrhosis an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV and / or HDV-infected cells in the subject with cirrhosis. Other embodiments described herein relate to the manufacture of a medicament for treating cirrhosis using a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for the treatment of cirrhosis.

[0118] Some embodiments disclosed herein relate to methods for treating liver cancer (such as hepatocellular carcinoma) developed due to HBV and / or HDV infection. These methods may include administering to a subject with liver cancer an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV and / or HDV-infected cells in the subject with liver cancer. Other embodiments described herein relate to the manufacture of medicaments for treating liver cancer (such as hepatocellular carcinoma) using a compound as described herein or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for treating liver cancer (such as hepatocellular carcinoma).

[0119] Some embodiments disclosed herein relate to methods for treating liver failure developed due to HBV and / or HDV infection, which may include administering to a subject with liver failure an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, and / or contacting HBV and / or HDV-infected cells in the subject with liver failure. Other embodiments described herein relate to the manufacture of a medicament for treating liver failure using a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for treating liver failure.

[0120] Various indicators used to determine 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, but are not limited to, indicators based on HBV DNA (or viral load) (e.g., a reduction of <10 in serum). 5 A reduction in HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) indicates a decrease in viral load, a decrease in plasma viral load, a decrease in viral replication, a shortening of seroconversion time (undetectable virus in patient serum), an increase in sustained viral response rate to therapy, an improvement in liver function, and / or a decrease in morbidity or mortality in clinical outcomes.

[0121] As used herein, the terms “treat,” “treating,” “treatment,” and “therapeutic” do not necessarily mean the complete cure or elimination of a disease or condition. Any degree of relief from any undesirable sign or symptom of a disease or condition may be considered a treatment and / or therapy. Furthermore, treatment may include behaviors that may worsen a subject’s overall feeling of health or appearance.

[0122] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates (e.g., monkeys, chimpanzees, and apes), and especially humans. In some embodiments, the subject is a human.

[0123] The term "effective amount" is used to indicate the amount of an active compound or agent that elicits the indicated biological or pharmaceutical response. For example, an effective amount of a compound may be the amount required to alleviate or improve symptoms of a disease, or to prolong the survival of a treated subject. This response can occur in tissues, systems, animals, or humans, and includes the reduction of signs or symptoms of the treated disease. Based on the disclosure provided herein, the determination of an effective amount is entirely within the capabilities of those skilled in the art. The effective amount of the compounds disclosed herein as a dosage will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal under consideration. The dosage may be modulated to achieve the desired effect, but this dosage will depend on factors such as body weight, diet, concomitant drug treatments, and other factors that a person skilled in the medical field will recognize.

[0124] In some implementations, an effective amount of the compound or a pharmaceutically acceptable salt thereof, as described herein, is an amount that effectively achieves a sustained virological response (e.g., a sustained virological response 12 months after the completion of treatment).

[0125] Subjects clinically diagnosed with HBV and / or HDV infection include “naive” subjects (e.g., subjects who have not previously been treated for HBV and / or HDV) and subjects who have previously failed HBV and / or HDV treatment (“treatment failure” subjects). Treatment failure subjects include “non-responders” (subjects who have not achieved a sufficient reduction in ALT (alanine aminotransferase) levels, for example, subjects who have failed to achieve a reduction of more than 1 log10 from baseline within 6 months of starting anti-HBV and / or anti-HDV treatment) and “relapsed” subjects (subjects who have previously been treated for HBV and / or HDV but whose ALT levels have increased, for example, ALT > twice the upper limit of normal, and serum HBV DNA is detectable by hybridization assay). Further examples of subjects include asymptomatic subjects with HBV and / or HDV infection.

[0126] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof may be given to a treatment-failed subject with HBV and / or HDV. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof may be given to a non-responsive subject with HBV and / or HDV. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof may be given to a relapsed subject with HBV and / or HDV. In some embodiments, the subject may have HBeAg-positive chronic hepatitis B. In some embodiments, the subject may have HBeAg-negative chronic hepatitis B. In some embodiments, the subject may have cirrhosis. In some embodiments, the subject may be asymptomatic; for example, the subject may be infected with HBV and / or HDV but does not exhibit any symptoms of viral infection. In some embodiments, the subject may be immune-disabled. In some embodiments, the subject may be undergoing chemotherapy.

[0127] Examples of agents already used to treat HBV and / or HDV include immunomodulators and nucleosides / nucleotides. Examples of immunomodulators include interferons (such as IFN-α and pegylated interferon including PEG-IFN-α-2a); and examples of nucleosides / nucleotides include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil. However, some disadvantages associated with interferon treatment are undesirable side effects, the need for subcutaneous administration, and high cost. The potential advantages of compounds of formula (I), or pharmaceutically acceptable salts of any of the aforementioned compounds, are fewer undesirable side effects, delayed onset of undesirable side effects, and / or reduced severity of undesirable side effects. Disadvantages of nucleoside / nucleotide therapy include the development of resistance, including cross-resistance.

[0128] Resistance can be a cause of treatment failure. As used herein, the term "resistance" refers to a viral strain exhibiting a delayed, weakened, and / or ineffective response to an antiviral agent. In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof may be administered to subjects infected with HBV and / or HDV strains resistant to one or more anti-HBV and / or anti-HDV agents. Examples of antiviral agents from which resistance can develop include lamivudine, telbivudine, adefovir dipivoxil, clavidine, entecavir, tenofovir alafenamide, and tenofovir disoproxil fumarate. In some embodiments, the development of resistant HBV and / or HDV strains is delayed when subjects are treated with compounds as described herein or pharmaceutically acceptable salts thereof, compared to the development of resistant HBV and / or HDV strains resistant to other HBV and / or HDV antiviral agents (such as those described herein).

[0129] Previously 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 a signal that a compound has the potential to induce liver injury. Therefore, the formation of glutathione adducts can be used as a predictive signal of safety. Surprisingly, many compounds described herein, such as those of formula (I) and their pharmaceutically acceptable salts, 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 demonstrated potency in assays based on HepG2.2.15 cells, where EC 50>1000 pM. Many of the compounds described herein, such as those of formula (I) and their pharmaceutically acceptable salts, unexpectedly showed enhanced potency in HepG2.2.15 cell-based assays, among which EC 50 <1000 pM range. Therefore, the compounds described herein (including compounds of formula (I) and their pharmaceutically acceptable salts) are at least 16 times more potent than previously known compounds. In some embodiments, the increased potency can lead to a significant reduction in dose requirements, and thus improve daily dose burden and safety margin.

[0130] Combination therapy

[0131] In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof may be used in combination with one or more adjunct agents for the treatment and / or inhibition of HBV and / or HDV replication. Adjunct agents include, but are not limited to, interferons, nucleoside / nucleotide analogs, sequence-specific oligonucleotides (such as antisense oligonucleotides and siRNA), nucleic acid polymers (NAPs, such as nucleic acid polymers that reduce HBsAg levels), entry inhibitors, and / or small molecule immunomodulators. Examples of adjunct agents include recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavidine, entecavir, tenofovir alafenamide, and tenofovir disoproxil fumarate. Examples of NAPs include, but are not limited to, those described in REP 2139, REP 2165, and U.S. Application 62 / 757632, filed November 8, 2018, which is hereby incorporated by reference for the purposes of the NAPs described herein.

[0132] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, as described herein, may be administered in a single pharmaceutical composition together with one or more adjuvant agents. In some embodiments, the compound or a pharmaceutically acceptable salt thereof may be administered together with one or more adjuvant agents as two or more separate pharmaceutical compositions. Furthermore, the order of administration of the compound or a pharmaceutically acceptable salt thereof, as described herein, with one or more adjuvant agents may vary.

[0133] Example

[0134] Further embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0135] Example 1

[0136] Compound A

[0137] To a 250 mL three-necked round-bottom flask purged with and maintained under an inert N2 atmosphere, add 5.00 g (19.3 mmol, 1.00 equivalent) of 4-methyl-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylic acid-3-tert-butyl ester and 50 mL of toluene. Slowly add 38.6 mL (38.6 mmol, 2.00 equivalent, 1 M toluene solution) of diisobutylaluminum hydride at -78 °C. Adjust the addition rate to maintain the internal temperature below -65 °C. Stir the resulting solution at -78 °C for 2 h, and quench the reaction by slowly adding 10 mL of cold CH3OH. Slowly pour the mixture into 100 mL of ice-cold 1 M HCl and extract the mixture with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (4.20 g, crude product), which was a colorless oil.

[0138] To a 40 mL vial, add 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (4.20 g, 18.3 mmol, 1.00 equivalent), (1-diazo-2-oxopropyl)phosphonate dimethyl ester (4.22 g, 22.0 mmol, 1.20 equivalent), K₂CO₃ (5.06 g, 36.6 mmol, 2.00 equivalent), and methanol (20 mL). Stir the resulting solution overnight at room temperature (rt). Quench the reaction mixture with water (20 mL) and dilute with ethyl acetate (3 × 20 mL). Wash the mixture with brine (20 mL) and water (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated by chromatography using ethyl acetate (EA): petroleum ether (PE) (1:10) on a silica gel column to provide 3.20 g (70% yield) of tert-butyl 4-ethynyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as a yellow oil.

[0139] A solution of tert-butyl 4-ethynyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.00 g, 4.44 mmol), 1,4-dioxolane in 4M hydrochloric acid (5 mL), and ethanol (10 mL) was stirred overnight at 60 °C. The mixture was concentrated under reduced pressure to provide 2-aminobutyr-3-yn-1-ol hydrochloride (538 mg, crude) as a yellow solid. 1 H NMR (300MHz, methanol-) d 4) δ 4.14 (br, 1H), 3.89 (dd, J = 11.6, 4.2Hz, 1H), 3.75-3.68 (m, 1H), 3.25 (d, J=2.4Hz, 1H). LCMS (ES) m / z = 86 (M+H-HCl) + .

[0140] Example 2

[0141] Compound B

[0142] A mixture of 3-(benzyloxy)cyclobut-1-one (5.00 g, 28.4 mmol, 1.00 equivalent), titanium isopropoxide (8.80 g, 30.9 mmol, 1.09 equivalent), tert-butylsulfinamide (3.70 g, 30.5 mmol, 1.08 equivalent), and dichloromethane (50 mL) was stirred overnight at 45 °C. The mixture was cooled to room temperature. A saturated sodium bicarbonate solution (5 mL) was added. The mixture was stirred for 30 minutes, and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE (1:10) to give N-[3-(benzyloxy)cyclobutyryl]-2-methylpropane-2-sulfinamide (4.50 g, 57% yield) as a pale yellow oil.

[0143] Under a nitrogen atmosphere and at -78°C, n-BuLi (13.0 mL, 32.5 mmol, 2.02 equivalents, 2.5 M hexane solution) was added dropwise to a mixture of trimethylsilylacetylene (4.70 g, 47.8 mmol, 2.97 equivalents) in diethyl ether (100 mL) with stirring. The mixture was stirred at -78°C for 1 hour. At -78°C, a solution of N-[3-(benzyloxy)cyclobutylene]-2-methylpropane-2-sulfinamide (4.50 g, 16.1 mmol, 1.00 equivalents) in Et₂O (10 mL) was added dropwise. The mixture was stirred at -78°C for 2 hours. The reaction mixture 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.

[0144] While stirring, BBr3 (3.00 mL, 3.00 mmol, 3.70 equivalent, 1 M DCM solution) was added to a mixture of N-[3-(benzyloxy)-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]-2-methylpropane-2-sulfinamide (300 mg, 0.800 mmol, 1.00 equivalent) in chloromethane (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. Water (0.1 mL) was added to the mixture and stirred for 0.5 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure to give 3-amino-3-((trimethylsilyl)ethynyl)cyclobut-1-ol hydrobromide (130 mg, 62% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-) d 4) δ 4.42-4.31 (m, 1H), 2.83 (ddt, J = 9.1, 7.0, 2.5Hz, 2H),2.37 (ddt, J = 11.6, 7.6, 2.2Hz, 2H), 0.22 (s, 9H). LCMS (ESI, m / z ): 184 [M+H-HBr] + .

[0145] Example 3

[0146] Compound C

[0147] 3-oxetane (5.00 g, 69.4 mmol, 1.00 equivalent), tert-butylsulfinamide (9.20 g, 75.9 mmol, 1.10 equivalent), titanium isopropoxide (21.6 g, 76.0 mmol, 1.10 equivalent), and dichloromethane (50.00 mL) were stirred overnight at 45 °C. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution (5.0 mL). The mixture was stirred for 30 minutes and the solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE (1:10) to give 2-methyl-N-(oxetane-3-yl)propane-2-sulfinamide (5.00 g, 39% yield) as a pale yellow oil. LCMS (ESI, m / z ): 176 [M+H] + .

[0148] Under a volatile atmosphere, while stirring, n-BuLi (30.0 mL, 2.5 M hexane solution, 75.0 mmol, 2.63 equivalence) was added dropwise to a mixture of trimethylsilylacetylene (8.40 g, 85.5 mmol, 3.00 equivalence) in THF (50.00 mL). The mixture was stirred at -78 °C for 1 h. At -78 °C, a mixture of 2-methyl-N-(oxetane-3-yl)propane-2-sulfinamide (5.00 g, 28.5 mmol, 1.00 equivalence) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 2 h, then quenched with water (100 mL). The mixture was extracted with EA (3 × 100 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE (1:10) to give 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetane-3-yl]propane-2-sulfinamide (7.00 g, 88% yield) as a yellow solid. LCMS (ESI, m / z ): 274 [M+H] + .

[0149] Hydrochloric acid (7.5 mL, 30.0 mmol, 2.05 equivalents, 4 M solution of 1,4-dioxane) was added to a mixture of 2-methyl-N-[3-[2-(trimethylsilyl)ethynyl]oxetane-3-yl]propane-2-sulfinamide (4.00 g, 14.6 mmol, 1.00 equivalents) and 1,4-dioxane (50 mL). The mixture was stirred at room temperature for 2 hours. The solid was collected by filtration, washed with PE, and dried to give 2.70 g, 89% yield, of 3-[2-(trimethylsilyl)ethynyl]oxetane-3-amine hydrochloride as a pale yellow solid. LCMS (ESI, m / z ): 170 [M+H-HCl] + .

[0150] Example 4

[0151] Compound D

[0152] To a 250 mL round-bottom flask, add ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 equivalent) and dimethyl sulfoxide (100 mL). Add KOH (5.03 g, 89.7 mmol, 1.50 equivalent) in portions at 0 °C. Stir the mixture at room temperature for 30 minutes. Add iodomethane (10.2 g, 71.8 mmol, 1.20 equivalent) dropwise at room temperature. Stir the resulting solution at room temperature for 4 hours. Quench the reaction mixture with water (100 mL) and dilute with EA (500 mL). Wash the mixture with brine (200 mL) and water (5 × 100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to provide 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] + .

[0153] Under N2 conditions, ethyl 1,3,5-trimethylpyrrole-2-carboxylate (2.00 g, 11.0 mmol, 1.00 equivalent), 5-amino-2-fluorobenzonitrile (3.00 g, 22.1 mmol, 2.00 equivalent), and tetrahydrofuran (20 mL) were placed in a 100 mL three-necked round-bottom flask. At 0 °C, hexamethyldisilamide lithium (33.0 mL, 33.0 mmol, 3.00 equivalent, 1 M THF solution) was added dropwise to the mixture. The resulting solution was stirred overnight at room temperature, and the reaction mixture 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 grinding with EA:hexane (1:1), the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-1,3,5-trimethylpyrrole-2-carboxamide (2.50 g, 75% yield) as a white solid. LCMS (ESI, m / z ): 272[M+H] + .

[0154] Place ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.50 g, 13.8 mmol, 1.00 equivalent) and dichloromethane (100 mL) in a 50 mL three-necked round-bottom flask. Add dropwise a solution of ethyl chloroxamate (2.82 g, 20.0 mmol, 1.50 equivalent) in dichloromethane (20 mL) at 0 °C. Add aluminum chloride (4.23 g, 31.7 mmol, 2.50 equivalent) in portions at 0 °C. Stir the solution overnight at room temperature and quench the reaction mixture with water / ice. Extract the solution with dichloromethane (3 × 100 mL). Combine the organic layers and wash with saturated sodium bicarbonate solution (100 mL) and water (100 mL). Dry the mixture over anhydrous sodium sulfate and concentrate under vacuum. The residue was purified by grinding with EA:hexane (1:1), the solid was collected by filtration and dried to give ethyl 4-(2-ethoxy-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.00 g, 56% yield) as a white solid. LCMS (ESI, m / z ): 372 [M+H] + .

[0155] To a 50 mL round-bottom flask, add ethyl 4-(2-ethoxy-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate (2.00 g, 5.39 mmol, 1.00 equivalent), lithium hydroxide (21.6 mg, 10.8 mmol, 2.00 equivalent), methanol (50 mL), and water (10 mL). Stir the resulting solution overnight at room temperature. Remove methanol under reduced pressure. Dissolve the residue in water (50 mL) and extract with EA (3 × 20 mL). Adjust the pH of the aqueous layer to 3 with hydrochloric acid (1 mol / L). Extract the mixture with EA (3 × 50 mL). The organic layers were combined, dried over anhydrous sulfate, filtered, and concentrated under reduced pressure to provide the desired product, 2-(5-((3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrolo-3-yl)-2-oxoacetic acid (1.50 g, 81% yield), as a white solid. LCMS (ESI, m / z ): 344 [M+H] + .

[0156] Example 5

[0157] Compound E

[0158] To a 250 mL round-bottom flask, add ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10.0 g, 59.8 mmol, 1.00 equivalent) and dimethyl sulfoxide (100 mL). Add KOH (5.03 g, 89.7 mmol, 1.50 equivalent) in portions at 0 °C. Stir the mixture at room temperature for 30 minutes. Add iodomethane (10.2 g, 71.8 mmol, 1.20 equivalent) dropwise to the mixture at room temperature. Stir the resulting solution at room temperature for 4 hours. Quench the reaction mixture with water (100 mL) and dilute with EA (500 mL). Wash the mixture with brine (200 mL) and water (5 × 100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to provide 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] + .

[0159] Ethyl 1,3,5-trimethylpyrrole-2-carboxylate (5.00 g, 27.6 mmol, 1.00 equivalent), 4-fluoro-3-(trifluoromethyl)aniline (7.40 g, 41.3 mmol, 1.50 equivalent), and tetrahydrofuran (50.00 mL) were placed in a 250 mL round-bottom flask purged with N2 and maintained under this inert atmosphere. LiHMDS (80.0 mL, 80.0 mmol, 2.90 equivalent, 1 mol / L THF solution) was added dropwise to the mixture at 0 °C. The resulting solution was stirred overnight at room temperature, and the reaction mixture 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 grinding with EA:hexane (1:1). The solid was collected by filtration and dried to provide 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] + .

[0160] Place N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethylpyrrole-2-carboxamide (3.00 g, 9.55 mmol, 1.00 equivalent) and dichloromethane (100 mL) in a 250 mL three-necked round-bottom flask purged with and maintained under an inert N2 atmosphere. At 0 °C, add dropwise a solution of ethyl oxaloyl chloride (1.56 g, 11.5 mmol, 1.20 equivalent) in dichloromethane (20 mL). At 0 °C, add aluminum chloride (1.90 g, 14.3 mmol, 1.50 equivalent) to the mixture in portions. Stir the resulting solution overnight at room temperature and quench the reaction mixture with ice / water (100 mL). Extract the mixture with dichloromethane (3 × 100 mL). The organic layers were combined, washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE (1:2) to give ethyl 2-(5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrolo-3-yl)-2-oxoethyl acetate (2.00 g, 48% yield) as a white solid. LCMS (ESI, m / z ): 415 [M+H] + .

[0161] To a 100 mL round-bottom flask, add ethyl 2-(5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrolo-3-yl)-2-oxoethyl acetate (2.00 g, 4.83 mmol, 1.00 equivalent), LiOH (0.231 g, 9.65 mmol, 2.00 equivalent), methanol (50.00 mL), and water (10.00 mL). Stir the resulting solution overnight at room temperature and dilute with water (100 mL). Adjust the pH of the mixture to 3 with hydrochloric acid (1 mol / L). Extract the mixture with EA (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide (5-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-1,2,4-trimethylpyrrolo-3-yl)(oxo)acetic acid (1.85 g, 94% yield) as a white solid. LCMS (ESI, m / z ): 387 [M+H] + .

[0162] Example 6

[0163] Compound 26

[0164] A mixture of compound D (1.00 g, 2.91 mmol, 1.00 equivalent), HATU (3.30 g, 8.68 mmol, 2.98 equivalent), 1,2-dichloromethane (50 mL), N,N-diisopropylethylamine (1.50 mL, 8.61 mmol, 2.96 equivalent), and compound C (0.900 g, 4.37 mmol, 1.50 equivalent) was stirred overnight at room temperature. The reaction mixture 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 grinding with EA (50 mL), and the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-4-[([3-[2-(trimethylsilyl)ethynyl]oxetane-3-yl]carbamoyl)carbonyl]pyrrole-2-carboxamide (1.30 g, 90% yield) as a white solid. LCMS (ESI, m / z ):495 [M+H + .

[0165] A mixture of N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-4-[([3-[2-(trimethylsilyl)ethynyl]oxecyclobutane-3-yl]carbamoyl)carbonyl]pyrrole-2-carboxamide (1.30 g, 2.63 mmol, 1.00 equivalent), potassium carbonate (1.10 g, 7.89 mmol, 3.00 equivalent), methanol (5 mL), and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hours. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was ground with water (100 mL), the solid was collected by filtration and dried to give N-(3-cyano-4-fluorophenyl)-4-[[(3-ethynyloxetane-3-yl)carbamoyl]carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (compound 26) (784.8 mg, 68% yield) as a grayish-white solid. 1 HNMR (400MHz, DMSO- d 6) δ 10.53 (s, 1H), 9.75 (s, 1H), 8.20 (dd, J = 5.8,2.7Hz, 1H), 7.95 (ddd, J = 8.0, 4.7, 2.6Hz, 1H), 7.53 (t, J = 9.1Hz, 1H), 4.72 (d, J = 6.6Hz, 4H), 3.65 (s, 1H), 3.59 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H). LCMS (ESI, m / z ): 423 [M+H] + .

[0166] Example 7

[0167] Compounds 31a and 31b

[0168] 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 equivalent) were added to a 40 mL vial. The resulting solution was stirred overnight at room temperature, and the reaction mixture was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product mixture (360 mg) was separated by preparative chiral HPLC (column: CHIRALPAK IG, 20 mm). 250 nm, 5 µm; Mobile phase A: Hex (8 mmol / L NH3.MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 18 mL / min; Gradient: 50B to 50B over 22 min; 254 / 220 nm; RT1: 12.491; RT2: 17.162). Appropriate fractions were identified by UV absorbance (254 nm) to obtain a pure first eluting isomer, 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), as a white solid. LCMS (ES) m / z = 411 (M+H) + . 1H NMR (300MHz, DMSO- d 6) δ 10.52 (s, 1H), 9.05 (d, J = 8.2Hz, 1H), 8.19 (dd, J = 5.8, 2.7Hz, 1H), 7.92-7.98 (m,1H), 7.53 (t, J = 9.2Hz, 1H), 5.13 (t, J = 5.9Hz, 1H), 4.58-4.65 (m, 1H), 3.66-3.46 (m, 5H), 3.22 (d, J = 2.3Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H).

[0169] The second eluting isomer, 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), is a white solid. LCMS (ES) m / z = 411 (M+H) + . 1 H NMR (300MHz, DMSO- d 6) δ 10.52 (d, J = 3.5Hz, 1H), 9.07 (d, J = 8.2Hz, 1H), 8.28-8.11 (m, 1H), 7.92-7.98 (m, 1H), 7.60-7.45 (m, 1H), 5.14(s, 1H), 4.61 (s, 1H), 3.57 (s, 5H), 3.21-3.23 (m, 1H), 2.39 (d, J = 4.0Hz, 3H), 2.24 (d, J = 4.1Hz, 3H).

[0170] Example 8

[0171] Compound 32

[0172] 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 equivalent), 1-hydroxy-7-azabenzotriazole (220 mg, 1.60 mmol, 1.50 equivalent), N,N-diisopropylethylamine (220 mg, 1.70 mmol, 1.56 equivalent), and 1,2-dichloroethane (10 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in EA (50 mL) and washed with water (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (EA:PE = 2:1) to give N-(3-cyano-4-fluorophenyl)-4-[([3-hydroxy-1-[2-(trimethylsilyl)ethynyl]cyclobutyl]carbamoyl)carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (170 mg, 46% yield) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6) δ 10.55 (s, 1H), 9.29 (s, 1H), 8.22 (dd, J =5.8, 2.7Hz, 1H), 7.98 (ddd, J = 9.3, 4.9, 2.7Hz, 1H), 7.56 (t, J = 9.1Hz, 1H), 5.33 (d, J = 6.7Hz, 1H), 4.14 (q, J = 7.2Hz, 1H), 3.60 (s, 3H), 2.77(ddd, J = 9.5, 6.9, 3.0Hz, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 2.22-2.10 (m, 2H), 0.14 (s, 9H). LCMS (ESI, m / z ): 509 [M+H] + .

[0173] 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 equivalent), methanol (5 mL), and potassium carbonate (150 mg, 1.10 mmol, 3.22 equivalent) was stirred at room temperature for 2 hours. The solids were 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 preparative column, 19 mm × 250 mm; mobile phase A: water (0.05% TFA), mobile phase B: THF-HPLC; flow rate: 25 mL / min; gradient: 25% to 55% over 7 minutes; 220 nm. Purification yielded N-(3-cyano-4-fluorophenyl)-4-[[(1-ethynyl-3-hydroxycyclobutyl)carbamoyl]carbonyl]-1,3,5-trimethylpyrrole-2-carboxamide (26.1 mg, 18% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-) d 6) δ 10.50 (s, 1H), 9.26 (s, 1H), 8.20 (dd, J = 5.8, 2.7Hz,1H), 8.03-7.91 (m, 1H), 7.53 (t, J = 9.2Hz, 1H), 5.30 (d, J = 6.7Hz, 1H), 4.15 (q, J = 7.3Hz, 1H), 3.60(s, 3H), 3.22 (s, 1H), 2.83-2.71 (m, 2H), 2.42(s, 3H), 2.27 (s, 3H), 2.17 (t, J = 10.1Hz, 2H). LCMS (ESI, m / z ): 437 [M+H] + .

[0174] Example 9

[0175] Compound 54

[0176] While stirring, cesium carbonate (9.78 g, 30 mmol, 3 equivalents) was added to an anhydrous DMSO (40 mL) solution of compound 26 (4.22 g, 10 mmol), di-tert-butylchloromethyl phosphate (3.89 g, 15 mmol, 1.5 equivalents), and tetrabutylammonium iodide (738 mg, 2 mmol, 0.2 equivalents). The mixture was stirred overnight at room temperature and then partitioned between water and ethyl acetate. The organic phase was separated and washed (twice) with dilute brine. 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 pale yellow foam (9 g). The residue was purified by column chromatography in 40% to 100% ethyl acetate-hexane to give di-tert-butyl phosphate intermediate (1.72 g, 27%).

[0177] Add 6 mL of 0.2 M sodium acetate aqueous solution (1.2 mmol, 0.46 equivalence) and 2 mL of 0.2 M acetic acid aqueous solution (2 mL, 0.4 mmol, 0.15 equivalence) to a 10 mL IPA solution of the di-tert-butyl phosphate intermediate (1.7 g, 2.6 mmol) from the previous step. Heat the mixture at 55–60 °C for 3 hours. After cooling to room temperature, adjust the mixture to alkaline (pH 8.5) with 3.1 mL of 2 N NaOH aqueous solution (6.2 mmol). Concentrate the resulting solution under reduced pressure to approximately 8 mL. Filter off some of the precipitate and discard it. Dilute the filtrate with acetone (40 mL) and incubate the resulting mixture overnight at 4 °C. Fine crystalline solids formed and were collected by filtration, washed with acetone and dried under vacuum to provide sodium (2-(5-((3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrolo-3-yl)-N-(3-ethynyloxetane-3-yl)-2-oxoacetamido)methylphosphate (1.15 g, 76%). LC-MS: (ES, m / z ): 531 [MH] - . 1 H NMR (400MHz, 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).

[0178] Example 10

[0179] Compound 73

[0180] Sodium hydride (176 mg, as 60% dispersion in mineral oil, 4.4 mmol, 2.2 equivalents) was added to a DMF (15 mL) solution of compound 26 (844 mg, 2 mmol) and chloromethyl isobutyrate (0.379 mL, 3 mmol, 1.5 equivalents) while stirring at 0 °C. The mixture was stirred at room temperature for 2 hours and then partitioned between ammonium chloride and a semi-saturated aqueous solution of ethyl acetate. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. Methyl 2-methylpropionic acid [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrolo-3-yl]-2-oxo-acetyl]-(3-ethynyloxetane-3-yl)amino] ester (compound 73, 530 mg, 50.8%) was separated by column chromatography (5% to 25% ethyl acetate in dichloromethane solution) and then crystallized from isopropyl acetate. LC-MS: (ES, m / z ): 523 [M+H)] + . 1 H NMR (400MHz, DMSO-) d 6 ), 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).

[0181] Example 11

[0182] Compound 77

[0183] As described in Example 10, 2,2-dimethylpropionic acid [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrolo-3-yl]-2-oxo-acetyl]-(3-ethynyloxetane-3-yl)amino]methyl was synthesized using pentanoyl chloride instead of chloromethyl isobutyrate. Compound 77 (800 mg, 74.6%) was separated by column chromatography (5%–25% ethyl acetate in dichloromethane solution) and then crystallized from ethyl acetate:hexane. LC-MS: (ES, m / z ): 537 [M+H)] + . 1 H NMR (400MHz, 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).

[0184] Example 12

[0185] Compound 78

[0186] As described in Example 10, isopropyl chloromethyl carbonate was used instead of chloromethyl isobutyrate to synthesize [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrolo-3-yl]-2-oxo-acetyl]-(3-ethynyloxetane-3-yl)amino]methylisopropyl carbonate. Compound 78 (770 mg, 71.6%) was separated by column chromatography (5%–30% ethyl acetate in dichloromethane solution) and then crystallized from ethyl acetate:hexane. LC-MS: (ES, m / z ):539 [M+H)] + . 1 H NMR (400MHz, DMSO- d 6 ), 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).

[0187] Example 13

[0188] Compound 66b

[0189] 90% hydroxyacetone (16.59 g) and 4-dimethylaminopyridine (1.37 g, 0.05 equivalents) were combined in a reactor and diluted with dichloromethane (100 mL). Tert-butyldiphenylsilyl chloride (63.40 g, 1.03 equivalents) was added, followed by washing 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, a solid began to precipitate. After 18 hours, the mixture was concentrated and hexane (350 mL) and water (200 mL) were added. The aqueous phase was removed via a separatory funnel. The organic phase was washed with water (2 × 150 mL), dried over sodium sulfate, and concentrated to provide 1-((tert-butyldiphenylsilyl)oxy)prop-2-one (72.62 g). 1 H NMR (CDCl3, 400MHz): δ 7.70 (4H, d), 7.47 (6H, m), 4.20 (2H, s), 2.22 (3H, s), 1.13 (9H, s).

[0190] (R)-(+)-2-methyl-2-propanesulfinamide (18.47 g, 1.0 equivalent), 1-((tert-butyldiphenylsilyl)oxy)prop-2-one (47.62 g, 1.0 equivalent), and toluene (500 mL) were combined in a reactor under Ar conditions. Tetraisopropoxide titanium (75.8 g, 1.75 equivalent) was added, followed by washing the mixture with toluene (400 mL). The solution was heated at 100 °C for 23 hours. After cooling to room temperature, saturated sodium bicarbonate (50 mL) was added, and the mixture was stirred for 2 minutes. The resulting slurry was filtered through diatomaceous earth, and the organic phase was dried with 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 sulfinimide (13.8 g), which was a red oil. The product was dissolved in toluene (90 mL) and then loaded into a feed funnel above the reaction flask. Trimethylsilylacetylene (9.78 g, 3.0 equivalent) and toluene (230 mL) were loaded into a reaction flask. An Ar atmosphere was established, the mixture was stirred, and cooled in a dry ice-acetone bath. A 2.5 M n-butyllithium solution in hexane (33.1 mL, 2.5 equivalent) was added at an internal temperature below -61 °C. After stirring for 1 hour and 10 minutes, a sulfinylimide solution was added over 1 hour, while the internal temperature was maintained below -67 °C. The mixture was stirred for 1.5 hours, and then the cooling bath was removed. The mixture was slowly heated to -20 °C by the action of ambient air, at which point the reaction system was warmed to 0 °C by immersion in a room temperature water bath. Water (20 mL) was added, and the mixture was stirred for 2 minutes. The mixture was then filtered through diatomaceous earth. The organic phase was dried over sodium sulfate and concentrated to give a brown oil (16.8 g), which was purified by normal-phase silica gel chromatography using a dichloromethane-ethyl acetate gradient to give an orange oil (R)-. N -(( S)- 1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (6.00g). 1 H NMR(CDCl3, 400MHz): 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).

[0191] (R)- N -( (S)-1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (6.00 g, 1.0 equivalent) was dissolved in 1,4-dioxane (70 mL), and then dissolved in 1,4-dioxane (4.1 equivalent) solution of 4M HCl (12 mL). The solution was stirred for 1 hour and then concentrated. Toluene (75 mL) was added and the solution was concentrated. 2-(5-(4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl- 1H 3-pyrrolo-3-yl)-2-oxoacetic acid (4.50 g, 1.0 equivalent), HATU (6.47 g, 1.46 equivalent), N,N-dimethylformamide (250 mL), and N,N-diisopropylethylamine (17.8 mL, 9.0 equivalent). The solution was stirred for 21 hours and then concentrated. Ethyl acetate (250 mL) was added. The resulting solution was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, concentrated, and mixed with dichloromethane (60 mL). The slurry was filtered. The filtrate was concentrated and purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to provide a product (7.58 g) as a yellow foam. 1 H NMR (CDCl3,400MHz): 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].

[0192] The raw material (7.58 g) was dissolved in THF (75 mL), and a THF solution of 1.0 M tetrabutylammonium fluoride (24 mL, 2.5 equivalents) was added. The solution was stirred for 2 hours and then concentrated. The concentrate was dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (3 × 50 mL) and brine (30 mL), dried over sodium sulfate, and concentrated to give a yellow oil (7.3 g). The oil was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give a yellow foam (4.11 g), which was dissolved in DMF (30 mL). The mixture was stirred while water (30 mL) was slowly added. A white solid began to crystallize after 3 minutes. The resulting slurry was stirred for 1 hour and then cooled in an ice bath for 0.5 hours. The slurry was filtered, washed with a 2:1 water:DMF solution (10 mL), and then washed with water (20 mL). The filter cake was dried under vacuum at 65 °C to give a white powder. (S) - N -(4-Fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1 H -Pyrrole-2-carboxamide (3.46g). 1 H NMR (CDCl3, 400MHz): 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 = 1.03, methanol).

[0193] Example 14

[0194] Compound 66a

[0195] (S)-(+)-2-methyl-2-propanesulfinamide (4.82 g, 1.0 equivalent), 1-((tert-butyldiphenylsilyl)oxy)prop-2-one (12.43 g, 1.0 equivalent), and toluene (310 mL) were combined in a reactor under Ar conditions. Tetraisopropoxide titanium (13.57 g, 1.20 equivalent) was added, followed by rinsing the residue with toluene (400 mL). The resulting solution was heated at 100 °C for 18 hours. After cooling to room temperature, saturated sodium bicarbonate (13 mL) was added, and the mixture was stirred for 5 minutes. The resulting slurry was filtered through diatomaceous earth, and the organic phase was dried with 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 sulfinimide (6.07 g), which was an orange oil. The oily substance was dissolved in toluene (50 mL) and then loaded into a feeding funnel above the reaction flask. Trimethylsilylacetylene (4.30 g, 3.0 equivalent) and toluene (195 mL) were loaded into the reaction flask, and an argon atmosphere was established. The mixture was stirred and cooled with a dry ice-acetone bath. A 2.5 M n-butyllithium solution in hexane (14.6 mL, 2.5 equivalent) was added at an internal temperature below -63 °C. After stirring for 1 hour and 10 minutes, the solution was warmed to -20 °C and held for 2 minutes. The mixture was cooled to below -67 °C while a sulfinylimide solution was added over 14 minutes. The mixture was stirred from -73 °C to -67 °C for 1 hour, and then the cooling bath was removed. The contents were slowly heated to -40 °C due to the ambient air, at which point the reaction system was warmed to 0 °C by immersion in a room temperature water bath. Water (10 mL) was added. The mixture was stirred for 5 minutes and then filtered through diatomaceous earth. The organic phase was dried over sodium sulfate and concentrated to obtain an orange oil (7.55 g). This orange oil was partially purified using normal-phase silica gel chromatography with an ethyl acetate-hexane gradient to obtain an orange oil (4.10 g). The oil was further purified using normal-phase silica gel chromatography with an ethyl acetate-dichloromethane gradient to obtain a yellow oil -(S)- N -(( R)- 1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (1.93 g). 1 H NMR(CDCl3, 400MHz): 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).

[0196] (S)- N -( (R)- 1-((tert-butyldiphenylsilyl)oxy)-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfinamide (1.93 g, 1.0 equivalent) was dissolved in 1,4-dioxane (40 mL), and then a solution of 4M hydrogen chloride in 1,4-dioxane (4 mL, 4.3 equivalent) was added. The solution was stirred for 3 hours and then concentrated. 2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl- 1H 1,2-pyrrolo-3-yl)-2-oxoacetic acid (1.21 g, 0.83 equivalents), HATU (1.79 g, 1.25 equivalents), N,N-dimethylformamide (75 mL), and N,N-diisopropylethylamine (4.2 mL, 6.42 equivalents). The solution was stirred for 16 hours and then concentrated. Ethyl acetate (75 mL) was added. The solution was washed with water (30 mL) and brine (25 mL), dried over sodium sulfate, and concentrated to a red solid (5.6 g). The red solid was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to provide the product amide (2.57 g) as a yellow foam. 1 ¹H NMR (CDCl₃, 400MHz): 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].

[0197] The raw material (2.57 g) was dissolved in THF (25 mL), and a THF solution of 1.0 M tetrabutylammonium fluoride (8.2 mL, 2.5 equivalents) was added. The solution was stirred for 1.5 hours and then concentrated. The concentrate was dissolved in ethyl acetate (30 mL). The solution was washed with water (3 × 20 mL) and then with brine (15 mL). The solution was dried over sodium sulfate and concentrated to a yellow oil (2.6 g), which was purified by normal-phase silica gel chromatography using an ethyl acetate-hexane gradient to give a yellow wax (1.4 g). The wax was dissolved in dichloromethane (80 mL), and then heated to dissolve all solids. The mixture was removed from the heat source and stirred while the solution was allowed to cool slowly. A slurry formed within 1.5 hours. The mixture was cooled in an ice bath for 1 hour and then filtered. The filter cake was washed with ice-cold dichloromethane and then dried under vacuum at 60 °C to provide a white powder. (R) - N -(4-Fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1 H -Pyrrole-2-carboxamide (0.90g). 1 H NMR (CDCl3, 400MHz): 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 = 0.98, methanol).

[0198] Example 15

[0199] Compounds 165a and 165b

[0200] While stirring, isobutyryl chloride (0.126 mL, 1.2 mmol) was added to a 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) in DCM (3 mL) and pyridine (0.2 mL). The mixture was warmed to 40 °C and stirred overnight. After quenching the reaction system with methanol, the mixture was partitioned between isopropyl acetate and 1 M sodium dihydrogen phosphate. The organic layer was separated and the solvent was removed under reduced pressure. The residue was purified by column chromatography (20% to 50% ethyl acetate-hexane) to provide 165a (192 mg, 71%) as a pale yellow foam. LC-MS: (ES, m / z ): 538.4 [M+H]. 1 H NMR(CDCl3, 400MHz): 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).

[0201] As described for the (R)-enantiomer, the (S)-enantiomer was synthesized using (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, m / z ): 538.4 [M+H].

[0202] Example 16

[0203] Compounds 166a and 166b

[0204] Following the procedure described in Example 15, compounds 166a and 166b were synthesized from the parent alcohol (233 mg, 0.5 mmol) using pentanoyl chloride instead of isobutyryl chloride. 166a (237 mg, 86%). LC-MS: (ES, m / z ): 552.5 [M+H]. 1HNMR (CDCl3, 400MHz): 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].

[0205] Example 17

[0206] Compounds 167a and 167b

[0207] While stirring, carbonyl diimidazole (160 mg, 0.99 mmol) was added to a solution of Boc-L-valine (214 mg, 0.99 mmol) in acetonitrile (3 mL). After 1 hour, the imidazole solution was added to a solution of (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (307 mg, 0.66 mmol), DIPEA (0.343 mL, 1.97 mmol), and DMAP (16 mg, 0.13 mmol) in acetonitrile (2 mL). The reaction was allowed to proceed at room temperature for 1 hour, and then the reaction system was quenched with water. The solution was placed 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% to 50% ethyl acetate-hexane) to give a pale yellow foamy Boc-protected intermediate, which was then dissolved in ethyl acetate (4 mL). The solution was treated with a 4M dioxane solution of hydrogen chloride (1.9 mL, 7.6 mmol). After 3.5 hours, the mixture was concentrated under reduced pressure, and the residue was ground with MTBE (5 mL). The resulting solid was separated by filtration. The filter cake was washed with MTBE, and the product (370 mg, 93%) was dried under vacuum. LC-MS: (ES, m / z ): 567.7 [M-HCl+H]. 1 H NMR (400MHz, DMSO-) d 6) 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).

[0208] As described for the (S)-enantiomer, the (R)-enantiomer was obtained using (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, m / z ): 567.7 [M-HCl+H].

[0209] Example 18

[0210] Compounds 168a and 168b

[0211] Phosphorus oxychloride (2.88 mL, 31 mmol) was added to a THF (100 mL) 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) and a pyridine (2.44 mL, 31 mmol) solution while stirring at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then the reaction system was quenched with water (30 mL). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate and the solution was washed with water (3 times). The organic phase was concentrated to dryness, and the residue was dissolved in isopropanol (100 mL). NaOH aqueous solution (2 M) was slowly added until the pH was about 8.5 (9.7 mL). A precipitate was formed upon the addition of NaOH, and the precipitate was separated by filtration. The filter cake was washed with isopropanol and dried under vacuum to give the product (5.19 g, 83%). LC-MS: (ES, m / z ): 548.1 [M-2Na+3H]. 1H NMR (400MHz, D2O) δ:7.83 (m, H), 7.66 (m, 1H), 7.31 (dd, 1H), 3.91 (split dd, 2H), 3.54 (s, 3H), 2.80 (s, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 1.61 (s, 3H). 31 P NMR (162MHz, D2O)δ: 4.08 (s).

[0212] As described for the (S)-enantiomer, the (R)-enantiomer was obtained using (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(2-((1-hydroxy-2-methylbut-3-yn-2-yl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide. LC-MS: (ES, ​ ): 548.1 [M-2Na+3H].

[0213] Example 19

[0214] The following compounds were prepared using a procedure and raw materials similar to those described in the above embodiments.

[0215]

[0216] Example 20

[0217] Additional compounds

[0218] The foregoing synthesis is exemplary and can serve as a starting point for the preparation of a wide range of additional compounds. Examples of compounds of formula (I) that can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to identify modifications to the disclosed synthesis and to design routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0219]

[0220] (Including pharmaceutically acceptable salts of any of the aforementioned compounds).

[0221] Example A

[0222] HBV-DNA antiviral assay using HepG2.2.15 cells

[0223] The following assay procedure describes the HBV antiviral assay. This assay uses HepG2.2.15 cells transfected with the HBV genome and uses extracellular HBV DNA quantification as the endpoint. It was performed using CellTiter-Glo, obtained from Promega. ® The reagent measures intracellular ATP content to assess cell viability in parallel.

[0224] On day 0, HepG2.2.15 cells were cultured at a rate of 6.0 × 10⁻⁶. 4 Cells were seeded at a density of 10 cells / well (0.1 mL / well) in 96-well plates. The cells were incubated at 37°C and 5% CO2.

[0225] On day 1, the test products were diluted and added to cell culture wells (8 concentrations, 4-fold dilution, duplicate). GLS4, tenofovir, and sorafenib were used as reference compounds. 100 µL of culture medium containing the compounds was added to each plate, resulting in a final total volume of 200 µL per well. The final concentration of DMSO in the medium was 0.5%. The plate pattern of the compound treatments is shown below. Cells were cultured at 37 °C and 5% CO2 for 3 days.

[0226] Plate spectroscopy of compound treatment

[0227] On day 4, the plate was refreshed with a culture medium containing the compound.

[0228] On day 7, use CellTiter-Glo ® Cell viability was assessed, and cell culture supernatant was collected for HBV DNA assay by qPCR.

[0229] HBV DNA quantification by qPCR

[0230] Extracellular DNA was isolated using the QIAamp 96 DNA Blood Kit, following the manufacturer's instructions. HBV DNA was then quantified by qPCR using the Roche FastStart Universal MasterMix on an ABI-7900HT with HBV-specific primers and probes as specified in Table 1. The PCR cycling program consisted of 40 cycles: 95°C for 10 minutes, followed by 95°C for 15 seconds and 60°C for 1 minute.

[0231] Table 1: HBV DNA Primers and Probes

[0232] DNA standards were prepared by diluting pAAV2 HBV1.3 plasmid at concentrations ranging from 10 to 1 × 10⁷ copies / µL and were used to generate a standard curve by plotting Ct values ​​against the concentration of the HBV plasmid DNA standards. The amount of HBV DNA in each sample was determined by interpolation from the standard curve.

[0233] Cell vitality

[0234] After harvesting the supernatant, follow the manufacturer's instructions via CellTiter-Glo ® Cell viability was assessed. In short, 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 using a BioTek Synergy 2 plate reader.

[0235] Data Analysis

[0236] Cell viability was calculated as follows: %Cell viability = (Crystal luminescence value of test sample - Average luminescence value of blank) / (Average luminescence value of 0.5% DMSO control - Average luminescence value of blank) × 100%. HBV DNA inhibition rate was calculated as follows: 100 - (HBV DNA copy number of test sample - HBV DNA copy number of ETV) / (HBV DNA copy number of 0.5% DMSO control - HBV DNA copy number of ETV) × 100%. 50 EC 50 and EC 90The values ​​were determined by a dose-response curve fitted using "log(agonist) vs. response-variable slope" by GraphPad Prism.

[0237] As shown in Table 2, compounds of formula (I) are active against HBV, where 'A' indicates EC. 50 <1nM, 'B' indicates EC 50 ≥1nM and <10nM, 'C' indicates EC 50 ≥10nM and <100nM, 'D' indicates EC 50 ≥100nM and <1000nM, and 'E' indicates EC 50 >1000nM.

[0238] Table 2 - Activity of Compounds

[0239] Furthermore, although some detailed description has been provided for clarity and understanding purposes by way of illustration and example, those skilled in the art will understand that many and various modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of this disclosure, but rather to cover all modifications and alternatives consistent with the true scope and spirit of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, having the following structure: (I) in: R 1 It is an unsubstituted C2 alkynyl group; R 2 For unreplaced C 1-4 Alkyl groups; and R 3 Selected from the replaced C 1-4 Alkyl and unsubstituted C 1-4 Hydroxyalkyl, and wherein the substituted C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate group, O-linked α-amino acid group, and O-carboxyl group; or R 1 It is an unsubstituted C2 alkenyl or an unsubstituted C2 ynyl; and R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-4 Cycloalkyl, or unsubstituted or substituted monocyclic 3-4 membered heterocyclic groups, wherein when the C 3-4 When the cycloalkyl group and the 3-4 membered heterocyclic group are substituted, the C 3-4 The cycloalkyl group and the 3-4 membered heterocyclic group are substituted by one or two substituents independently selected from halogens and hydroxyl groups; R 4 and R 5 Each is an unreplaced C 1-4 alkyl; R 6 For unreplaced C 1-4 Alkyl; and X 1 For CR A ; R 7a R 7c and R 7d Each is hydrogen; R 7b For unreplaced C 1-4 Halogenated alkyl or cyano groups; R 8 -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), -CH2OC(=O)-O- (unsubstituted C) 1-4 Alkyl group, -CH2-(α-amino acid) or -CH2-phosphate group; and R A It is a halogen.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, having the following structure: (I) in: R 1 It is an unsubstituted C2 alkynyl group; R 2 For unreplaced C 1-4 Alkyl groups; and R 3 Selected from the replaced C 1-4 Alkyl and unsubstituted C 1-4 hydroxyalkyl, wherein the substituted C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate group, O-linked α-amino acid group, and O-carboxyl group; or R 1 It is an unsubstituted C2 alkenyl or an unsubstituted C2 ynyl; and R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-4 Cycloalkyl or unsubstituted or substituted monocyclic 3-4-membered heterocyclic groups, wherein when the C 3-4 When cycloalkyl groups and 3-4 membered heterocyclic groups are substituted, the C 3-4 The cycloalkyl group and the 3-4 membered heterocyclic group are substituted by one or two substituents independently selected from halogens and hydroxyl groups; R 4 and R 5 Each is an unreplaced C 1-4 alkyl; R 6 For unreplaced C 1-4 alkyl; X 1 For CR A ; R 7a R 7c and R 7d Each is hydrogen; R 7b Cyano or unsubstituted C 1-4 Halogenated alkyl groups; R 8 For hydrogen; and R A It is a halogen.

3. The compound according to claim 1 or 2, wherein R 2 For unreplaced C 1-4 Alkyl, and R 3 Selected from the replaced C 1-4 Alkyl and unsubstituted C 1-4 hydroxyalkyl, wherein the substituted C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate, O-linked α-amino acid, and O-carboxyl group.

4. The compound according to claim 1 or 2, wherein R 2 For unreplaced C 1-4 Alkyl, and R 3 To replace C 1-4 Alkyl, wherein when the C 1-4 When the alkyl group is substituted, the C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate, O-linked α-amino acid, and O-carboxyl group.

5. The compound according to claim 1 or 2, wherein R 2 For unreplaced C 1-4 Alkyl, and R 3 For unreplaced C 1-4 Hydroxyalkyl.

6. The compound according to claim 1 or 2, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted monocyclic carbon atoms. 3-4 Cycloalkyl, or unsubstituted or substituted monocyclic 3-4 membered heterocyclic groups, wherein when the C 3-4 When the cycloalkyl group and the 3-4 membered heterocyclic group are substituted, the C 3-4 The cycloalkyl group and the 3-4 membered heterocyclic group are substituted by one or two substituents independently selected from halogens and hydroxyl groups.

7. The compound according to claim 6, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted monocyclic C atoms. 3-4 Cycloalkyl.

8. The compound according to claim 6, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form substituted monocyclic carbon atoms. 3-4 Cycloalkyl.

9. The compound according to claim 6, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted monocyclic 3-4 membered heterocyclic groups.

10. The compound according to claim 6, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form substituted monocyclic 3-4 membered heterocyclic groups.

11. The compound according to claim 6, wherein the monocyclic 3-4 membered heterocyclic group is selected from: unsubstituted or substituted oxetanes, unsubstituted or substituted cyclopropanes, unsubstituted or substituted... and unreplaced or replaced .

12. The compound according to claim 11, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted oxobutanes.

13. The compound according to claim 11, wherein R 4 For methyl, R 5 It is methyl, and R 6 It is a methyl group.

14. The compound according to claim 13, wherein R 7b For unreplaced C 1-4 Halogenated alkyl groups.

15. The compound according to claim 13, wherein R 7b It is a cyano group.

16. The compound according to claim 1, wherein R 8 -CH2OC(=O)- (unsubstituted C) 1-4 Alkyl), –CH2OC(=O)–O(unsubstituted C) 1-4 Alkyl groups or –CH2– (α-amino acids).

17. The compound according to claim 1, wherein R 8 It is -CH2-phosphate.

18. The compound according to claim 1, wherein: R 2 For unreplaced C 1-4 Alkyl groups; and R 3 Selected from the replaced C 1-4 Alkyl and unsubstituted C 1-4 hydroxyalkyl, wherein when the C 1-4 When the alkyl group is substituted, the C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate, O-linked α-amino acid, and O-carboxyl group.

19. The compound according to claim 2, wherein: R 2 For unreplaced C 1-4 Alkyl groups; and R 3 Selected from the replaced C 1-4 Alkyl and unsubstituted C 1-4 hydroxyalkyl, wherein when the C 1-4 When the alkyl group is substituted, the C 1-4 The alkyl group is substituted by one or more substituents independently selected from the following: phosphate, O-linked α-amino acid, and O-carboxyl group.

20. The compound according to claim 1, wherein: R 1 It is an unsubstituted C2 ynyl group; and R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms come together to form an unsubstituted or substituted monocyclic 3-4-membered heterocyclic group, wherein when the 3-4-membered heterocyclic group is substituted, the 3-4-membered heterocyclic group is substituted by one or two substituents independently selected from halogens and hydroxyl groups.

21. The compound according to claim 2, wherein: R 1 It is an unsubstituted C2 ynyl group; and R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms come together to form an unsubstituted or substituted monocyclic 3-4-membered heterocyclic group, wherein when the 3-4-membered heterocyclic group is substituted, the 3-4-membered heterocyclic group is substituted by one or two substituents independently selected from halogens and hydroxyl groups.

22. The compound according to claim 20 or 21, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted oxobutanes.

23. The compound according to claim 20 or 21, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted oxobutanes.

24. The compound according to claim 22, wherein R 7b It is a cyano group.

25. The compound according to claim 24, wherein R A It is F.

26. The compound according to claim 22, wherein R 7b It is unreplaced C 1-4 Halogenated alkyl groups.

27. The compound according to claim 26, wherein R 7b It is -CF3.

28. The compound according to claim 26, wherein R A It is F.

29. The compound according to claim 18 or 20, wherein R 7b It is cyano, and R 8 It is –CH2-phosphate.

30. The compound according to claim 29, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted oxobutanes.

31. The compound according to claim 29, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted oxobutanes.

32. The compound according to claim 18 or 20, wherein R 7b For unreplaced C 1-4 Halogenated alkyl groups, and R 8 It is –CH2-phosphate.

33. The compound according to claim 32, wherein R 7b For –CF3.

34. The compound according to claim 32, wherein R 2 and R 3 Together with R 2 and R 3 The attached carbon atoms combine to form unsubstituted or substituted oxobutanes.

35. The compound according to claim 19 or 21, wherein R 7b It is cyano, and R A It is F.

36. The compound according to claim 19 or 21, wherein R 7b For –CF3, and R A It is F.

37. Compounds having the following structure: Or, or a pharmaceutically acceptable salt thereof.

38. Compounds having the following structure: 。 39. Compounds having the following structure: 。 40. Compounds having the following structure: Or, or a pharmaceutically acceptable salt thereof.

41. Compounds having the following structure: Or, or a pharmaceutically acceptable salt thereof.

42. Compounds having the following structure: Or, or a pharmaceutically acceptable salt thereof.

43. Compounds having the following structure: Or, or a pharmaceutically acceptable salt thereof.

44. Compounds having the following structure: Or, or its pharmaceutically acceptable salt or stereoisomer.

45. Compounds selected from: , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

46. ​​Compounds selected from: , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

47. The compound according to claim 45 or 46, wherein the compound is selected from: , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

48. The compound according to claim 1, wherein the compound is selected from: , , , and Or a pharmaceutically acceptable salt of any of the aforementioned compounds.

49. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, and an excipient.

50. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 48 in the preparation of a medicament for treating hepatitis B.

51. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 48 in the preparation of a medicament for treating hepatitis D.

52. The use according to any one of claims 50 to 51, wherein the use further comprises the use of one or more adjuvant agents selected from: interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors and small molecule immunomodulators.

53. The use according to claim 52, wherein the one or more adjuvant agents are selected from: recombinant interferon α2b, IFN-α, PEG-IFN-α-2a, lamivudine, telbivudine, adefovir dipivoxil, clavidine, entecavir, tenofovir alafenamide, and tenofovir disoproxil fumarate.

54. Compounds having the following structure: .

55. A method for preparing compounds having the following structure: The method includes making Reaction with di-tert-butylchloromethyl phosphate to provide .

56. A method for preparing compounds having the following structure: The method includes removing The tert-butyl group was added with sodium ions using a sodium reagent.

57. The method according to claim 56, wherein the sodium reagent is selected from sodium acetate and sodium hydroxide.

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