Pd-l1 compounds with bicyclic groups

Abstract

The present disclosure relates to compounds capable of acting as inhibitors of PD-1, PD-L1 or PD-1 / PD-L1 interaction. Also disclosed herein are pharmaceutical compositions capable of comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of PD-L1 related diseases, including but not limited to liver diseases, cancer (e.g. hepatocellular carcinoma) and / or viral diseases, such as hepatitis B.

Description

[0001] Incorporate priority claims by reference

[0002] Any and all applications that specify foreign or domestic priority claims (such as in the application data sheet or request filed with this application) are hereby incorporated by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 550,953, filed February 7, 2024, and U.S. Provisional Application No. 63 / 670,541, filed July 12, 2024, each of which is expressly incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to the fields of chemistry, biochemistry, molecular biology, and medicine. This disclosure relates to compounds that can be used as inhibitors of PD-1, PD-L1, or PD-1 / PD-L1 interactions. Pharmaceutical compositions of the compounds described herein and uses or methods of using said compounds to treat PD-L1-related diseases, including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B. Background Technology

[0004] In activated CD4 + and CD8 + Programmed cell death 1 (PD-1), an immune checkpoint expressed on the surface of T cells, controls the suppression of autoimmunity. PD-1 binding to programmed death ligand 1 (PD-L1), expressed on various cell types including macrophages, dendritic cells, mast cells, and cancer cells, induces T cell exhaustion, leading to reduced or lost production of effector cytokines (e.g., IL-2, TNF-α, IFN-γ) and upregulation of other inhibitory receptors and immune checkpoints (e.g., CTLA-4, LAG-3, and BTLA), or T cell apoptosis. Many types of cancer exhibit high PD-L1 expression to evade tumor immune surveillance and are associated with poor prognosis. PD-1-mediated immunosuppression is also associated with some viral infections (such as hepatitis B). There is an ongoing need for PD-1 / PD-L1 therapies and their improvement in treating these diseases. Summary of the Invention

[0005] Some of the embodiments disclosed herein involve compounds of formula (I) or pharmaceutically acceptable salts thereof.

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

[0007] Some embodiments described herein relate to 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.

[0008] 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.

[0009] These and other implementation schemes are described in more detail below. Attached Figure Description

[0010] Figure 1A and Figure 1B The absolute configuration structure of the chloride salt of intermediate 10B-1 and the ORTEP crystal structure are shown. Detailed Implementation

[0011] Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC can be caused by a variety of conditions, such as alcohol consumption, cirrhosis, and viral infections that cause hepatitis, such as hepatitis B virus, hepatitis C virus, and hepatitis D virus. The inflammation, fibrosis, and cirrhosis associated with these conditions can induce malignant tumors in the affected hepatocytes. HCC has a relatively poor prognosis, with a five-year survival rate of approximately 30%, depending on whether complete surgical resection of the tumor is possible.

[0012] For early-stage disease, surgical resection is used. However, due to diagnostic difficulties, most HCCs are identified at a later stage. At late-stage diagnosis, the tumor is unresectable, and most patients are given systemic therapy. The current standard of care in the first line is multi-kinase inhibitors (including, for example, sorafenib and / or lenvatinib). Most patients are refractory or have relapsed from these treatments and experience second-line therapy with anti-angiogenic agents (including, for example, regorafinib, cabozantinib, and / or ramicirumab) or immune checkpoint inhibitors (including, for example, nivolumab and / or pembrolizumab). However, most patients do not respond to first- or second-line therapy and have poor clinical benefit, with overall survival not exceeding one year. Furthermore, there is a lack of biomarker-driven therapies. Therefore, there is a need to develop more tolerable and effective therapies for the treatment of HCC and related liver diseases.

[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. Part of replication involves the formation of covalently closed circular DNA (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 via 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 for hepatitis D.

[0016] Programmed cell death 1, or programmed cell death 1 (PD-1), is a 268-amino acid-long type I transmembrane protein found as a surface marker on T cells and other immune cells. As an immune checkpoint, PD-1 negatively regulates immune responses to prevent autoimmune diseases. The PD-1 protein (NCBI accession number NP_005009.2) is expressed by the differentiation cluster 279 (CD279) gene (NCBI accession number NG_012110.1) or mRNA transcript (NCBI accession number NM_005018.3). In some preferred embodiments, PD-1 is the human PD-1 protein, and CD279 is the human CD279 transcript or gene on chromosome 2. It should be understood that those skilled in the art will generally consider the terms PD-1 and CD279 to be nominally interchangeable when considering nucleic acids (DNA or RNA) or their corresponding translated proteins or sequences thereof.

[0017] Programmed cell death-ligand 1 (PD-L1), also known as B7 homologue 1 (B7-H1), is a 272-amino acid-long type I transmembrane protein found as a surface marker on many different cell types. PD-L1 is the major ligand of PD-1 and leads to suppression of T cell cytotoxicity and cytokine production. Cancer cells such as HCC cells exploit this immune checkpoint by upregulating PD-L1 expression, resulting in dysregulated proximal T cell antitumor immunity. Viral modulation of the PD-1 / PD-L1 pathway to suppress host immune responses has also been observed. Hepatitis B virus has been shown to upregulate PD-L1 in infected hepatocytes and PD-1 in associated T cells. The PD-L1 protein (NCBI accession number NP_054862.1) is expressed by the differentiation cluster 274 (CD274) transcript (NCBI accession number NM_014143.4). In some preferred embodiments, PD-L1 is the human PD-L1 protein, and CD274 is the human CD274 transcript or gene on chromosome 9. It should be understood that those skilled in the art will consider the terms PD-L1 and CD274 to be generally nominally interchangeable when considering nucleic acids (DNA or RNA) or their corresponding translated proteins or sequences thereof.

[0018] definition

[0019] 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. Unless otherwise stated, all patents, applications, publications, and other disclosures cited herein are incorporated herein by reference. In the event of any conflict between a cited publication and patent or patent application and any disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such conflicting material. Where multiple definitions exist for terms herein, the definitions in that section shall prevail unless otherwise stated.

[0020] 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 substituent 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 with one or more groups (such as one, two, or three groups) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), (heterocyclic)alkyl, hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-amine. Carboxyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, isocyanate, thiocyanate, isothiocyanate, nitro, azide, silyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amino, monosubstituted amine and disubstituted amine.

[0021] As used in this article, where "a" and "b" are integers, "C" represents the integers. a To C b “C” a -C b "or "C a-b The 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" (inclusive of the endpoints) of carbon atoms. 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.

[0022] 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.

[0023] 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.

[0024] 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-C20. 2-4 alkynyl group, C 2-6 alkynyl or C 2-8 Alkynyl group. Examples of alkynyl groups include ethynyl and propynyl. The alkynyl group can be unsubstituted or substituted.

[0025] 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 form. A cycloalkyl group may contain 3 to 10 atoms in the ring. It may also contain 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.

[0026] 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.

[0027] 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 pervading 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.

[0028] 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.

[0029] As used herein, a "heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic 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-dioxins, 1,3-dioxanes, 1,4-dioxanes, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxothiohexacyclohexane, 1,4-oxothiohexacyclohexadiene, 1,3-oxothiohexacyclopentane, 1,3-dithiohexacyclopentadiene, 1,3-dithiopentane, and 1,4-oxothiohexacyclohexacyclohexane. Hexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, 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 benzofused analogs (e.g., tetrahydroquinoline and 3,4-methylenedioxyphenyl).

[0030] 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).

[0031] 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.

[0032] "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).

[0033] A “lower alkylene group” is a straight-chain -CH2-chain group that forms a bond to connect a molecular segment via its terminal carbon atom. In some embodiments, the lower alkylene group may include 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). The lower alkylene group may be substituted by replacing one or more hydrogen atoms of the lower alkylene group with one or more substituents listed under the definition of “substituted”.

[0034] 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. In some cases, the alkoxy group may be -OR, where R is an unsubstituted C. 1-4 Alkyl groups. Alkoxy groups can be substituted or unsubstituted.

[0035] 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.

[0036] As used herein, “hydroxyalkyl” 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, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.

[0037] 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.

[0038] As used herein, “haloalkoxy” refers to an O-alkyl group (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) in which one or more hydrogen atoms are replaced by halogens. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some cases, the haloalkoxy group may be -OR, where R is a C-aryl group substituted with one, two, or three halogens. 1-4 Alkyl groups. Halogenated alkoxy groups can be substituted or unsubstituted.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] The “trihalomethanesulfonyl” group refers to the “X3CSO2-” group where each X is a halogen.

[0046] The "trihalomethanesulfonylamino" group refers to a group in which each X is a halogen and R is a halogen. A The "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.

[0047] As used in this article, the term "amino" refers to the -NH2 group.

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

[0049] The "cyano" group refers to the "-CN" group.

[0050] As used in this article, the term "azido" refers to the -N3 group.

[0051] The "isocyanate" group refers to the "-NCO" group.

[0052] The "thiocyanate" group refers to the "-SCN" group.

[0053] The "isothiocyanate" group refers to the "-NCS" group.

[0054] The "thiol" group refers to the "-SH" group.

[0055] The "carbonyl" group refers to the -C(=O)- group.

[0056] 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.

[0057] 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) AThe N-sulfonamide group can be substituted or unsubstituted.

[0058] 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 B The O-carbamoyl group can be substituted or unsubstituted.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] The "C-acylamino" group refers to the R group within it. 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.

[0063] 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.

[0064] "Monosubstituted amine" refers to an amine in which R A "-NHR" can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A Monosubstituted amines can be substituted or unsubstituted. In some cases, monosubstituted amines can be -NHR. A , where R A Can be unreplaced C 1-6 Alkyl or unsubstituted or substituted benzyl.

[0065] "Disubstituted amine" refers to an amine in which R A and R B "-NR" can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), or heterocyclic(alkyl). A R B Monosubstituted amines can be substituted or unsubstituted. In some cases, monosubstituted amines can be -NR. A R B , where R A and R B Can be independently of unsubstituted C 1-6 Alkyl or unsubstituted or substituted benzyl.

[0066] 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.

[0067] Where the number of substituents (e.g., haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" may contain one or more halogens, either the same or different. As another example, "C1 to C3 alkoxyphenyl" may include one or more alkoxy groups, either the same or different, containing one, two, or three atoms of alkoxy groups.

[0068] 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 Biochemistry Nomenclature Committee (see Biochem. 11:942-944 (1972)).

[0069] 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. Pharmaceutical 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. Pharmaceutical 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 compounds with bases to form salts, such as ammonium salts (e.g., ammonium salts or triethylammonium salts), alkali metal salts (e.g., lithium, sodium, or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tri(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reacting with amino acids (e.g., arginine and lysine).

[0070] 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 "containing 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.

[0071] 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.

[0072] 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 compound described.

[0073] 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)).

[0074] It should be understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may yield 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 contain 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.

[0075] 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.

[0076] compound

[0077] Examples of implementation schemes of this application include the following: Implementation Plan 1 A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: (I) Among them: A 1 Able to provide , , , or B 1 Able to provide , , or ;X 1 Able to be selected from CH, C-halogen groups and N (nitrogen); X 2 Able to be selected from CH, C-halogen groups and N (nitrogen); X 3 It can be selected from CH, C-halogen, N (nitrogen) and C-OR. Z1 ;Y 1 Able to be selected from CH, C-halogen groups and N (nitrogen); Y 2 Able to be selected from CH, C-halogen groups and N (nitrogen); R 1a Able to select from -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 -Cycloalkyl (monocyclic alkyl), -CH2 (4- to 6-membered monocyclic heterocyclic groups), and -CH2 (5- to 6-membered monocyclic heteroaryl); R 1b Able to select from -R x1 and -N(R) m1 )R n1 ;R x1 Able to select , , , , , , , and ;where R x1 It can be optionally substituted by one or two substituents, said one or two substituents being independently selected from halogen, cyano, -C 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Halogenated alkyl, -C 1-4 Halogenated alkoxy groups, -C(=O)OR Z1 -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z1 )R Z3 and -N(R) Z1 )S(=O)2N(R Z2 )R Z3 ;R m1Able to select from -C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl groups, 4- to 7-membered monocyclic heterocyclic groups, 8- to 11-membered fused heterocyclic groups, and -R x2 The 4- to 7-membered monocyclic heterocyclic groups and the 8- to 11-membered fused heterocyclic groups contain at least one atom or group of atoms, wherein the at least one atom or group of atoms is independently selected from O (oxygen), S (sulfur), C (=O), S (=O), S (=O)2, and N (nitrogen); wherein the -C 1-4 Alkyl groups are replaced by -C(=O)OR Z1 Replace, and the -C 1-4 The alkyl group can optionally be substituted with one, two, or three substituents, said substituents being independently selected from halogens, cyano groups, hydroxyl groups, and -C groups. 1-4 Alkoxy, -C 1-4 Halogenated alkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z2 )R Z3 and -N(R) Z1 )S(=O)N(R Z2 )R Z3 ; wherein C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl groups, the 4- to 7-membered monocyclic heterocyclic groups, and the 8- to 11-membered fused heterocyclic groups are -C(=O)OR Z1 Replacement, and the C 3-6 Monocyclic cycloalkyl, the C 5-12 The bicyclic cycloalkyl group, the 4- to 7-membered monocyclic heterocyclic group, and the 8- to 11-membered fused heterocyclic group can optionally be substituted by one, two, or three substituents, which are independently selected from halogens, cyano groups, and -C groups. 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Halogenated alkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1)R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) z1 )C(=O)N(R Z2 )R Z3 and -N(R) Z1 )S(=O)N(R Z2 )R Z3 ;R x2 Able to select , , , and ; Each R X3 Able to be -C(=O)OR Z1 ;R n1 Able to be selected from hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 Monocyclic cycloalkyl) and -C(=O)OR Z4 ;R 1c Can be selected from hydrogen, halogen, -OH, -CN, -CH3, -C 2-4 Alkyl and -C 2-4 Halogenated alkyl; R 1d Able to be selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 1e Able to be selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 1f Able to be selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 1g Able to be selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 1h Able to be selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 1i R 1j R 1k R 1l R 1m and R 1n Each can be independently selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R1p Able to be selected from -CH3, -C 2-4 Alkyl and -R 1p1 , where R 1p -CH3 or -C 2-4 When alkyl, the -CH3 and the -C 2-4 Alkyl groups are replaced by -C(=O)OR Z1 Replacement, and the -CH3 and the -C 2-4 The alkyl group can optionally be substituted with one or two substituents, said one or two substituents being independently selected from halogens, cyano groups, and -C groups. 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Halogenated alkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z2 )R Z3 and -N(R) Z1 )S(=O)2N(R Z2 )R Z3 ;R 1p1 Able to select , , and ;R 1q Capable of being independently selected from hydrogen, -C 1-4 Alkyl and -C 1-4 Halogenated alkyl; R 2a R 2b R 2c R 2e R 2g and R 2h Each can be independently selected from hydrogen and halogen; R 2d and R 2f Each can be independently selected from hydrogen, halogen, cyano, -CH3, -CH2CH3, -CH2OH, -OCH3, and -SCH3; R 3a Can be selected from hydrogen, -CH3, -C 2-4Alkyl and -C 2-4 Halogenated alkyl; R 3b Can be selected from hydrogen, -CH3, -C 2-4 Alkyl, -C 2-4 Halogenated alkyl groups and -C 1-4 Alkoxy; wherein R 3b It can be optionally substituted by one or two substituents, said one or two substituents being independently selected from halogens, -OH, -CN, -CH3, and -C. 2-4 Alkyl, -C 2-4 Halogenated alkyl groups, -CH2CH2OH and -CH2CH2OC 1-4 Halogenated alkyl; R 3c Can be selected from hydrogen, halogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl; R 4a Can be selected from hydrogen, -CH3, -C 2-4 Alkyl and -C 2-4 Halogenated alkyl; R 4b Can be selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Halogenated alkyl groups, -OH, -NH2, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl, wherein R 4b It can be optionally substituted by one or two substituents, said one or two substituents being independently selected from halogens, -OH, -CN, -CH3, and -C. 2-4 Alkyl, -C 2-4 Halogenated alkyl groups, -CH2CH2OH and -CH2CH2O-C 1-4 Halogenated alkyl; R 4c Can be selected from hydrogen, halogen, -C 1-2 Alkyl and -C 1-2 Alkyl halide; m1, m2, and m3 can each independently be 1 or 2; m4 can be 0, 1, or 2; m5 can be 1, 2, 3, or 4; n1 can independently be 0, 1, or 2; and R Z1 R Z2 R Z3 and R Z4 Each can be independently selected from hydrogen, -C 1-4 Alkyl and -C 1-4 Halogenated alkyl groups.

[0078] Implementation Plan 2

[0079] According to embodiment 1, the compound or its pharmaceutically acceptable salt, wherein A 1 Able to provide .

[0080] Implementation Plan 3

[0081] According to embodiment 1 or 2, the compound or its pharmaceutically acceptable salt, wherein X 1 It can be N (nitrogen).

[0082] Implementation Plan 4

[0083] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 3, wherein X 2 It can be CH.

[0084] Implementation Plan 5

[0085] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 4, wherein X 3 It can be CH.

[0086] Implementation Plan 6

[0087] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 4, wherein X 3 It can be N.

[0088] Implementation Plan 7

[0089] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 6, wherein R 1a Able to be -C 1-4 Alkyl group. C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0090] Implementation Plan 8

[0091] According to embodiment 7, the compound or its pharmaceutically acceptable salt, wherein R 1a It can be -CH3.

[0092] Implementation Plan 9

[0093] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8, wherein R 1q It can be hydrogen.

[0094] Implementation Plan 10

[0095] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 9, wherein R 1b Able to be -R x1 .

[0096] Implementation Plan 11

[0097] The compound or a pharmaceutically acceptable salt thereof according to embodiment 10, wherein -R x1 Able to provide In some implementations, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide In other implementations, m4 can be 2, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide In other implementations, m4 and m5 can each be 2, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide .

[0098] Implementation Plan 12

[0099] According to embodiment 11, the compound or a pharmaceutically acceptable salt thereof, wherein R Z1 Able to be -C 1-4 Alkyl or hydrogen. When -R Z1 C 1-4 When alkyl or hydrogen, Examples are or .

[0100] Implementation Plan 13

[0101] The compound or a pharmaceutically acceptable salt thereof according to embodiment 10, wherein -R x1 Able to provide In some implementations, R X3 It can be -C(=O)OH. In other embodiments, R X3 It can be -C(=O)OCH3. In other embodiments, R X3 It can be -C(=O)OCH2CH3.

[0102] Implementation Plan 14

[0103] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 9, wherein R 1b Able to be -N(R) m1 )R n1 .

[0104] Implementation Plan 15

[0105] According to embodiment 14, the compound or a pharmaceutically acceptable salt thereof, wherein R n1 It can be hydrogen, so that R 1b Able to be -NH(R) m1 ).

[0106] Implementation Plan 16

[0107] The compound or a pharmaceutically acceptable salt thereof as described in embodiment 14 or 15, wherein R m1 Able to be -R x2 .

[0108] Implementation Plan 17

[0109] According to embodiment 1, the compound or its pharmaceutically acceptable salt, wherein A 1 Able to provide .

[0110] Implementation Plan 18

[0111] According to embodiment 17, the compound or its pharmaceutically acceptable salt, wherein X 1 It can be N (nitrogen).

[0112] Implementation Plan 19

[0113] According to embodiment 17 or 18, the compound or its pharmaceutically acceptable salt, wherein X 2 It can be CH.

[0114] Implementation Plan 20

[0115] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 17 to 19, wherein R 1a Able to be -C 1-4 Alkyl group. Example C 1-4 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0116] Implementation Plan 21

[0117] According to embodiment 20, the compound or a pharmaceutically acceptable salt thereof, wherein R 1a It can be -CH3.

[0118] Implementation Plan 22

[0119] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 17 to 21, wherein R1c R 1d R 1e and R 1f Each can be hydrogen.

[0120] Implementation Plan 23

[0121] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 17 to 22, wherein R 1b Able to be -R x1 .

[0122] Implementation Plan 24

[0123] The compound or a pharmaceutically acceptable salt thereof according to embodiment 23, wherein -R x1 Able to provide In some implementations, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide In other implementations, m4 can be 2, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide In other implementations, m4 and m5 can each be 2, R X3 Able to be -C(=O)OR Z1 This makes -R x1 Able to provide .

[0124] Implementation Plan 25

[0125] According to embodiment 24, the compound or a pharmaceutically acceptable salt thereof, wherein R Z1 Able to be -C 1-4 Alkyl or hydrogen. Where R... Z1 Able to be -C 1-4 alkyl Examples are When R Z1 When it is hydrogen, Able to provide .

[0126] Implementation Plan 26

[0127] The compound or a pharmaceutically acceptable salt thereof according to embodiment 23, wherein -R x1 Able to provide In some implementations, R X3 It can be -C(=O)OH. In other embodiments, RX3 It can be -C(=O)OCH3. In other implementations, R X3 It can be -C(=O)OCH2CH3.

[0128] Implementation Plan 27

[0129] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 17 to 22, wherein R 1b Able to be -N(R) m1 )R n1 .

[0130] Implementation Plan 28

[0131] According to embodiment 27, the compound or a pharmaceutically acceptable salt thereof, wherein R n1 It can be hydrogen.

[0132] Implementation Plan 29

[0133] The compound or a pharmaceutically acceptable salt thereof according to embodiment 27 or 28, wherein R m1 Able to be -R x2 .

[0134] Implementation Plan 30

[0135] According to embodiment 1, the compound or its pharmaceutically acceptable salt, wherein A 1 Able to provide .

[0136] Implementation Plan 31

[0137] According to embodiment 30, the compound or a pharmaceutically acceptable salt thereof, wherein X 1 It can be N (nitrogen).

[0138] Implementation Plan 32

[0139] According to embodiment 30 or 30, the compound or its pharmaceutically acceptable salt, wherein X 2 It can be CH.

[0140] Implementation Plan 33

[0141] The compound according to any one of embodiments 30 to 32, wherein R 1i R 1j R 1k R 1l R 1m and R 1n Each can be hydrogen.

[0142] Implementation Plan 34

[0143] The compound according to any one of embodiments 30 to 33, wherein R 1p Able to be -R 1p1 .

[0144] Implementation Plan 35

[0145] According to the compound of embodiment 34, wherein -R 1p1 Able to provide .

[0146] Implementation Plan 36

[0147] According to the compound of embodiment 35, n1 can be 1, and R Z1 It is possible for H to be such that -R 1p1 Able to provide .

[0148] Implementation Plan 37

[0149] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 36, wherein B 1 Able to provide .

[0150] Implementation Plan 38

[0151] The compound or a pharmaceutically acceptable salt thereof according to embodiment 37, wherein Y1 can be CH.

[0152] Implementation Plan 39

[0153] According to embodiment 37, the compound or its pharmaceutically acceptable salt, wherein Y 1 It can be N (nitrogen).

[0154] Implementation Plan 40

[0155] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 37 to 39, wherein R 3a and R 3b Each can be -CH3.

[0156] Implementation Plan 41

[0157] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 37 to 40, wherein R 3c It can be hydrogen.

[0158] Implementation Plan 42

[0159] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 37 to 40, wherein R 3c It can be -CH3.

[0160] Implementation Plan 43

[0161] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 37 to 40, wherein R 3c Able to be -C 1-2 Halogenated alkyl groups, such as -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CF3 or -CH2CHF2.

[0162] Implementation Plan 44

[0163] According to embodiment 43, the compound or its pharmaceutically acceptable salt, wherein R 3c It can be -CF3.

[0164] Implementation Plan 45

[0165] According to embodiment 43, the compound or its pharmaceutically acceptable salt, wherein R 3c It can be -CHF2.

[0166] Implementation Plan 46

[0167] According to embodiment 37, the compound or its pharmaceutically acceptable salt, wherein B 1 Able to select , , , , , , and .

[0168] Implementation Plan 47

[0169] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 36, wherein B 1 Able to provide .

[0170] Implementation Plan 48

[0171] The compound or a pharmaceutically acceptable salt thereof according to embodiment 47, wherein Y2 can be CH.

[0172] Implementation Plan 49

[0173] The compound or a pharmaceutically acceptable salt thereof as described in embodiment 47 or 48, wherein R 4a It can be -CH3.

[0174] Implementation Plan 50

[0175] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 47 to 49, wherein R 4b It can be hydrogen.

[0176] Implementation Plan 51

[0177] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 47 to 50, wherein R 4c It can be hydrogen.

[0178] Implementation Plan 52

[0179] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 47 to 50, wherein R 4c It can be -CH3.

[0180] Implementation Plan 53

[0181] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 47 to 50, wherein R 4c Able to be -C 1-2 Halogenated alkyl groups, such as -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CF3 or -CH2CHF2.

[0182] Implementation Plan 54

[0183] According to embodiment 53, the compound or its pharmaceutically acceptable salt, wherein R 4c It can be -CF3.

[0184] Implementation Plan 55

[0185] According to embodiment 53, the compound or its pharmaceutically acceptable salt, wherein R 4c It can be -CHF2.

[0186] Implementation Plan 56

[0187] According to embodiment 47, the compound or its pharmaceutically acceptable salt, wherein B 1 Able to select , , , , , , and .

[0188] Implementation Plan 57

[0189] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 56, wherein R 2a R 2b R 2c R 2e R 2g and R 2h Each can be hydrogen.

[0190] Implementation Plan 58

[0191] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 57, wherein R 2d and R 2f Each can be a halogen.

[0192] Implementation Plan 59

[0193] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 57, wherein R 2d It can be halogen; and R 2f It can be -CH3.

[0194] Implementation Plan 60

[0195] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 57, wherein R 2d It can be -CH3; and R 2f It can be halogen.

[0196] Implementation Plan 61

[0197] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 58 to 60, wherein the halogen can be chlorine.

[0198] Implementation Plan 62

[0199] The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f Each can be -CH3.

[0200] Implementation Plan 63

[0201] According to embodiment 1, the compound or a pharmaceutically acceptable salt thereof is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned.

[0202] Implementation Plan 64

[0203] According to embodiment 1, the compound or a pharmaceutically acceptable salt thereof is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned.

[0204] Implementation Plan 65

[0205] A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64, and an excipient.

[0206] Implementation Plan 66

[0207] A method for treating a subject with hepatitis B, the method comprising administering to the subject in need an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64.

[0208] Implementation Plan 67

[0209] A method for treating a subject with hepatocellular carcinoma (HCC), the method comprising administering to the subject in need an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64.

[0210] Implementation Plan 68

[0211] The method according to any one of embodiments 66 to 67 may further include the application of surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, and / or antiviral therapy.

[0212] Implementation Plan 69

[0213] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64 is used in the treatment of hepatitis B.

[0214] Implementation Plan 70

[0215] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64 is used in the treatment of hepatocellular carcinoma (HCC).

[0216] Implementation Plan 71

[0217] The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 69 to 70, wherein the use may further include surgical administration, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy and / or antiviral therapy.

[0218] Implementation Plan 72

[0219] Use of any compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64 in the preparation of a medicament for treating hepatitis B.

[0220] Implementation Plan 73

[0221] Use of any compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 64 in the preparation of a medicament for treating hepatocellular carcinoma (HCC).

[0222] Implementation Plan 74

[0223] According to any one of embodiments 72 to 73, the drug can be used in combination with surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy and / or antiviral therapy.

[0224] In some embodiments (including any of embodiments 1 to 74), the compound of formula (I) or a pharmaceutically acceptable salt thereof, Y 1 It cannot be a C-halogenated group, such as CF. In some embodiments (including any of embodiments 1 to 74), the compound of formula (I) or a pharmaceutically acceptable salt thereof, Y 1 It cannot be a C-halogenated group, such as CF. In some embodiments (including any of embodiments 1 to 74), the compound of formula (I) or a pharmaceutically acceptable salt thereof, Y 2 It cannot be a C-halogenated group, such as CF. In some embodiments (including any of embodiments 1 to 74), the compound of formula (I) or a pharmaceutically acceptable salt thereof, Y 2 It cannot be a C-halogenated group, such as CF.

[0225] Preparation method

[0226] In this section, as in all other sections, unless the context otherwise indicates, references to formula (I) and its pharmaceutically acceptable salts include all other subgroups and examples thereof as provided herein. This document describes the general preparation of some representative examples of compounds of formula (I), which are generally prepared from commercially available starting materials or by standard synthetic processes used by those skilled in the art.

[0227] The following scheme represents an exemplary preparation of compounds of formula (I) and their pharmaceutically acceptable salts. Compounds of formula (I) and their pharmaceutically acceptable salts can also be prepared by similar reaction schemes as described in the following general scheme, in addition to standard synthetic processes used by those skilled in the art.

[0228] General Option 1

[0229] Generally, compounds having the structure of intermediate I-3 can be prepared according to Scheme 1. All variables in Scheme 1 are defined according to the description provided herein. In Scheme 1, the following reaction conditions apply: (1) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) and a suitable ligand (e.g., 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., t-BuONa), at a suitable temperature (e.g., 100°C); (2) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., KOAc), at a suitable temperature (e.g., 85°C); (3) in the presence of a suitable catalyst (e.g., [1,1'-bis(di-tert-butylphosphine)ferrocene]-palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., K2CO3), at a suitable temperature (e.g., 100°C).

[0230] General Option 2

[0231] Generally, compounds having the structure of intermediate II-3 can be prepared according to Scheme 2. All variables in Scheme 2 are defined according to the description provided herein. In Scheme 2, the following reaction conditions apply: (1) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) and a suitable ligand (e.g., 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., t-BuONa), at a suitable temperature (e.g., 100°C); (2) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., KOAc), at a suitable temperature (e.g., 85°C); (3) in the presence of a suitable catalyst (e.g., [1,1'-bis(di-tert-butylphosphine)ferrocene]-palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., K2CO3), at a suitable temperature (e.g., 100°C).

[0232] General Scheme 3

[0233] Generally, compounds having the structure of intermediate III-3 can be prepared according to Scheme 3. All variables in Scheme 3 are defined as described herein. In Scheme 3, the following reaction conditions apply: (1) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) and a suitable ligand (e.g., 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., t-BuONa), at a suitable temperature (e.g., 100°C); (2) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., KOAc), at a suitable temperature (e.g., 85°C); (3) in the presence of a suitable catalyst (e.g., [1,1'-bis(di-tert-butylphosphine)ferrocene]-palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., K2CO3), at a suitable temperature (e.g., 100°C).

[0234] General Scheme 4

[0235] Generally, compounds having the structure of intermediate IV-3 can be prepared according to Scheme 4. All variables in Scheme 4 are defined according to the description provided herein. In Scheme 4, the following reaction conditions apply: (1) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) and a suitable ligand (e.g., 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., t-BuONa), at a suitable temperature (e.g., 100°C); (2) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., KOAc), at a suitable temperature (e.g., 85°C); (3) in the presence of a suitable catalyst (e.g., [1,1'-bis(di-tert-butylphosphine)ferrocene]-palladium(II) chloride), in a suitable solvent (such as 1,4-dioxane), with a suitable base (e.g., K2CO3), at a suitable temperature (e.g., 100°C).

[0236] Pharmaceutical Composition

[0237] Some embodiments described herein relate to pharmaceutical compositions comprising, substantially consisting of, or consisting of an effective amount of a compound described herein (such as a compound of formula (I) 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.

[0238] As used in this article, the terms “function” and “functionality” refer to biological, enzymatic, or therapeutic functions.

[0239] The term "effective amount" or "effective dose" is used to indicate the amount of an active compound or agent that elicits an indicated biological or pharmaceutical response. For example, an effective amount of a compound may be the amount required to reduce or alleviate symptoms of a disease or to prolong the survival of a subject receiving treatment. This response may occur in tissues, systems, animals, or humans and includes the reduction of signs or symptoms of the disease being treated. 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 compound disclosed herein as a dose 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 dose may be modulated to achieve the desired effect, but this dose will depend on factors such as weight, diet, concomitant drug treatments, and other factors that a person skilled in the medical field will recognize.

[0240] The term "pharmaceutically acceptable salt" includes relatively non-toxic inorganic and organic acid or base addition salts of compositions, including but not limited to analgesics, therapeutic agents, and other substances. Examples of pharmaceutically acceptable salts include those derived from inorganic acids (such as hydrochloric acid and sulfuric acid) and those derived from organic acids (such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). Examples of suitable inorganic bases for forming salts include hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, etc. Salts can also be formed from suitable organic bases, including those that are non-toxic and sufficiently strong to form such salts. For example, such organic bases may include, but are not limited to, monoalkylamines, dialkylamines, and trialkylamines, including methylamine, dimethylamine, and triethylamine; monohydroxyalkylamines, dihydroxyalkylamines, or trihydroxyalkylamines, including monoethanolamine, diethanolamine, and triethanolamine; amino acids, including glycine, arginine, and lysine; guanidine; N-methylglucosamine; N-methylglucosamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenylethylamine; and tris(hydroxymethyl)aminoethane.

[0241] As used interchangeably in this document, “preparation,” “pharmaceutical composition,” and “composition” refer to equivalent terms for a substance composition intended for administration to a subject.

[0242] The term "pharmaceutically acceptable" means that it is compatible with the treatment of the subject, and in particular, the human.

[0243] The term "pharmaceutical" refers to an active agent that is biologically active and can be used in a therapeutic process. Additionally, "pharmaceutical" can be synonymous with "at least one pharmaceutical agent," "compound," or "at least one compound," and can refer to any form of pharmaceutical agent, such as its derivatives, analogs, salts, or prodrugs. Pharmaceutical agents can exist in various forms, as components of molecular complexes, and as pharmaceutically acceptable salts (e.g., hydrochlorides, hydrobroms, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates). The term "pharmaceutical" can also refer to any drug molecule or compound, therapeutic molecule or compound, matrix-forming molecule or compound, polymer, synthetic molecule and compound, natural molecule and compound, and any combination thereof.

[0244] As used herein, the term "subject" has its common meaning as understood in this specification and refers to an animal as the object of treatment, inhibition or improvement, observation or experimentation. "Animal" has its common meaning as understood in this specification and includes cold-blooded and warm-blooded vertebrates and / or invertebrates, such as fish, shellfish or reptiles, and particularly mammals. "Mammalian" has its common meaning as understood in this specification and includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates such as humans, monkeys, chimpanzees or apes. In some embodiments, the subject is a human.

[0245] The correct formulation depends on the chosen route of administration. Techniques for formulating and administering 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 enteric, oral, rectal, topical, sublingual, oral, intraauricular, epidural, epidermal, aerosol, and parenteral delivery (including intramuscular, subcutaneous, intra-arterial, intravenous, portal venous, intra-articular, intradermal, intraperitoneal, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection). Pharmaceutical compositions are typically formulated according to a specific intended route of administration. Pharmaceutical compositions may also be administered to isolated cells from a patient or individual, such as T cells, natural killer cells, B cells, macrophages, lymphocytes, stem cells, bone marrow cells, or hematopoietic stem cells.

[0246] Drug compounds can also be administered locally rather than systemically, for example, by direct injection of the compound into an organ, tissue, cancer, tumor, or infected area, typically in the form of a reservoir or sustained-release formulation. Alternatively, the compound can be administered into targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. Liposomes can target and selectively take up organs, tissues, cancer, tumors, or infected areas.

[0247] 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.

[0248] As used herein, “carrier” refers to a compound, particle, solid, semi-solid, liquid, or diluent that facilitates the passage, delivery, and / or binding of a compound to cells, tissues, and / or organs of the body. For example, but not limited to, lipid nanoparticles (LNPs) are one type of carrier that encapsulates compounds as described herein or pharmaceutically acceptable salts thereof, thereby protecting the compounds as described herein or pharmaceutically acceptable salts thereof from degradation during blood flow and / or facilitating delivery to desired organs, such as the liver.

[0249] As used herein, a “diluent” refers to a component in a pharmaceutical composition that does not have 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.

[0250] The term “excipient” has its common meaning as understood in this specification and refers to an inert substance, compound or material added to a pharmaceutical composition to provide (but not limited to) volume, consistency, stability, binding ability, lubricity, disintegration ability, etc. Excipients having the desired properties include, but are not limited to, preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizers, detergents, surfactants, chelating agents, antioxidants, alcohols, ketones, aldehydes, ethylenediaminetetraacetic acid (EDTA), citric acid, salts, sodium chloride, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, potassium chloride, potassium phosphate, magnesium sulfate, sugars, dextrose, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, serum, amino acids, polysorbate 20, polysorbate 80, sodium deoxycholate, taurine deoxycholate, magnesium stearate, octylphenol ethoxylate, benzyl chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea, or vitamins, or any combination thereof. The amount of excipient may be present in the pharmaceutical composition as a percentage of 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% w / w or any weight percentage within the range defined by any two of the foregoing figures.

[0251] As used herein, the term "adjuvant" refers to a substance, compound, or material that stimulates an immune response and enhances the efficacy of protective immunity and is administered in combination with an immunogenic antigen, epitope, or composition. Adjuvants are used to improve immune responses by enabling sustained release of antigens, upregulation of cytokines and chemokines, cell recruitment at the site of application, increased antigen uptake and presentation in antigen-presenting cells, or activation of antigen-presenting cells and inflammasomes. Commonly used adjuvants include, but are not limited to: alum, aluminum salts, aluminum sulfate, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, potassium aluminum sulfate, oils, mineral oils, paraffin oils, oil-in-water emulsions, detergents, and MF59. ® Squalene, AS03, α-tocopherol, polysorbate 80, AS04, monophospholipid A, polysorbate, virion, nucleic acid, polyinosinic acid: polycytidylic acid, saponin, QS-21, protein, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21, imidazoquinone, CpG oligonucleotide, lipid, phospholipid, dioleoylphosphatidylcholine (DOPC), trehalose dimethicone, peptidoglycan, bacterial extract, lipopolysaccharide or Freund's adjuvant, or any combination thereof.

[0252] As used herein, the term "purity" for any given substance, compound, or material refers to the actual abundance of the substance, compound, or material relative to an expected abundance. For example, a substance, compound, or material may be at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure, including all decimals in between. Purity may be affected by unwanted impurities, including but not limited to byproducts, isomers, enantiomers, degradation products, solvents, carriers, mediators, or contaminants, or any combination thereof. Techniques for measuring purity include, but are not limited to, chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-Vis spectroscopy, infrared spectroscopy, mass spectrometry, nuclear magnetic resonance, gravimetric analysis, or titration, or any combination thereof.

[0253] How to use

[0254] Some of the embodiments disclosed herein involve selecting subjects or patients in need. In some embodiments, patients requiring treatment, suppression, improvement, prevention, or mitigation of a disease or condition associated with PD-L1 dysregulation are selected. In some embodiments, such diseases or conditions associated with PD-L1 dysregulation may include, for example, cancer, HCC, viral infection, and / or HBV. In some embodiments, subjects who have previously been treated for the diseases or conditions described herein may be selected. In some embodiments, subjects who have previously been treated and are at risk for the diseases or conditions described herein may be selected. In some embodiments, subjects who have developed a relapse of the diseases or conditions described herein may be selected. In some embodiments, subjects who have developed resistance to the therapies for the diseases or conditions described herein may be selected. In some embodiments, subjects who may have any combination of the foregoing selection criteria may be selected.

[0255] The efficacy and toxicity of the compounds disclosed herein and their pharmaceutically acceptable salts can be evaluated using known methods. A non-limiting list of potential benefits of the compounds described herein or their pharmaceutically acceptable salts includes improved stability, enhanced safety profiles, increased efficacy, increased binding to targets, and increased specificity for targets such as cancer cells or virus-infected cells.

[0256] As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” have their common meaning as understood in accordance with this specification and do not necessarily mean the complete cure or elimination of a disease or symptom. As used herein, the terms “treating” or “treatment” (and as well as as fully understood in the art) also mean a method of obtaining a beneficial or desired outcome (including clinical outcomes) in a subject’s condition. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction of disease severity, stabilization (i.e., non-exacerbation) of the disease state, prevention of the spread or diffusion of the disease, delay or slowing of disease progression, improvement or relief of the disease state, reduction of disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. As used herein, “treating” and “treatment” also include preventative treatment. Treatment methods include administering a therapeutically effective amount of the active agent to the subject. Administration steps may consist of a single administration or may include a series of administrations. The composition is administered to the subject in an amount and for a duration sufficient to treat the subject. The length of treatment depends on a variety of factors, such as the severity of symptoms, the age and genetic characteristics of the subject, the concentration of the active agent, the activity of the composition used in treatment, or a combination thereof. It should also be understood that the effective dose of a drug used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dosage can be produced and become apparent by standard diagnostic assays known in the art. In some cases, prolonged administration may be necessary.

[0257] Some embodiments described herein relate to methods for treating, inhibiting, improving, preventing, or alleviating the diseases or conditions described herein. In some embodiments, the method includes administering to a subject identified as suffering from the diseases or conditions described herein an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of the compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, inhibiting, improving, preventing, or alleviating the diseases or conditions described herein. Still other embodiments described herein relate to the use of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, for treating, inhibiting, improving, preventing, or alleviating the diseases or conditions described herein.

[0258] Some embodiments described herein relate to methods for inhibiting the replication of cancer cells or viruses, which may include contacting cells or viruses with an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or administering to a subject identified as having cancer or a viral infection an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the replication of cancer cells or viruses. Still other embodiments described herein relate to an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting the replication of cancer cells or viruses. In some embodiments, the cancer cells are HCC cells. In some embodiments, the virus is hepatitis B.

[0259] Some embodiments described herein relate to methods for inhibiting cell proliferation, such as inhibiting the proliferation of cancer cells or virus-infected cells, the method comprising administering to a subject identified as suffering from a disease in which inhibition of cell proliferation is required, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting the proliferation of cancer cells or virus-infected cells. Still other embodiments described herein relate to an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting cell proliferation, such as inhibiting the proliferation of cancer cells or virus-infected cells. In some embodiments, the cancer cells are HCC cells. In some embodiments, the virus-infected cells are infected with hepatitis B virus.

[0260] Some embodiments described herein relate to methods for inducing apoptosis in cells (e.g., cancer cells or virus-infected cells), which may include contacting the cells with an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing apoptosis in cells such as cancer cells or virus-infected cells. Still other embodiments described herein relate to the use of an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, for inducing apoptosis in cells such as cancer cells or virus-infected cells. In some embodiments, the cancer cells are HCC cells. In some embodiments, the virus-infected cells are infected with hepatitis B virus.

[0261] Some embodiments described herein relate to methods for reducing the viability of cells (e.g., cancer cells or virus-infected cells), which may include contacting the cells with an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of the compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the viability of cells such as cancer cells or virus-infected cells. Still other embodiments described herein relate to the use of an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, for reducing the viability of cells such as cancer cells or virus-infected cells. In some embodiments, the cancer cells are HCC cells. In some embodiments, the virus-infected cells are infected with hepatitis B virus.

[0262] Those skilled in the art of treating such diseases can determine the effective daily dose from the test results. The effective daily dose will be from about 0.005 mg / kg to 50 mg / kg, particularly from 0.01 mg / kg to 50 mg / kg body weight, more particularly from 0.01 mg / kg to 25 mg / kg body weight, preferably from about 0.01 mg / kg to about 15 mg / kg, more preferably from about 0.01 mg / kg to about 10 mg / kg, even more preferably from about 0.01 mg / kg to about 1 mg / kg, and most preferably from about 0.05 mg / kg to about 1 mg / kg body weight.

[0263] In some embodiments, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is administered more than once. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered every 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or 1, 2, 3, 4, 5 years, or at any time period within any of the foregoing timeframes, or a combination thereof. In some embodiments, at least one loading dose and at least one maintenance dose are administered to the subject, wherein the at least one loading dose is a higher dose of the compound described herein or a pharmaceutically acceptable salt thereof than the at least one maintenance dose.

[0264] As used herein, the term "combination therapy" is intended to define a therapy that includes a combination of two or more pharmaceutical compounds / agents or therapies. Therefore, the use of "combination therapy," "combination," and "combination" of compounds / agents in this application may refer to compounds / agents administered as part of the same overall treatment regimen. Thus, the dosage or timing of each of the two or more compounds / agents may differ: each may be administered simultaneously or at different times. Therefore, the combined compounds / agents may be administered sequentially (e.g., before or after) or simultaneously in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., individually). Each of the two or more compounds / agents in a combination therapy may also differ relative to the route of administration.

[0265] As used herein, the term "inhibitor" refers to an enzyme inhibitor or receptor inhibitor, which is a molecule that binds to an enzyme or receptor and reduces and / or blocks its activity. The term may include reversible or irreversible inhibitors.

[0266] Cancer can be treated with surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or hormone therapy. Any of these mentioned therapies can be combined with another therapy as a combination therapy. Chemotherapy compounds include, but are not limited to, alemtuzumab, altretamine, azacitidine, bendamustine, bleomycin, bortezomib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, and chlorambucil. IL), nitrogen mustard (chlormethine), cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denosumab, docetaxel, doxorubicin, epirubicin. Estramustine, etoposide, everolimus, fluorouridine, fludarabine, fluorouracil, fotemustine, gemcitabine, gemtuzumab, hydroxyurea, ibritumomab, idarubicin, ifosfamide, irinotecan, ixabepilone, lomustine, melphalan Melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, ofatumumab, oxaliplatin, paclitaxel, pemetrexed, pentostatin, pertuzumab, procarbazine, raltitrexedStreptozotocin, tegafur, temozolomide, temsirolimus, teniposide, thioguanine, topotecan, tositumomab, valrubicin, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0267] As used herein, the term "protein kinase inhibitor" refers to an inhibitor of a protein kinase, serine / threonine kinase, tyrosine kinase, or bispecific kinase used to treat cancer or other diseases. In some embodiments, the protein kinase inhibitor may be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide (and pharmaceutically acceptable salts of any of the foregoing).The non-limiting list of protein kinase inhibitors includes, but is not limited to, acalabrutinib, adavosertib, afatinib, alectinib, axitinib, binimetinib, bosutinib, brigatinib, cediranib, ceritinib, cetuximab, cobimetinib, and crizotinib. tinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erdafitinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, lortatinib, masitinib b) Molotinib, mubritinib, neratinib, nilotinib, nintedanib, olmutinib, osimertinib, pacritinib, panitumumab, pazopanib, pegaptanib, ponatinib, radotinib, regorafe Nib), rociletinib, ruxolitinib, selumetinib, semaxanib, sorafenib, sunitinib, SU6656, tivozanib, toceranib, trametinib, trastuzumab, vandetanib, and vemurafenib, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0268] As used herein, the term "checkpoint inhibitor" refers to an immunotherapy that targets immune checkpoints to stimulate immune function. In some embodiments, checkpoint inhibitors can be small molecules, compounds, polysaccharides, lipids, peptides, polypeptides, proteins, antibodies, nucleosides, nucleoside analogs, nucleotides, nucleotide analogs, nucleic acids, or oligonucleotides (and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the immune checkpoint can be a PD-1 / PD-L1 checkpoint. Examples of PD-1 checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, spartalizumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, and AMP-514, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing). Additional examples of PD-L1 checkpoint inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170, and BMS-986189, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the immune checkpoint may be the CTLA-4 checkpoint. A non-limiting list of CTLA-4 checkpoint inhibitors includes, but is not limited to, ipilimumab and tremilimumab, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0269] As used herein, the term "VEGF inhibitor" refers to an inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR). In some embodiments, the VEGF inhibitor may be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide (and pharmaceutically acceptable salts of any of the foregoing). Examples of VEGF inhibitors include, but are not limited to, aflibercept, axitinib, bevacizumab, brivanib, cabozantinib, sidinib, lenvatinib, linivatinib, nintedanib, pazopanib, ponatinib, ramucirumab, regorafenib, semasanib, sorafenib, sunitinib, tevozanib, torenib, and vandetanib, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0270] As used herein, the term "antiviral drug" refers to a pharmaceutical composition administered to treat a viral infection. In some embodiments, the viral infection may be caused by adenovirus, Ebola virus, coronavirus, Epstein-Barr virus (EBV), Fried virus, Hantavirus, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), human metapneumovirus, human papillomavirus (HPV), influenza virus, Japanese encephalitis virus, Kaposi's sarcoma-associated herpesvirus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus, and / or varicella-zoster virus.

[0271] In some embodiments, the antiviral agent may be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide (and pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the antiviral agent may be interferon, capsid assembly modulator, sequence-specific oligonucleotide, entry inhibitor, or small molecule immunomodulator. A non-limiting list of antiviral agents includes, but is not limited to, AB-423, AB-506, ABI-H2158, vebicorvir (ABI-HO731), acyclovir, adapromine, adefovir, adefovir dipivoxil, alafenamide, amantadine, asunaprevir, and baloxavir. Marboxil, Beclabuvir, Boceprevir, Brivudine, Cidofovir, Ciluprevir, Clevudine, Cytarabine, Daclatasvir, Danoprevir, Dasabuvir, Delobuvir, Dipivoxil, Edoxudine, Elbasvir, Entecavir (entecavir), faldaprevir, famciclovir, favipiravir, filibuvir, fomivirsen, foscarnet, galidesivir, ganciclovir, glecaprevir, GLS4, grazoprevir, idoxuridine, imiquimod, IFN-α, interferon-α2b. JNJ-440, JNJ-6379 (JNJ-56136379), Lamivudine, Laninamivir, Leadipasvir, Melitabine, Methisazone, MK-608, Moroxydine, Narlaprevir, NITD008, NZ-4, Odalasvir, Ombitasvir, Oseltamivir tamivir), paritaprevir, pegylated interferon alpha-2a, penciclovir, peramivir, pibrentasvir, pimodivir, pleconaril, podophyllotoxin, presatovir, radalbuvir, ravidasvir, remdesivir, REP 2139, REP 2165, Resiquimod, R07049389 (RG7907), Ribavirin, Rifampicin, Rimantadine, Ruzasvir, Samatasvir, Setrobuvir, Simepirvir, Sofosbuvir, Sorivudine, Sovaprevir, Taribavirin, Telaprevir, Telbivudine, Tenofovir, Tenofovir Disoproxil, Tenofovir Acetonidealfenamide, triazavirin, trifluridine, tromantadine, umifenovir, uprifosbuvir, valaciclovir, valgancicovir, vaniprevir, vedroprevir, velpatasvir, vidarabine Abine, voxilaprevir, zanamivir, cledvudine, ANA-380 / LB80380, thymalfasin (Zadaxin), ATI-2173, VIR-2218, RG6346, JNJ-73763989 (JNJ-3989), AB-729, BB-103, Hepcludex (Bulevirtide, formerly Myrcludex) B), hzVSF, morphothiadin, JNJ-56136379, EDP-514, QL-007, ABI-H3733, ZM-H1505R, B-836, VNRX-9945, GLP-26, ABI-4334, IONIS-HBVRx (GSK) 3228836), EBT107, NASVAC, GS-4774, HepTcell, VBI-2601 (BRII-179), VVX001, VTP-300, CVI-HBV-002, AIC-649, HB- 110. JNJ-64300535, CARG-201, PRGN-2013, SA104, VRON-0200, selgantolimod, RG7854, SBT-8230, YS-HBV-0 02. Lenvervimab, Vir-3434, IMC-I109V, LTCR-H2-1, APG-1387, ASC42, EYP001, EDP-721, ENOB-HB-01, GV1001, CP101, DF-006, ALG-000184, ALG-010133, ALG-125097, ALG-020572 and ALG-125755, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0272] As used herein, the terms “% w / w” or “% wt / wt” have their ordinary meaning as understood in this specification and refer to a percentage expressed as the weight of an ingredient or pharmaceutical agent relative to the total weight of the composition multiplied by 100. As used herein, the terms “% v / v” or “% vol / vol” have their ordinary meaning as understood in this specification and refer to a percentage expressed as the liquid volume of a compound, substance, ingredient, or pharmaceutical agent relative to the total liquid volume of the composition multiplied by 100.

[0273] Example

[0274] Some aspects of the embodiments discussed above are disclosed in more detail in the following embodiments, which are not intended to limit the scope of this disclosure in any way. Those skilled in the art will understand that many other embodiments also fall within the scope of this disclosure, as set forth above and in the claims.

[0275] In the following text, the terms “rt”, “rt”, or “RT” mean room temperature; “Me” means methyl; “MeOH” means methanol; “Et” means ethyl; “EtOH” means ethanol; “NaH” means sodium hydride; “NaBH(AcO)3” or “NaBH(Oac)3” means sodium triacetoxyborohydride; “NBS” means N-bromosuccinimide; “AIBN” means azobisisobutyronitrile; “EtOAc” means ethyl acetate; “TEA” or “Et3” means sodium triacetoxyborohydride. "N" refers to triethylamine; "DCM" refers to dichloromethane; "MeNHNH2" refers to methylhydrazine; "MeNH2HCl" refers to methylamine hydrochloride; "MeCN" or "ACN" refers to acetonitrile; "DMF" refers to dimethylformamide; "DMA" refers to dimethylacetamide; "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphine)ferrocene]-palladium(II) dichloride; "PdCl2(dtbpf)" or "PD-118" refers to [1,1'-... -bis(di-tert-butylphosphino)ferrocene]-palladium(II) dichloride; "THF" refers to tetrahydrofuran; "HATU" refers to azirmonazine tetramethylurea hexafluorophosphate; "LDA" refers to lithium diisopropylamino; "DABCO" refers to 1,4-diazabicyclo[2.2.2]octane; "(Boc)2O" refers to di-tert-butyl-dicarbonate; "i-PrOH" or "iPrOH" refers to 2-propanol; "triphosgene" refers to bis(trichloromethyl) carbonate; "TM "T" refers to 2,4,6-trimercapto-s-triazine; "LC" refers to liquid chromatography; "LCMS" refers to liquid chromatography / mass spectrometry; "HPLC" refers to high-performance liquid chromatography; "preparative HPLC" refers to preparative high-performance liquid chromatography; "SFC" refers to supercritical fluid chromatography; "TFA" refers to trifluoroacetic acid; "RP" refers to reversed-phase chromatography; "min" refers to minutes; "h" refers to hours; "PE" refers to petroleum ether; "v / v" refers to volume ratio; "Celite" refers to... ®"Pd2" refers to diatomaceous earth; "DMSO" refers to dimethyl sulfoxide; "SFC" refers to supercritical fluid chromatography; "DIPE" refers to diisopropyl ether; "DIPEA" or "DIEA" refers to N,N-diisopropylethylamine; "BINAP" refers to (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); "Pd2(dba)3" refers to tris(dibenzylideneacetone)-dipalladium; "Pd(Oac)2" refers to palladium(II) acetate; "Pd(PPh3)4" refers to tetra(tris(diphenylacetone)-dipalladium); Phenylenyl)palladium(0); "AcOH" means acetic acid; "DMAP" means 4-(dimethylamino)pyridine; "t-BuOK", "BuO" or "KotBu" means potassium tert-butoxide; "t-BuONa" means sodium tert-butoxide; "TLC" means thin-layer chromatography; "prep-TLC" means preparative TLC; "KOAc" or "AcOK" means potassium acetate; "NaOAc" means sodium acetate; "Pin2B2" means bis(pinacol)diboron.

[0276] For intermediates used in the next reaction step in the form of crude product or partially purified intermediate, the estimated molar amount is indicated in the reaction scheme below (in some cases by ~), or alternatively, the theoretical molar amount is indicated.

[0277] The abbreviations in nuclear magnetic resonance spectroscopy have the following meanings: s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = double doublet of doublet, Sept = seventuplet, t = triplet, m = multiplet, br = broad peak, brs = broad singlet, q = quartet.

[0278] Preparation of intermediates

[0279] Example A1

[0280] Preparation of Intermediate 1

[0281] Add HCOONa to a solution of ethyl 2-bromo-4-(bromomethyl)pyridine-3-carboxylate (1.1 g, 3.4 mmol) in EtOH (10 mL) and H2O (2 mL). 2H₂O (1.06 g, 10.2 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1-1 (500 mg) as a white solid. The calculated m / z value of C₇H₅BrNO₂ for MS: ES was [M+H]. + 212.9, the actual measured value is 213.8.

[0282] Under N2 conditions at 25 °C, N-bromosuccinimide (NBS, 499 mg, 2.80 mmol) and azobisisobutyronitrile (AIBN, 38.4 mg, 234 μmol) were added in a single addition to a mixture of intermediate 1-1 (500 mg, 2.34 mmol) and CCl4 (15 mL). The mixture was stirred at 80 °C for 3 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1-2 (380 mg) as a white solid. The calculated m / z value of C7H4Br2NO2 by MS:ES was [M+H]. + 293.9, measured value is 293.8; 1 ¹H NMR (400MHz, chloroform-d) δ = 8.76–8.69 (m, 1H), 7.60–7.53 (m, 1H), 7.34–7.30 (m, 1H).

[0283] The mixture of intermediates 1-2 (380 mg, 1.30 mmol) in H₂O (10 mL) was stirred at 60 °C for 2 h. The mixture was then poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give crude intermediates 1-3 (300 mg) as a white solid. The calculated m / z value of C₇H₅BrNO₃ for MS: ES was [M+H]. + 229.9, the actual measured value is 229.8.

[0284] At 25 °C, HOAc (299 μL, 5.22 mmol) and methylhydrazine (263 μL, 2.00 mmol) were added in a single batch to a mixture of intermediates 1-3 (300 mg) in i-PrOH (10 mL) and DCM (10 mL). The mixture was stirred at 25 °C for 16 h. The mixture was then poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give intermediates 1-4 (160 mg) as a yellow solid. The calculated m / z value of C₈H₇BrN₃O by MS:ES was [M+H]. + 234.0, the actual measured value is 239.8.

[0285] At 25°C, NH3 was added in a single step to a mixture of intermediates 1-4 (160 mg, 667 μmol) and dioxane (5 mL) in a sealed tube. H₂O (1.71 mL, 30% purity, 13.3 mmol). The mixture was stirred at 15 psi and 80 °C for 6 h. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1, 1:1) to give intermediate 1 (140 mg) as a yellow solid. The MS:ES m / z calculated value of C₈H₁₉N₄O was [M+H]. + 177.1, the actual measured value is 177.2.

[0286] Example A1-a

[0287] Preparation of intermediate 1a

[0288] TEA (17.8 mL, 128.16 mmol) was added to a solution of methylamine hydrochloride (5.77 g, 85.4 mmol) and ethyl-2,4-dichloro-6-methylpyridine-3-carboxylate (10 g, 42.7 mmol) in CH3CN (150 mL). The mixture was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1a-1 (3.6 g, 95% purity) as a white solid. 10 H 14 The calculated MS:ES m / z value for ClN2O2 is [M+H]. + 229.1, actual measured value is 228.9; 1 ¹H NMR (400MHz, chloroform-d) δ = 7.15 (br s, 1H), 6.32 (s, 1H), 4.38 (q, J = 7.2Hz, 2H), 2.88 (d, J = 5.0Hz, 3H), 2.41 (s, 3H), 1.40 (t, J = 7.1Hz, 3H).

[0289] LiOH was added to a solution of intermediate 1a-1 (3.6 g, 15.7 mmol) in a mixture of THF (20 mL) and H2O (4 mL). H₂O (1.98 g, 47.2 mmol). The mixture was stirred at 60 °C for 12 h. The mixture was then freeze-dried. Crude intermediate 1a-2 (3.4 g, crude product) was obtained as a white solid. C₈H₂O 10 The calculated ES m / z value for ClN2O2 is [M+H]. + 201.0, the actual measured value is 201.2.

[0290] To a solution of crude intermediate 1a-2 (4.0 g, 19.94 mmol) and methylamine hydrochloride (2.69 g, 39.88 mmol) in DMF (20 mL), azirmonatriazole hexafluorophosphate tetramethylureonium (HATU, 9.10 g, 23.93 mmol) and DIEA (7.73 g, 59.81 mmol, 10.42 mL, 3 equivalents) were added. The mixture was diluted with H2O (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give intermediate 1a-3 (3.8 g) as a white solid. C9H 13 The calculated ES m / z value for ClN3O is [M+H]. + 214.1, the actual measured value is 214.1.

[0291] Under nitrogen atmosphere, bis(trichloromethyl) carbonate (triphosgene, 1.25 g, 4.21 mmol) was added to a solution of intermediate 1a-3 (1.1 g) in THF (20 mL) at 25 °C, and the resulting mixture was stirred at 25 °C for 1 h. After adding TEA (2.15 mL, 15.44 mmol) to the mixture, the mixture was stirred at 25 °C for 12 h. The reactants were quenched by adding a saturated aqueous solution of NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (50 mL). The EtOAc layer was collected, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1a (154 mg) as a yellow solid. 10 H 11 The calculated ES m / z value for ClN3O2 is [M+H]. + 240.1, the actual measured value is 240.0.

[0292] Example A1-b

[0293] Preparation of intermediate 1b

[0294] At -78 °C, lithium diisopropylamino (LDA, 2 M, 17.83 mL) was added dropwise to a solution of 2,4-dichloro-6-(trifluoromethyl)pyridine (7 g, 32.41 mmol) in THF (150 mL). After the addition of LDA, the mixture was stirred at -78 °C for 30 min. Then, at -78 °C, a solution of I2 (9.05 g, 35.65 mmol, 7.18 mL, 1.1 equivalent) in THF (2 mL) was added dropwise to the mixture. The resulting mixture was stirred at -78 °C for 1 h. After the temperature of the mixture returned to room temperature, ethyl acetate (100 mL) was added. The reaction mixture was further quenched with a saturated aqueous solution of ammonium chloride (60 mL) and a saturated aqueous solution of Na₂S₂O₃ (60 mL). The organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to obtain intermediate 1b-1 (6.77 g), which was a white solid. 1 H NMR (400MHz, DMSO- d 6 δ = 8.21 (s, 1H).

[0295] A mixture of intermediate 1b-1 (6.77 g, 19.8 mmol), methylamine hydrochloride (2.67 g, 39.6 mmol), and TEA (8.27 mL, 59.4 mmol) in CH3CN (50 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1b-2 (4.4 g, 93% purity) as a white solid. 1 H NMR (400MHz, DMSO- d 6 δ = 6.80 (br d, J = 4.5Hz, 1H), 6.74 (s, 1H), 2.90 (d, J = 4.8Hz, 3H); the calculated ES m / z value for C7H6ClF3IN2 is [M+H]. + 336.9, the actual measured value is 336.7.

[0296] To a solution of intermediate 1b-2 (2 g, 5.94 mmol) in CH3CN (30 mL), methylamine hydrochloride (602 mg, 8.92 mmol), Pd(OAc)2 (107 mg, 476 μmol), Na2CO3 (1.57 g, 14.9 mmol), and 1,4-diazabicyclo[2.2.2]octane (DABCO, 105 μL, 951 μmol) were added. The mixture was degassed and purged three times with N2. The mixture was stirred at 80 °C for 16 h under a CO atmosphere. The reactants were quenched by adding H2O (50 mL). The aqueous layer was extracted by DCM (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give intermediate 1b-3 (310 mg) as a yellow solid. C9H 10 The calculated ES m / z value for ClF3N3O is [M+H]. + 268.0, the actual measured value is 267.9.

[0297] To a solution of intermediate 1b-3 (310 mg, 1.16 mmol) in DCM (5 mL), (Boc)₂O (266 μL, 1.16 mmol), DMAP (7.1 mg, 58 μmol, 0.05 equivalent), and TEA (484 μL, 3.47 mmol) were added. The mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1b-4 (260 mg) as a yellow solid. 10 The calculated ES m / z value for H8ClF3N3O2 is [M+H]. + 294.0, the actual measured value is 293.9.

[0298] Intermediate 1b-4 (400 mg, 1.36 mmol, 1 equivalent), NH3 . A mixture of H2O (795.69 mg, 6.81 mmol, 874.39 μL, 30% purity, 5 equivalents) in dioxane (4 mL) was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was milled twice at 15 °C with EA:PE = 1:1 (10 mL). Intermediate 1b (370 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.39 (br s, 1H), 7.95 (br s, 1H), 6.88 (s,1H), 3.48 (s, 3H), 3.28 (s, 3H); C10 H 10 The calculated ES m / z value for F3N4O2 is [M+H]. + 275.1, the actual measured value is 274.9.

[0299] Example A1-c

[0300] Preparation of intermediate 1c

[0301] TEA (2.89 mL, 20.8 mmol) and methylamine hydrochloride (701 mg, 10.4 mmol) were added to a solution of 4,6-dichloro-5-iodo-2-methylpyrimidine (2.0 g, 6.92 mmol) in THF (20 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1c-1 (2.0 g) as a white solid. The calculated ES m / z value for C6H8ClIN3 was [M+H]. + 283.9, the actual measured value is 283.

[0302] A mixture of intermediate 1c-1 (2.4 g, 8.47 mmol), methylamine hydrochloride (1.43 g, 21.16 mmol), Na₂CO₃ (3.59 g, 33.86 mmol), DABCO (93 μL, 847 μmol), and Pd(OAc)₂ (190 mg, 847 μmol) in CH₃CN (30 mL) was degassed and purged three times with N₂ at 20 °C. The mixture was then stirred at 80 °C for 16 h under a CO (50 psi) atmosphere. The mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by rapid silica gel extraction to give intermediate 1c-2 (0.45 g) as a white solid. C₈H₂O 12 The calculated ES m / z value for ClN4O is [M+H]. + 215.1, the actual measured value is 215.0.

[0303] Under a nitrogen atmosphere, bis(trichloromethyl) carbonate (triphosgene, 510 mg, 1.72 mmol) was added to a solution of intermediate 1c-2 (455 mg) in THF (8.0 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. After adding TEA (442 μL, 3.18 mmol) to the mixture, the resulting mixture was stirred further at 20 °C for 12 h. The reactants were quenched by adding a saturated aqueous solution of NaHCO3 (20 mL). The mixture was extracted with EtOAc (30 mL). The EtOAc layer was collected, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1c (130 mg) as a white solid. 10 The calculated ES m / z value for ClN4O2 is [M+H]. + 241.0, the actual measured value is 241.1.

[0304] Example A1-d

[0305] Preparation of intermediate 1d

[0306] At -78°C, LDA (2M, 15.55mL) was added dropwise over 5 min to a solution of 4,6-dichloro-2-(trifluoromethyl)pyrimidine (4.5g, 20.7mmol) in THF (50mL). After the addition of LDA, the mixture was stirred at -78°C for 30 min. Then, at -78°C, a solution of I2 (5.79g, 22.81mmol) in THF (3mL) was added dropwise to the mixture. The mixture was stirred at -78°C for 1 h. After the temperature of the mixture was slowly raised to room temperature, ethyl acetate (100mL) was added. The reaction mixture was further quenched with saturated ammonium chloride aqueous solution (100mL) and saturated Na2S2O3 aqueous solution (100mL). The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 1d-1 (8g) as a colorless oil.

[0307] TEA (9.74 mL, 70.00 mmol) was added to a solution of intermediate 1d-1 (8 g) and methylamine hydrochloride (3.15 g, 46.66 mmol) in MeCN (100 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by adding H2O (50 mL). The aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by column chromatography to give intermediate 1d-2 (6 g, 17.07 mmol, 73.15% yield, 96% purity) as a yellow solid. The calculated ES m / z value of C6H5ClF3IN3 was [M+H]. + 337.9, the actual measured value is 337.8.

[0308] A mixture of intermediate 1d-2 (3.0 g, 8.89 mmol), methylamine; hydrochloride (0.60 g, 8.89 mmol), Pd(OAc)2 (200 mg, 889 μmol), Na2CO3 (2.36 g, 22.22 mmol), and DABCO (196 μL, 1.78 mmol) in MeCN (200 mL) was degassed and purged three times with N2. The mixture was stirred at 50 °C for 16 h under a CO (50 psi) atmosphere. After cooling the mixture to room temperature, the reactants were quenched by adding H2O (100 mL). The aqueous layer was extracted by DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel chromatography to give intermediate 1d-3 (0.65 g) as a yellow oil. The calculated ES m / z value for C8H8ClF3N4O is [M+H]. + 269.0, the actual measured value is 269.0.

[0309] Under a nitrogen atmosphere, bis(trichloromethyl) carbonate (1.15 g, 3.87 mmol, 0.8 equivalents) was added to a solution of intermediate 1d-3 (1.3 g, 4.84 mmol) in THF (10 mL) at 25 °C. After stirring the mixture at 25 °C for 1 h, TEA (2.94 g, 29.04 mmol, 4.04 mL, 6 equivalents) was added. The mixture was further stirred at 25 °C for 16 h. The reaction mixture was quenched by adding a saturated aqueous solution of NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (30 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give intermediate 1d (500 mg) as a yellow oil. The calculated ES m / z value of C9H7ClF3N4O2 was [M+H].+ 295.0, the actual measured value is 294.9.

[0310] Example A1-e

[0311] Preparation of intermediate 1e

[0312] DMAP (33 mg, 266 μmol) and TEA (1.11 mL, 7.99 mmol) were added to a solution of 6-amino-5-cyano-1,3-dimethyluracil (480 mg, 2.66 mmol), 2,2-difluoroacetate (2,2-difluoroacetyl) ester (696 mg, 4.00 mmol) in DCM (5 mL). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by adding H2O (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 1e-1 (250 mg) as a yellow oil. 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.92 (br s, 1H), 5.94 (t, J =56.0Hz, 1H), 3.20 (s, 3H), 3.12 (s, 3H).

[0313] A solution of intermediate 1e-1 (250 mg, 968 μmol) in sulfuric acid (75% H₂SO₄ aqueous solution, 4 mL) was stirred at 90 °C for 1 h. The reaction mixture was quenched by adding H₂O (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain the residue. The residue was purified by rapid silica gel chromatography to give intermediate 1e (110 mg) as a yellow oil. 1 H NMR (400MHz, DMSO- d 6 ) δ = 6.60(t, J = 53.7Hz, 1H), 3.40 (s, 3H), 3.14 (s, 3H).

[0314] Example A1-f

[0315] Preparation of intermediate 1f

[0316] Ethyl 2,4-dichloro-6-methyl-3-pyridinecarboxylate (5.0 g, 21.4 mmol) was reacted with 1,4-dioxane (20 mL) and NH3. The solution of the mixture of H2O (27.4 mL, based on 30% NH3) was stirred at 120 °C for 16 hours in a sealed tube (100 mL). The reaction mixture was quenched by adding H2O (50 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 1f-1 (2.4 g) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ = 6.56 (s, 1H), 6.14 (s, 2H), 4.39 (q, J = 7.2Hz, 2H), 2.33 (s, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0317] At 25 °C, DMAP (273.20 mg, 2.24 mmol) and TEA (9.34 mL, 67.09 mmol) were added to a reaction mixture of intermediate 1f-1 (2.4 g, 11.2 mmol) and Boc anhydride (10.3 mL, 44.7 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding H2O (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 1f-2 (4.2 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ =7.65 (s, 1H), 4.30 (d, J = 7.2Hz, 2H), 2.53-2.51 (m, 3H), 1.34 (s, 18H), 1.27(t, J = 7.2Hz, 3H).

[0318] Pd(dppf)Cl2 (740 mg, 1.0 mmol) and K2CO3 (2.80 g, 20.3 mmol) were added to a solution of intermediate 1f-2 (4.2 g, 10.1 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane (2.58 mL, 15.2 mmol) in a mixture of 1,4-dioxane (40 mL) and H2O (4 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography to give intermediate 1f-3 (2.4 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.64 (s, 1H), 6.85 (dd, J =11.2, 17.2Hz, 1H), 6.12 (d, J = 17.6Hz, 1H), 5.61 (d, J = 11.2Hz, 1H), 4.27(q, J = 7.2Hz, 2H), 2.53-2.50 (m, 3H), 1.33 (s, 18H), 1.26 (t, J = 7.2Hz, 3H).

[0319] At 25 °C, NaIO4 (3.16 g, 14.76 mmol), 2,6-dimethylpyridine (1.38 mL, 11.8 mmol), and potassium osmium tetroxide dihydrate (43.5 mg, 118 μmol) were added in a single addition to a solution of intermediate 1f-3 (2.4 g, 5.9 mmol) in a mixture of dioxane (30 mL) and H2O (4 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was then poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1f-4 (2.7 g, 4.69 mmol, 79.49% yield, 71% purity) as a yellow oil. 20 H 29 The calculated MS:ES m / z value for N₂O₇ is [M+H]. + 409.2, the actual measured value is 409.0.

[0320] At 25 °C, methylhydrazine (1.91 mL, 14.50 mmol) was added in a single step to a mixture of intermediate 1f-4 (2.7 g, 6.61 mmol), HOAc (1.89 mL, 33.1 mmol), and MgSO4 (3.98 g, 33.05 mmol) in i-PrOH (15 mL) and DCM (15 mL). The mixture was stirred at 25 °C for 14 hours. After adding DBU (9.96 mL, 66.1 mmol) at 25 °C, the mixture was heated to 60 °C and stirred at 60 °C for 2 hours. The reaction mixture was quenched by adding water (30 mL) and then extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 1f-5 (1.87 g) as a white solid.

[0321] At 25°C, TFA (2.20 mL, 3.38 g) was added dropwise to a solution of intermediate 1f-5 (220 mg, 563.48 μmol) in DCM (3 mL). The mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched by adding H2O (20 mL) and then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 1f (100 mg) as a white solid. 11 The calculated MS:ES m / z value for N4O is [M+H]. + 190.09, the actual measured value is 191.0.

[0322] Example A1-g

[0323] Preparation of 1g of intermediate

[0324] At -78 °C, LDA (2 M, 12.73 mL) was added dropwise over 5 min to a solution of 2,4-dichloro-6-(trifluoromethyl)pyridine (5.0 g, 23.2 mmol). After stirring the mixture at this temperature for 30 min, a solution of I2 (5.13 mL, 25.5 mmol) in THF (100 mL) was added dropwise to the mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. After slowly warming the mixture to room temperature, EtOAc (100 mL), ammonium chloride (60 mL), and a saturated Na2S2O3 solution (60 mL) were added to the mixture. The organic layer of the mixture was separated, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give intermediate 1 g⁻¹ (10.4 g) as a white solid. The calculated MS:ES m / z value for C6H2Cl2F3IN is [M+H]. + 341.9, the actual measured value is 341.7.

[0325] Intermediate 1 g-1 (10 g, 29.2 mmol) was reacted with 1,4-dioxane (60 mL) and NH3. . The solution in the mixture of H2O (37.6 mL, based on 30% NH3) was stirred at 120 °C for 16 hours in a sealed tube (100 mL). After cooling the mixture to room temperature, the reactants were quenched by adding H2O (100 mL) and then extracted by DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to obtain the residue. This residue was purified by rapid silica gel chromatography to give intermediate 1 g⁻² (3.47 g) as a white solid. The MS:ES m / z calculated value of C₆H₄ClF₃IN₂ is [M+H]. + 322.9, the actual measured value is 322.8.

[0326] A mixture of intermediate 1 g⁻² (3.47 g, 10.76 mmol), Na₂CO₃ (2.85 g, 26.9 mmol), DABCO (237 μL, 2.15 mmol), and Pd(OAc)₂ (241.60 mg, 1.08 mmol) in MeOH (100 mL) was degassed and purged with N₂ (3 ×). The mixture was then stirred at 60 °C for 16 h under a CO (50 PSi) atmosphere. The mixture was cooled to 25 °C and purged with Ar (3 ×). The reactants were quenched by adding H₂O (60 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, and concentrated under vacuum to give a residue, which was purified by rapid silica gel chromatography to give intermediate 1 g⁻³ (2.45 g) as a white solid. The calculated MS:ES m / z value for C8H7ClF3N2O2 is [M+H]. + 255.0, the actual measured value is 255.0.

[0327] To a solution of intermediate 1g-3 (2.45 g, 9.62 mmol) and TEA (8.04 mL, 57.7 mmol) in DCM (35 mL), Boc anhydride (8.84 mL, 38.49 mmol) and DMAP (117 mg, 962 μmol) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography to give intermediate 1g-4 (3.6 g) as a colorless oil.

[0328] At room temperature, intermediate 1 g-4 (3 g, 6.60 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane (3.36 mL, 19.8 mmol) in a solution of dioxane (30 mL) and H2O (3 mL) were reacted with K2CO3 (1.82 g, 13.2 mmol) and Pd(dppf)Cl2 (483 mg, 660 μmol). After degassing the mixture and purging it with N2 (3×), the mixture was heated to 100 °C and stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by rapid silica gel chromatography to give intermediate 1 g-5 (2.57 g) as a yellow oil. 15 H 18 The calculated MS:ES m / z value for F3N2O4 is [M+H]+ 347.1, while the measured value is 347.0.

[0329] At 20 °C, intermediate 1 g-5 (2.07 g, 4.64 mmol) was added to a solution of dioxane (40 mL) and H₂O (8 mL) with NaIO₄ (2.48 g, 11.6 mmol), 2,6-dimethylpyridine (1.08 mL, 9.27 mmol), and potassium osmium tetroxide dihydrate (34.2 mg, 92.7 μmol). The mixture was stirred at 20 °C for 16 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and purified by rapid silica gel chromatography to give intermediate 1 g-6 (1.29 g) as a yellow oil.

[0330] At 20 °C, intermediate 1 g-6 (1.49 g, 3.32 mmol) was added to a solution of i-PrOH (20 mL) and DCM (20 mL) with AcOH (951 μL, 16.62 mmol), MgSO4 (2.00 g, 16.6 mmol), and methylhydrazine (1.09 mL, 8.25 mmol). The mixture was stirred at 20 °C for 2 hours. After adding DBU (10.0 mL, 66.5 mmol), the mixture was stirred at 20 °C for another 2 hours. The reaction mixture was quenched by adding H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give a residue. This residue was purified by rapid silica gel chromatography to give intermediate 1 g-7 (783 mg) as a yellow solid. 14 H 16 The calculated MS:ES m / z value for F3N4O3 is [M+H]. + 345.1, the actual measured value is 345.1.

[0331] The intermediate 1 g-7 (783 mg, 1.76 mmol) was stirred in a mixture of TFA (5 mL) and DCM (20 mL) at 20 °C for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography to give intermediate 1 g (430 mg) as a white solid. The calculated MS:ES m / z value of C9H8F3N4O was [M+H]. + 245.1, the actual measured value is 244.9.

[0332] Example A1-h

[0333] Preparation of intermediate 1h

[0334] At room temperature, DIEA (2.42 mL, 13.9 mmol) was added to a solution of 5,7-dichloro-3H-pyrido[3,4-d]pyridazin-4-one (387 mg, 2.31 mmol) and 2,4-dimethoxybenzylamine (348 μL, 2.31 mmol) in dioxane (60 mL). The mixture was heated to 120 °C and then stirred at 120 °C for 16 hours. The mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography to give intermediate 1 h⁻¹ (710 mg) as a white solid. 16 H 16 The calculated MS:ES m / z value for ClN4O3 is [M+H]. + 347.1, the actual measured value is 347.0.

[0335] At room temperature, Pd(dppf)Cl2 (150 mg, 205 μmol) and K2CO3 (566 mg, 4.09 mmol) were added to a solution of intermediate 1h⁻¹ (710 mg, 2.05 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane (695 μL, 4.09 mmol) in dioxane (10 mL) and H₂O (1 mL). The mixture was heated to 100 °C and then stirred at 100 °C for 16 hours under a N₂ atmosphere. The mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography to give intermediate 1h⁻² (560 mg) as a white solid. 18 H 19 The calculated MS:ES m / z value for N4O3 is [M+H]. + 339.1, the measured value is 339.1.

[0336] At 25 °C, intermediate 1h⁻² (400 mg, 1.18 mmol) was added in a single batch to a solution of dioxane (10 mL) and H₂O (2 mL) with NaIO₄ (632 mg, 2.96 mmol), 2,6-dimethylpyridine (275 μL, 2.36 mmol), and potassium osmium tetroxide dihydrate (8.71 mg, 23.64 μmol). The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1h⁻³ (280 mg) as a yellow solid. 17 H 17 The calculated MS:ES m / z value for N4O4 is [M+H]. +341.12, the actual measured value is 341.0.

[0337] At 0 °C, DAST (217 μL, 1.65 mmol) was added in a single addition to a solution of intermediate 1h⁻³ (280 mg, 823 μmol) in DCM (10 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was then poured into water (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1h⁻⁴ (230 mg) as a white solid. 17 H 17 The calculated MS:ES m / z value for F2N4O3 is [M+H]. + 363.1, the actual measured value is 363.2.

[0338] MeI (59 μL, 952 μmol) was added in a single batch to a mixture of intermediate 1h⁻⁴ (230 mg, 635 μmol) and K₂CO₃ (263 mg, 1.90 mmol) in DMF (3 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into water (2 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1h⁻⁵ (170 mg) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ = 9.50–9.37 (m, 1H), 7.92 (s, 1H), 7.29–7.26 (m, 1H), 6.80 (s, 1H), 6.61–6.31 (m, 3H), 4.68 (d, J = 5.6Hz, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H).

[0339] At room temperature, TFA (2 mL) was added dropwise to a solution of intermediate 1h⁻⁵ (170 mg, 452 μmol) in DCM (2 mL). The mixture was stirred at 40 °C for 2 hours. The pH of the mixture was adjusted to 7–8 by adding a saturated aqueous solution of NaHCO₃. The aqueous phase was extracted with DCM (5 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give intermediate 1h (60 mg) as a white solid. 1H NMR (400MHz, DMSO-d6) δ= 8.43 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.08 (s, 1H), 6.79 (t, J =56.0Hz, 1H), 3.68 (s, 3H).

[0340] Example A1-i

[0341] Preparation of intermediate 1i

[0342] NBS (297 mg, 1.67 mmol) was added to a solution of intermediate 1a (200 mg, 835 μmol) in CH3CN (50 mL). The mixture was stirred at 20 °C under blue light for 2 hours. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give intermediate 1i-1 (130 mg) as a white solid. 10 H 10 The calculated MS:ES m / z value of BrClN3O2 is [M+H]. + 318.0, the actual measured value is 318.1.

[0343] At 25 °C, NMO (88 mg, 753 μmol) was added to a solution of intermediate 1i-1 (120 mg, 377 μmol) in CH3CN (3.0 mL). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1i-2 (50 mg) as a white solid.

[0344] At 0 °C, DAST (47 μL, 354.83 μmol) was added to a solution of intermediate 1i-2 (30 mg, 118 μmol) in DCM (5.0 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (5 mL). The aqueous layer was extracted with 10 mL of DCM (5 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give intermediate 1i (30 mg) as a white solid. 10 The calculated MS:ES m / z value for H9ClF2N3O2 is [M+H]. + 276.0, the actual measured value is 276.0.

[0345] Example A1-j

[0346] Preparation of intermediate 1j

[0347] A mixture of 6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxynitrile (1.5 g, 8.33 mmol) and 1,1-dimethoxy-N,N-dimethyl-methylamine (3.97 g, 33.30 mmol, 4.42 mL, 4 equivalents) in DMF (40 mL) was degassed and purged with N2 (3×) at room temperature. The mixture was stirred at 145 °C for 0.5 h under N2 atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 1j-1 (1.22 g) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.26 (s, 1H), 3.27 (s, 3H), 3.19 (s, 3H), 3.15 (s, 3H), 3.07 (s, 3H).

[0348] The mixture of intermediate 1j-1 (1.22 g, 5.19 mmol) in H2SO4 (75% v / v aqueous solution, 12 mL) was degassed and purged with N2 (3×) at room temperature. The mixture was stirred at 90 °C for 3.5 h under N2 atmosphere. The mixture was cooled to room temperature and diluted with ice-cold water (30 mL). The mixture was filtered and the filter cake was dried directly to give intermediate 1j-2 (0.83 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.74 (br s, 1H), 8.32 (s, 1H), 3.40 (s, 3H), 3.11 (s, 3H).

[0349] At room temperature, POCl3 (516 μL, 5.53 mmol) and N,N-dimethylaniline (585 μL, 4.61 mmol) were added to a solution of intermediate 1j-2 (0.96 g, 4.61 mmol) in toluene (20 mL). The mixture was stirred at 115 °C for 24 h. The reaction mixture was quenched by adding H2O (30 mL) and NaHCO3 (50 mL). The mixture was extracted with DCM (40 mL × 3). The combined organic layers were washed with H2O (40 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give intermediate 1j (0.25 g) as a white solid. MS:ES m / z calculated value of C8H8ClN4O2: [M+H] +227.0, the actual measured value is 226.9.

[0350] Example A2

[0351] Preparation of intermediate 2-1

[0352] A mixture of 5-amino-1,3-dimethylpyrido[3,4-e]pyrimidin-2,4-dione (200 mg, 970 μmol), 1,3-dibromo-2-methylbenzene (291 mg, 1.16 mmol), NaOtBu (280 mg, 2.91 mmol), Pd2(dba)3 (44 mg, 49 μmol), and BINAP (36 mg, 58 μmol) in toluene (6 mL) was degassed and purged three times with N2. The mixture was then stirred at 110 °C for 16 h under N2 atmosphere. After completion, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was milled three times with EtOAc at 15 °C to give intermediate 2-1 (300 mg, crude product) as a white solid. 16 H 16 The calculated MS:ES m / z value of BrN4O2 is [M+H]. + 375.0, the actual measured value is 374.9.

[0353] The intermediates shown in Table A-1 are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 2-1.

[0354] Table A-1

[0355] Example A2-a

[0356] Preparation of intermediate 2a-1

[0357] Hydrochloric acid (12 M, 2.1 μL) was added to a solution of intermediate 1a (60 mg, 250 μmol) and 3-bromo-2-methylaniline (62 μL, 501 μmol) in isopropanol (iPrOH, 0.5 mL). The mixture was stirred at 90 °C for 12 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 2a-1 (65 mg) as a white solid. 17 H 18 The calculated MS:ES m / z value of BrN4O2 is [M+H]. +389.1, the actual measured value is 389.0.

[0358] The intermediates shown in Table A-1a are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 2a-1.

[0359] Table A-1a

[0360] Example A2-b

[0361] Preparation of intermediate 2b-1

[0362] A mixture of intermediate 1b-4 (260 mg, 885.47 μmol, 1 equivalent), 3-bromo-2-methylaniline (197.69 mg, 1.06 mmol, 130.92 μL, 1.2 equivalent), and DIEA (572.20 mg, 4.43 mmol, 771.16 μL, 5 equivalent) in i-PrOH (3 mL) was stirred at 90 °C for 48 h under N2 atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography. The crude product was milled twice with MeOH at 25 °C. Intermediate 2b-1 (140 mg) was given as a white solid. 17 H 15 The calculated MS:ES m / z value of BrF3N4O2 is [M+H]. + 443.0, the actual measured value is 442.9.

[0363] The intermediates shown in Table A-1b are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 2b-1.

[0364] Table A-1b

[0365] Example A2-c

[0366] Preparation of intermediate 2c-1

[0367] HATU (243 mg, 639 μmol) was added to a solution of intermediate 1e (110 mg, 426 μmol), 3-bromo-2-methylaniline (63 μL, 511 μmol), and DIEA (148 μL, 852 μmol) in DMF (1 mL). The mixture was stirred at 25 °C for 16 h. The reactants were quenched by adding H₂O (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 2c-1 (70 mg) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 11.13 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.22 (t, J = 8.0Hz, 1H), 6.70 (t, J = 54.0Hz, 1H), 3.52 (s, 3H), 3.31 (s, 3H), 2.36 (s, 3H).

[0368] The intermediates shown in Table A-1c are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 2c-1.

[0369] Table A-1c

[0370] Example A2-d

[0371] Preparation of intermediates 2a-4a

[0372] At 0 °C, pyridine (285 μL, 3.53 mmol) and Tf₂O (291 μL, 1.76 mmol) were added to a solution of intermediate 2a-4 (0.45 g, 1.18 mmol) in DCM (5.0 mL). The mixture was stirred at 20 °C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give intermediate 2a-4a as a yellow solid. 1HNMR (400MHz, DMSO-d6) δ = 11.94 (s, 1H), 8.89 (d, J = 8.4Hz, 1H), 7.58 (t, J= 8.4Hz, 1H), 7.34 (d, J = 8.4Hz, 1H), 7.19 (s, 1H), 6.96 (t, J = 54.4Hz,1H), 3.55 (s, 3H), 3.35 (s, 3H).

[0373] Example A3

[0374] Preparation of intermediate 3-1

[0375] The mixture of intermediate 2-1 (150 mg, crude), Pin2B2 (203 mg, 800 µmol), KOAc (118 mg, 1.20 mmol), and Pd(dppf)Cl2 (23 mg, 32 µmol) in dioxane (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 16 h under N2 atmosphere. The mixture was filtered. The filtrate was directly concentrated. The residue was purified by rapid silica gel chromatography to give intermediate 3-1 (168 mg) as a white solid. 22 H 28 The calculated MS:ES m / z value for BN4O4 is [M+H]. + 423.2, the actual measured value is 423.1.

[0376] The intermediates shown in Table A-2 are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 3-1.

[0377] Table A-2 :

[0378] Example A4

[0379] Preparation of intermediate 4

[0380] A mixture of 6-chloro-2-methoxynicotinaldehyde (1.5 g, 8.74 mmol), (3-bromo-2-chlorophenyl)boronic acid (2.06 g, 8.74 mmol), K₂CO₃ (3.62 g, 26.23 mmol), and Pd(PPh₃)₄ (1.01 g, 874 µmol) in dioxane (30 mL) and H₂O (3 mL) was degassed and purged three times with N₂. The mixture was then stirred at 95 °C for 3 h under N₂ atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel extraction to give intermediate 4 (2.24 g) as a white solid. C 13 H 10 The calculated MS:ES m / z value for BrClNO2 is [M+H]. + 326.0, the actual measured value is 325.7.

[0381] The intermediates shown in Table A-2a are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 4-1.

[0382] Table A-2a

[0383] Example A5

[0384] Preparation of intermediate 5-1

[0385] Intermediate 4 (263 mg, 805.33 μmol, 1 equivalent) and ethyl piperidine-4-carboxylate (379.82 mg, 2.42 mmol, 372.37 μL, 3 equivalents) were added to a solution of DCM (3 mL) and i-PrOH (3 mL) along with AcOH (193.45 mg, 3.22 mmol, 184.41 μL, 4 equivalents) and borane; 2-methylpyridine (344.56 mg, 3.22 mmol, 4 equivalents). The mixture was stirred at 25 °C for 3 h. LCMS showed that intermediate 4 was completely consumed and 50% by mass was detected. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (ISCO) ® 4g SepaFlash ® Purification was performed using a rapid silica column elution with a gradient of 0%–37% EA / PE at 50 mL / min. Intermediate 5-1 (311 mg, 418.85 μmol, 52.01% yield, 63% purity) was obtained as a yellow oil. 21 H 24The calculated MS:ES m / z value of BrClN2O3 is [M+H]. + 467.07, the actual measured value is 467.0.

[0386] The intermediates shown in Table A-3 are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of intermediate 5-1.

[0387] Table A-3

[0388] Example A6

[0389] Preparation of intermediate 6

[0390] 3-chloro-1-methoxy-5,6-dihydro-7 H A mixture of cyclopentano[c]pyridin-7-one (7.0 g, 35 mmol), Pin2B2 (18 g, 71 mmol), AcOK (10.4 g, 106 mmol), and PdCl2(dtbpf) (1.15 g, 1.77 mmol) in dioxane (70 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 16 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was milled at 15 °C with a mixture of methyl tert-butyl ether and ethyl acetate (MTBE:EA = 3:1) for 16 h to give intermediate 6-1 (15 g, crude product), a black oil, which can be used in the next step without further purification.

[0391] The mixture of intermediate 6-1 (15.00 g), 1,3-dibromo-2-chlorobenzene (23.5 g, 87.0 mmol), K₂CO₃ (18.0 g, 130 mmol), and Pd(dppf)Cl₂ (3.18 g, 4.35 mmol) in dioxane (150 mL) was degassed and purged three times with N₂. The mixture was then stirred at 100 °C for 12 h under N₂ atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by rapid silica gel chromatography to give intermediate 6 (5 g) as a brown solid. 15 H 12 The calculated MS:ES m / z value for BrClNO2 is [M+H]. + 352.0, the actual measured value is 352.0.

[0392] Example A7

[0393] Preparation of intermediate 10B-1

[0394] A mixture of intermediate 6 (3 g, 8.52 mmol), ethyl piperidine-4-carboxylate (6.54 mL, 42.54 mmol), and 4A molecular sieve (3 g) in EtOH (60 mL) was adjusted to pH 5–6 and stirred at 80 °C for 16 h. Then, NaBH3CN (1.60 g, 25.50 mmol, 3 equivalents) was added to the mixture, and the mixture was stirred at 80 °C for 24 h. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative HPLC to give intermediate 10 (1.7 g, 96% purity) as a yellow oil. 23 H 27 The calculated MS:ES m / z value of BrClN2O3 is [M+H]. + 493.1, the measured value is 493.1.

[0395] The mixture of intermediate 10 (1.7 g, 3.44 mmol) was separated by SFC to obtain intermediate 10A (790 mg, 99% purity), a yellow oil, and intermediate 10B (750 mg, yield, 99% purity), also a yellow oil. Under analytical SFC conditions (column: Chiral NS-3 100 × 4.6 mm inner diameter, 3 µm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: 5% to 40% B over 2 min and hold at 40% for 1 min, then hold at 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 35 °C; ABPR: 1500 psi), the retention time of intermediate 10A was 2.33 min, and the retention time of intermediate 10B was 2.57 min.

[0396] Intermediate 10B (6 mg) and 15 μL of HCl (1 mol / L in water) were dissolved in 400 μL of methanol and kept in a 4 mL vial. The solution was slowly evaporated at room temperature. Crystals of intermediate 10B-1 were observed the next day. The HCl salt crystals of intermediate 10B-1 were colorless, plate-like crystals with the following dimensions: 0.20 × 0.15 × 0.02 mm. 3The symmetry of the crystal structure is assigned to the orthorhombic space group P212121 with the following parameters: a = 7.5631(2) Å, b = 7.7926(2) Å, c = 35.4625(8) Å, α = 90°, β = 90°, γ = 90°, V = 2090.03(9) Å. 3 Z = 4, Dc = 1.596 g / cm³ 3 , F(000) = 1024.0, μ(CuKα) = 5.252mm -1 And T = 149.99(10) K. Figure 1A The absolute configuration of the chloride salt of intermediate 10B-1 is shown, and Figure 1B The ORTEP crystal structure of this chloride salt is shown.

[0397] Example A8

[0398] Preparation of intermediates 11A and 11B

[0399] A solution of intermediate 6 (2 g, 5.67 mmol) and (1R,5S,6R)-rel-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (1.76 g, 11.34 mmol) in EtOH (22 mL) was stirred at 85 °C for 16 h. Once the mixture was cooled to 25 °C, NaBH3CN (1.07 g, 17.02 mmol) was added. The mixture was heated to 85 °C and stirred for 32 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography to give intermediate 11 (2.2 g) as a colorless oil. 23 H 25 The calculated MS:ES m / z value of BrClN2O3 is [M+H]. + 491.1, the actual measured value is 490.9.

[0400] Intermediate 11 was purified by SFC to obtain intermediate 11A (980 mg), a colorless oil, and intermediate 11B (970 mg), also a colorless oil. Under analytical SFC conditions (column: Chiralpak OJ-3 50 × 4.6 mm inner diameter, 3 µm; mobile phase: A: CO2, B: isopropanol (0.05% DEA); gradient: 5% to 40% B over 2.5 min and hold at 40% for 0.5 min, then hold at 5% B for 1 min; flow rate: 4.0 mL / min; column temperature: 35 °C; ABPR: 1500 psi), the retention time of intermediate 11A was 1.24 min, and the retention time of intermediate 11B was 1.55 min.

[0401] Example A9

[0402] Preparation of intermediate 12

[0403] At 0 °C, CH3NO2 (2.54 mL, 46.9 mmol) was added to a solution of 6-chloro-4-iodo-2-methoxynicotinaldehyde (9.20 g, 30.9 mmol) and TEA (12.9 mL, 92.8 mmol) in DCM (180 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding H2O (150 mL) and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give intermediate 12-1 (5.17 g) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ = 7.49 (s, 1H), 5.74 (dd, J = 3.6, 10.8Hz, 1H), 4.89–4.77 (m, 2H), 4.51 (dd, J = 3.6, 12.4Hz, 1H), 4.07 (s, 3H).

[0404] At 0 °C, methanesulfonyl methanesulfonate (3.77 g, 21.63 mmol) was added to a solution of intermediate 12-1 (5.17 g, 14.42 mmol) and TEA (6.02 mL, 43.3 mmol) in DCM (120 mL). After degassing the mixture and purging with N2 (3×), the mixture was stirred at 20 °C for 12 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to give intermediate 12-2 (2.5 g) as a yellow solid. 1¹H NMR (400MHz, chloroform-d) δ = 8.25 (dd, J = 2.0, 13.6Hz, 1H), 8.00 (dd, J = 1.6, 13.2Hz, 1H), 7.60 (d, J = 2.0Hz, 1H), 4.12 (d, J = 2.0Hz, 3H).

[0405] At 0 °C, HOAc (7.06 mL, 123.35 mmol) and NaBH4 (1.22 g, 32.3 mmol) were added to a solution of intermediate 12-2 (4.2 g, 12.3 mmol) in THF (110 mL). The resulting suspension was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give intermediate 12-3 (4.0 g) as a yellow solid. MS:ES m / z calculated value of C8H9ClIN2O3: [M+H] + 342.9, actual measured value is 342.8; 1 ¹H NMR (400MHz, chloroform-d) δ = 7.32 (s, 1H), 4.47–4.40 (m, 2H), 3.89 (s, 3H), 3.43–3.37 (m, 2H).

[0406] At room temperature, Fe (3.26 g, 58.4 mmol) and NH4Cl (3.12 g, 58.4 mmol) were added to a solution of intermediate 12-3 (4.0 g, 11.7 mmol) in MeOH (100 mL) and H2O (60 mL). The mixture was stirred at 80 °C for 16 hours under a N2 atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give intermediate 12-4 (2.5 g) as a white solid. C8H 11 The calculated MS:ES m / z value of ClIN2O is [M+H]. + 313.0, actual measured value is 312.8; 1 H NMR (400MHz, DMSO-d6) δ = 8.43-7.72 (m, 1H), 7.59 (s,1H), 7.45-6.38 (m, 1H), 3.87 (s, 3H), 3.01-2.96 (m, 2H), 2.86-2.81 (m, 2H).

[0407] A mixture of intermediate 12-4 (2.5 g, 8.00 mmol), Pd(OAc)2 (180 mg, 800 μmol), Na2CO3 (2.12 g, 20.0 mmol), and DABCO (176 μL, 0.60 mmol) in CH3CN (150 mL) was degassed and purged with N2 (3×) at room temperature. The mixture was stirred at 60 °C for 16 h under a CO (50 PSI) atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give intermediate 12-5 (1.1 g) as a yellow solid. C9H 10 The calculated MS:ES m / z value for ClN2O2 is [M+H]. + 213.04, actual measured value is 212.9; 1 H NMR (400MHz, DMSO-d6) δ = 8.32 (s, 1H), 7.31 (s, 1H), 3.92 (s, 3H), 3.38 (dt, J = 2.8, 6.8 Hz, 2H), 2.76 (t, J = 6.8Hz, 2H).

[0408] At room temperature, BH3-Me2S (10M, 1.03mL) was added to a solution of intermediate 12-5 (1.1g, 5.17mmol) in THF (40mL). The mixture was stirred at 40°C for 16 hours. The reaction mixture was quenched at 25°C by adding 10mL of MeOH and concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography to give intermediate 12-6 (100mg) as a white solid. C9H 12 The calculated MS:ES m / z value for ClN2O is [M+H]. + 199.06, the actual measured value is 199.0.

[0409] At 25 °C, borane-2-methylpyridine (162 mg, 1.51 mmol) was added to a solution of intermediate 12-6 (100 mg, 503 μmol), methyl 4-(2-oxoethyl)norbornane-1-carboxylate (99 mg, 503 μmol), and AcOH (1 mL, 17.5 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding H₂O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography to give intermediate 12 (200 mg) as a yellow oil.20 H 28 The calculated MS:ES m / z value for ClN2O3 is [M+H]. + 379.2, the actual measured value is 379.1.

[0410] Preparation of compounds

[0411] Example 1

[0412] Preparation of compound A-1

[0413] Intermediate 3-1 (115.00 mg, 245.84 μmol, 1 equivalent), intermediate 5-1 (103.81 mg, 245.84 μmol, 1 equivalent), K2CO3 (101.93 mg, 737.52 μmol, 3 equivalent), and di-tert-butyl(cyclopentyl)phosphine; palladium dichloride; iron (16.02 mg, 24.58 μmol, 0.1 equivalent) in dioxane (2 mL) and H2O (0.2 mL) were degassed and purged three times with N2. The mixture was then stirred at 100 °C for 2 h under N2 atmosphere. LCMS showed a detection of 62% by mass. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (ISCO) ® 4g SepaFlash ® Purification was performed using a rapid silica column elution with a gradient of 0%–27% EA / PE at 50 mL / min. Compound A-1 (180 mg, 213.41 μmol, 86.81% yield, 81% purity) was obtained as a yellow solid. 37 H 39 The calculated MS:ES m / z value for ClN6O5 is [M+H]. + 683.27, the actual measured value is 683.4.

[0414] The compounds shown in Table 1 below are prepared using suitable starting materials via a similar reaction scheme as that used for the preparation of compound A-1.

[0415] Table 1

[0416] Example 2

[0417] Preparation of compound B-1

[0418] Intermediate 3-1 (97.49 mg, 230.85 μmol, 1.2 equivalents), intermediate 10-B (95.00 mg, 192.38 μmol, 1 equivalent), K₂CO₃ (79.76 mg, 577.13 μmol, 3 equivalents), and di-tert-butyl(cyclopentyl)phosphine; palladium dichloride; iron (12.54 mg, 19.24 μmol, 0.1 equivalents) were degassed in a mixture of dioxane (3 mL) and H₂O (0.3 mL) and purged with N₂ (3×). The mixture was stirred at 100 °C for 5 h under N₂ atmosphere. LCMS showed detection of approximately 90% of the desired compound. The mixture was filtered. The filtrate was directly concentrated. The residue was subjected to rapid silica gel chromatography (ISCO). ® 4g SepaFlash ® Purification was performed using a rapid silica column elution with a 0%–100% EA / PE gradient at 40 mL / min. Compound B-1 (110 mg, 136.49 μmol, 70.95% yield, 88% purity) was obtained as a brown oil. 39 H 41 The calculated MS:ES m / z value for ClN6O5 is [M+H]. + 709.28, the actual measured value is 709.4.

[0419] The compounds shown in Table 2 below are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of compound B-1.

[0420] Table 2

[0421] Example 3

[0422] Preparation of compound C-1

[0423] Compound A-1 (160 mg, 234 µmol) and LiOH were added. A mixture of H2O (49 mg, 1.2 mmol) in THF (8 mL) and H2O (4 mL) was stirred at 45 °C for 3 h. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to give compound C-1 (37 mg, 99.95% purity) as a white solid. 1 H NMR (400MHz, DMSO- d6 ) δ= 11.12 (s, 1H), 8.38-8.26 (m, 2H), 7.76 (br d, J = 7.5Hz, 1H), 7.69-7.61 (m,1H), 7.51 (br t, J = 7.6Hz, 1H), 7.40-7.25 (m, 3H), 6.95 (br d, J = 7.1Hz,1H), 6.82-6.70 (m, 1H), 3.90 (s, 3H), 3.47 (s, 6H), 2.87-2.61 (m, 4H), 2.35-2.23 (m, 1H), 2.16-2.05 (m, 5H), 1.80 (br d, J = 10.1Hz, 2H), 1.66-1.53 ​​(m,2H); C 35 H 36 The calculated MS:ES m / z value for ClN6O5 is [M+H]. + 655.2, the actual measured value is 655.2.

[0424] Example 4

[0425] Preparation of compound C-2

[0426] The mixture of compound B-1 (100 mg, 141 μmol), LiOH·H₂O (30 mg, 705 μmol), and H₂O in THF (5 mL) and H₂O (1 mL) was degassed and purged three times with N₂. The mixture was then stirred at 45 °C for 2 h under N₂ atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified preparatively to give compound C-2 (46 mg, 100% purity) as a white solid. 1 H NMR (400MHz, DMSO- d 6) δ = 11.12 (s, 1H), 8.35-8.26 (m, 2H), 7.66-7.60(m, 1H), 7.50 (t, J = 7.6Hz, 1H), 7.38-7.27 (m, 2H), 7.19 (s, 1H), 6.98-6.92(m, 1H), 6.78 (d, J = 6.0Hz, 1H), 4.27 (br d, J = 6.0Hz, 1H), 3.90 (s, 3H), 3.48 (s, 3H), 3.28-3.25 (m, 3H), 3.01-2.93 (m, 1H), 2.82-2.71 (m, 2H), 2.66-2.60 (m, 1H), 2.32 (br t, J = 10.5Hz, 1H), 2.23-2.12 (m, 3H), 2.10 (br d, J =6.9Hz, 3H), 2.07-1.99 (m, 1H), 1.81-1.69 (m, 2H), 1.59-1.39 (m, 2H); C 37 H 38 The calculated MS:ES m / z value for ClN6O5 is [M+H]. + The measured value is 681.3.

[0427] The compounds shown in Table 3 below are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of compound C-2.

[0428] Table 3

[0429] Example 5

[0430] Preparation of compound D-1

[0431] A mixture of compound A-4 (40 mg, 53 μmol) in HCl (1 mL) and HOAc (1 mL) was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give compound D-1 (25 mg) as a white solid. 34 H 32 The calculated MS:ES m / z value for Cl2F2N7O5 is [M+H]. + 726.2, actual measured value is 726.1; 1H NMR (400MHz, DMSO-d6) 1H NMR (400MHz, DMSO-d6) δ = 11.77 (s, 1H), 8.60 (d,J = 8.4Hz, 1H), 7.78 (d, J = 7.2Hz, 1H), 7.70 (dd, J = 1.2, 7.6Hz, 1H), 7.55(dt, J = 3.6, 8.0Hz, 2H), 7.46-7.40 (m, 1H), 7.27 (dd, J = 7.6, 17.6Hz, 2H), 6.86 (t, J = 52.0Hz, 1H), 3.91 (s, 3H), 3.54 (s, 3H), 3.47 (s, 2H), 3.36-3.35(m, 3H), 2.80 (br d, J = 11.2Hz, 2H), 2.27-2.16 (m, 1H), 2.08 (br t, J =10.8Hz, 2H), 1.84-1.75 (m, 2H), 1.64-1.53 ​​(m, 2H).

[0432] The compounds shown in Table 4 below are prepared using appropriate starting materials via a similar reaction scheme as that used for the preparation of compound D-1.

[0433] Table 4

[0434] Example A

[0435] LCMS (Liquid Chromatography / Mass Spectrometry)

[0436] High-performance liquid chromatography (HPLC) measurements are performed using an LC pump, diode array (DAD) or UV detector and column as specified in the corresponding method. Additional detectors may also be included if necessary (see the table below for methods). The liquid stream from the column is carried to a mass spectrometer (MS) equipped with an atmospheric pressure ion source. Tuning parameters (e.g., scan range, residence time) are set to obtain ions with a nominal monoisotopic molecular weight (MW) that allows identification of the compound, to the knowledge of a person skilled in the art. Data acquisition is performed using appropriate software. The compound is described by its experimental retention time (Rt) and ion. If no different specification is given in the data table, the reported molecular ion corresponds to [M+H]. + (Protonated molecules) and / or [MH] - (Deprotonated molecules). In cases where the compound cannot be directly ionized, specify the type of adduct (i.e., [M+NH4)). + [M+Na] + [M+HCOO] - (etc.). For molecules with multiple isotopic modes (Br, CI), the reported values ​​are those obtained for the lowest isotopic mass. All results are obtained with experimental uncertainties typically associated with the methods used. In the following text, “SQD” means single quadrupole detector, “MSD” means mass-selected detector, “RT” means room temperature, “BEH” means bridged ethylsiloxane / silica hybrid, “DAD” means diode array detector, “HSS” means high-intensity silica, “Q-Tof” means quadrupole time-of-flight mass spectrometer, “CLND” means nitrogen chemiluminescence detector, and “ELSD” means evaporative light scattering detector.

[0437] Table A: LCMS Method Code

[0438] Flow rate is expressed in mL / min; column temperature (T) is expressed in °C; run time is expressed in min.

[0439]

[0440] Example A-1

[0441] NMR (Nuclear Magnetic Resonance)

[0442] Use CDCL3 (deuterated chloroform) or DMSO- d 6 Using deuterated DMSO (dimethyl-d6-sulfoxide) as a solvent, protons were recorded on a Bruker spectrometer operating at 400 MHz. 1H) NMR spectra. Chemical shifts (d) relative to tetramethylsilane (TMS) used as an internal standard are reported in parts per million (ppm).

[0443] Compound D-4 : 1 H NMR (400MHz, DMSO-d6) δ = 11.77 (s, 1H), 8.60 (d, J =8.0Hz, 1H), 8.50 (s, 1H), 7.77 (br d, J = 7.2Hz, 1H), 7.62 (t, J = 7.6Hz, 1H), 7.58-7.51 (m, 2H), 7.26 (d, J = 6.8Hz, 1H), 6.85 (t, J = 54.0Hz, 1H), 3.99 (s, 3H), 3.83-3.80 (m, 2H), 3.54 (s, 3H), 3.32 (s, 3H), 2.98-2.96 (m,2H), 2.35-2.01 (m, 3H), 1.85-1.82 (m, 2H), 1.71-1.53 ​​(m, 2H).

[0444] Compound D-12 : 1 H NMR (400MHz, DMSO-d6) δ = 12.09 (d, J = 2.4Hz, 1H), 8.89(dd, J = 1.6, 8.4Hz, 1H), 8.53 (s, 1H), 7.68 (td, J = 2.0, 8.0Hz, 1H), 7.56-7.47 (m, 3H), 7.42 (dd, J = 1.6, 7.6Hz, 1H), 7.21-6.89 (m, 3H), 4.30-4.21 (m,1H), 3.91 (s, 3H), 3.78 (s, 3H), 3.01-2.92 (m, 1H), 2.84-2.71 (m, 2H), 2.61-2.63 (m, 1H), 2.34-2.27 (m, 1H), 2.22-2.09 (m, 3H), 2.08-1.99 (m, 1H), 1.81-1.72 (m, 2H), 1.57-1.40 (m, 2H).

[0445] Compound D-14 : 1H NMR (400MHz, DMSO-d6) δ = 11.83 (d, J = 2.0Hz, 1H), 8.79(dd, J = 1.2, 8.4Hz, 1H), 7.68 (td, J = 2.0, 7.6Hz, 1H), 7.54 (t, J = 7.6Hz,1H), 7.48 (t, J = 8.0Hz, 1H), 7.41 (dd, J = 1.6, 7.6Hz, 1H), 7.20 (s, 1H),7.14-6.82 (m, 3H), 4.29-4.26 (m, 1H), 3.91 (s, 3H), 3.55 (s, 3H), 3.41 (s,3H), 3.02-2.93 (m, 1H), 2.80-2.62 (m, 3H), 2.35-2.29 (m, 1H), 2.21-2.02 (m,4H), 1.78-1.75 (m, 2H), 1.55-1.41 (m, 2H)。

[0446] Compound D-20 : 1 H NMR (400MHz, DMSO-d6) δ = 11.82 (d, J = 1.6Hz, 1H), 8.78(dd, J = 1.2, 8.4Hz, 1H), 7.66 (td, J = 1.6, 7.6Hz, 1H), 7.53 (t, J = 7.6Hz,1H), 7.47 (t, J = 8.0Hz, 1H), 7.41 (dd, J = 1.6, 7.6Hz, 1H), 7.20 (s, 1H),7.13-6.80 (m, 3H), 4.27 (t, J = 4.8Hz, 1H), 3.91 (s, 3H), 3.54 (s, 3H), 3.33(s, 3H), 3.00-2.98 (m, 1H), 2.89-2.87 (m, 1H), 2.80-2.71 (m, 3H), 2.56-2.52(m, 1H), 2.08-2.00 (m, 2H), 1.84-1.78 (m, 2H), 1.74-1.70 (m, 1H)。

[0447] Example B

[0448] PDL1 / PD1 binding assay

[0449] The compound to be tested was serially diluted in DMSO and further diluted in assay buffer (25 mM psi, pH 7.4, 150 mM NaCl, 0.005% Tween 20, BSA 0.01%). The diluted compound was added to the wells, with a final DMSO concentration of 1%. PDL1-6xHis protein was added to the wells and thoroughly mixed with the compound. The plate was incubated at room temperature for 30 min. PD1-Fc-Avi-Biotin protein was added to the wells. The final concentrations of PDL1 and PD1 protein were 0.3 nM and 2.5 nM, respectively. After a binding time of 30 min at room temperature, anti-6xHis receptor beads (final concentration 20 μg / mL) were added to the wells, and incubation continued for 1 h. Streptavidin donor beads (final concentration 20 μg / mL) were added under dim light. Before reading on an Envision microplate reader, the plate was sealed with foil and incubated in the dark for another 1 h or overnight. IC was determined by fitting a curve using a four-parameter equation in GraphPad Prism 8. 50 value.

[0450] Example C

[0451] PD-1 / PD-L1 NFAT reporter assay

[0452] The cellular activity of the compound was assessed using a co-culture reporter assay, in which PD-1 was constitutively inhibited by CHO cells expressing PD-L1 conjugation to TCR-mediated NFAT activity in Jurkat T cells. Blocking the PD-1 / PD-L1 interaction released the inhibitory signal and induced TCR signaling and NFAT-mediated luciferase activity.

[0453] CHO cells expressing surface-bound anti-CD3 antibody and PD-L1 were first seeded overnight and treated with the compound. Jurkat cells overexpressing PD-1 and a luciferase construct under the NFAT promoter were then immediately seeded onto a monolayer of CHO cells. The co-cultures were then incubated at 37°C for 6 h. Luciferase activity was assessed by adding ONE-Glo reagent and measuring luminescence using a microplate reader. EC50 was determined by fitting a dose-response curve. 50 value.

[0454] The compounds described herein, as illustrated by examples in the embodiments, exhibit EC values ​​within the following ranges. 50 or IC 50 Value: A: IC 50 or EC 50 ≤10nM; B: 10nM < IC 50 or EC 50 ≤100nM; C: 100nM < IC50 or EC 50 ≤1000nM; D: 1000nM < IC 50 or EC 50 ≤10000nM; E: IC 50 or EC 50 > 10000nM; nd = undetermined; nr = EC 50 The test concentration range of 1 nM to 5000 nM was not reached.

[0455]

[0456] Furthermore, although the foregoing has provided some detailed description by way of illustration and example for the purpose of clarity and understanding, 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 this disclosure.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: (I) in: A 1 for , , , or ; B 1 for , , or ; X 1 Selected from CH, C-halogenated groups and N; X 2 Selected from CH, C-halogenated groups and N; X 3 Selected from CH, C-halogenated groups, N and C-OR Z1 ; Y 1 Selected from CH, C-halogenated groups and N; Y 2 Selected from CH, C-halogenated groups and N; R 1a Selected from -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 -CH2 (4- to 6-membered monocyclic heterocyclic groups) and -CH2 (5- to 6-membered monocyclic heteroaryl groups); R 1b Selected from -R x1 and -N(R) m1 )R n1 ; R x1 Selected from , , , , , , , and ;where R x1 Optionally substituted with one or two substituents, wherein the one or two substituents are independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Halogenated alkoxy groups, -C(=O)OR Z1 -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z1 )R Z3 and -N(R) Z1 )S(=O)2N(R Z2 )R Z3 ; R m1 Selected from -C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl groups, 4- to 7-membered monocyclic heterocyclic groups, 8- to 11-membered fused heterocyclic groups, and -R x2 The 4- to 7-membered monocyclic heterocyclic groups and the 8- to 11-membered fused heterocyclic groups contain at least one atom or group of atoms, wherein the at least one atom or group of atoms is independently selected from O (oxygen), S (sulfur), C (=O), S (=O), S (=O)2, and N (nitrogen); wherein the -C 1-4 Alkyl groups are replaced by -C(=O)OR Z1 Replace, and the -C 1-4 The alkyl group is optionally substituted, optionally substituted by one, two, or three substituents, said substituents being independently selected from halogens, cyano groups, hydroxyl groups, and -C groups. 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z2 )R Z3 and -N(R) Z1 )S(=O)N(R Z2 )R Z3 ; wherein C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl groups, the 4- to 7-membered monocyclic heterocyclic groups, and the 8- to 11-membered fused heterocyclic groups are -C(=O)OR Z1 Replacement, and the C 3-6 Monocyclic cycloalkyl, the C 5-12 The bicyclic cycloalkyl group, the 4- to 7-membered monocyclic heterocyclic group, and the 8- to 11-membered fused heterocyclic group are optionally substituted by one, two, or three substituents, which are independently selected from halogens, cyano groups, and -C groups. 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 , -C(=O)N(R Z1 )R Z2 , -S(=O)₂R Z3 , -S(=O)₂N(R Z1 )R Z2 , -N(R Z1 )C(=O)R Z3 , -N(R Z1 )S(=O)R Z3 , -N(R z1 )C(=O)N(R Z2 )R Z3 and -N(R Z1 )S(=O)N(R Z2 )R Z3 ; R x2 Selected from , , , and ; Each R X3 -C(=O)OR Z1 ; R n1 Selected from hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 Monocyclic cycloalkyl) and -C(=O)OR Z4 ; R 1c Selected from hydrogen, halogens, -OH, -CN, -CH3, -C 2-4 Alkyl and -C 2-4 Halogenated alkyl groups; R 1d Selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1e Selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1f Selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1g Selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1h Selected from hydrogen, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1i R 1j R 1k R 1l R 1m and R 1n Each is independently selected from hydrogen and -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 1p Selected from -CH3, -C 2-4 Alkyl and -R 1p1 , where R 1p -CH3 or -C 2-4 When alkyl, the -CH3 and the -C 2-4 Alkyl groups are replaced by -C(=O)OR Z1 Replacement, and the -CH3 and the -C 2-4 The alkyl group is optionally substituted with one or two substituents, said one or two substituents being independently selected from halogens, cyano groups, and -C groups. 1-4 Alkyl, hydroxyl, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Halogenated alkoxy group, -C(=O)NHS(=O)2R Z3 -C(=O)N(R) Z1 )R Z2 -S(=O)2R Z3 -S(=O)2N(R) Z1 )R Z2 -N(R) Z1 )R Z2 -N(R) Z1 )C(=O)R Z3 -N(R) Z1 )S(=O)R Z3 -N(R) Z1 )C(=O)N(R Z2 )R Z3 and -N(R) Z1 )S(=O)2N(R Z2 )R Z3 ; R 1p1 Selected from , , and ; R 1q Independently selected from hydrogen, -C 1-4 Alkyl and -C 1-4 Halogenated alkyl groups; R 2a R 2b R 2c R 2e R 2g and R 2h Each is independently selected from hydrogen and halogens; R 2d and R 2f Each is independently selected from hydrogen, halogen, cyano, -CH3, -CH2CH3, -CH2OH, -OCH3 and -SCH3; R 3a Selected from hydrogen, -CH3, -C 2-4 Alkyl and -C 2-4 Halogenated alkyl groups; R 3b Selected from hydrogen, -CH3, -C 2-4 Alkyl, -C 2-4 Halogenated alkyl groups and -C 1-4 Alkoxy; wherein R 3b Optionally substituted with one or two substituents, said one or two substituents being independently selected from halogens, -OH, -CN, -CH3, -C 2-4 Alkyl, -C 2-4 Halogenated alkyl groups, -CH2CH2OH and -CH2CH2OC 1-4 Halogenated alkyl groups; R 3c Selected from hydrogen, halogens, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; R 4a Selected from hydrogen, -CH3, -C 2-4 Alkyl and -C 2-4 Halogenated alkyl groups; R 4b Selected from hydrogen, halogens, -C 1-4 Alkyl, -C 1-4 Halogenated alkyl groups, -OH, -NH2, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl, wherein R 4b Optionally substituted with one or two substituents, said one or two substituents being independently selected from halogens, -OH, -CN, -CH3, -C 2-4 Alkyl, -C 2-4 Halogenated alkyl groups, -CH2CH2OH and -CH2CH2O-C 1-4 Halogenated alkyl groups; R 4c Selected from hydrogen, halogens, -C 1-2 Alkyl and -C 1-2 Halogenated alkyl groups; m1, m2 and m3 are each independently 1 or 2; m4 is 0, 1, or 2; m5 can be 1, 2, 3, or 4; n1 is independently 0, 1, or 2; and R Z1 R Z2 R Z3 and R Z4 Each is independently selected from hydrogen and -C 1-4 Alkyl and -C 1-4 Halogenated alkyl groups.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A 1 for .

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 2 For CH.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X 3 For CH.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X 3 Let N be the number of elements in the array.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1a -C 1-4 alkyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1a It is -CH3.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1q It is hydrogen.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1b -R x1 .

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein -R x1 for .

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein -R x1 for or .

13. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein -R x1 for .

14. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1b -N(R) m1 )R n1 .

15. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R n1 It is hydrogen.

16. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein R m1 -R x2 .

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A 1 for .

18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

19. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein X 2 For CH.

20. The compound according to any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, wherein R 1a -C 1-4 alkyl.

21. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 1a It is -CH3.

22. The compound according to any one of claims 16 to 20, or a pharmaceutically acceptable salt thereof, wherein R 1c R 1d R 1e and R 1f Each is hydrogen.

23. The compound according to any one of claims 16 to 21, or a pharmaceutically acceptable salt thereof, wherein R 1b -R x1 .

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein -R x1 for .

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein -R x1 for or .

26. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein -R x1 for .

27. The compound according to any one of claims 16 to 21, or a pharmaceutically acceptable salt thereof, wherein R 1b -N(R) m1 )R n1 .

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R n1 It is hydrogen.

29. The compound according to claim 27 or 28, or a pharmaceutically acceptable salt thereof, wherein R m1 -R x2 .

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A 1 for .

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

32. The compound according to claim 30 or 31, or a pharmaceutically acceptable salt thereof, wherein X 2 For CH.

33. The compound according to any one of claims 30 to 32, wherein R 1i R 1j R 1k R 1l R 1m and R 1n Each is hydrogen.

34. The compound according to any one of claims 30 to 33, wherein R 1p -R 1p1 .

35. The compound according to claim 34, wherein -R 1p1 for .

36. The compound according to claim 35, wherein -R 1p1 for .

37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein B 1 for .

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein Y1 is CH.

39. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein Y1 is N.

40. The compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b Each is -CH3.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 37 to 40, wherein R 3c It is hydrogen.

42. The compound according to any one of claims 37 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3c It is -CH3.

43. The compound according to any one of claims 37 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3c -C 1-2 Halogenated alkyl groups.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 3c It is -CF3.

45. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 3c It is -CHF2.

46. ​​The compound or a pharmaceutically acceptable salt thereof according to embodiment 37, wherein B 1 Choose from the following groups: , , , , , , and .

47. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein B 1 for .

48. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein Y2 is CH.

49. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein R 4a It is -CH3.

50. The compound according to any one of claims 47 to 49, or a pharmaceutically acceptable salt thereof, wherein R 4b It is hydrogen.

51. The compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein R 4c It is hydrogen.

52. The compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein R 4c It is -CH3.

53. The compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein R 4c -C 1-2 Halogenated alkyl groups.

54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein R 4c It is -CF3.

55. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein R 4c It is -CHF2.

56. The compound or a pharmaceutically acceptable salt thereof according to embodiment 47, wherein B 1 Choose from the following groups: , , , , , , and .

57. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 2c R 2e R 2g and R 2h Each is hydrogen.

58. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f Each is a halogen.

59. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2d It is a halogen; and R 2f It is -CH3.

60. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2d It is -CH3; and R 2f It is a halogen.

61. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 58 to 60, wherein the halogen is chlorine.

62. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f Each is -CH3.

63. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or a pharmaceutically acceptable salt of any of the aforementioned.

64. A pharmaceutical composition comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63, and an excipient.

65. A method for treating a subject with hepatitis B, the method comprising administering to the subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63.

66. A method for treating a subject with hepatocellular carcinoma (HCC), the method comprising administering to the subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63.

67. The method according to any one of claims 65 to 66, further comprising administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

68. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63, wherein the compound or a pharmaceutically acceptable salt thereof is used in the treatment of hepatitis B.

69. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63, wherein the compound or a pharmaceutically acceptable salt thereof is used in the treatment of hepatocellular carcinoma (HCC).

70. The compound of any one of claims 68 to 69 or a pharmaceutically acceptable salt thereof, wherein the use further comprises surgical administration, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy or antiviral therapy.

71. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63 in the preparation of a medicament for treating hepatitis B.

72. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 63 in the preparation of a medicament for the treatment of hepatocellular carcinoma (HCC).

73. The use according to any one of claims 71 to 72, wherein the drug is used in combination with surgical, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy or antiviral therapy.

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