Methods and Compositions for Targeting PD-L1

Abstract

The present disclosure relates to compounds that may be useful as inhibitors of PD-1, PD-L1, or the PD-1 / PD-L1 interaction. Also disclosed herein are pharmaceutical compositions that may include a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and uses or methods of using a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the treatment of PD-L1-associated diseases, including, but not limited to, liver disease, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) For example, any and all applications in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application are incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 265,510, filed December 16, 2021.

[0002] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, molecular biology, and medicine. The disclosure relates to compounds that may be useful as inhibitors of PD-1, PD-L1, or PD-1 / PD-L1 interaction. Also disclosed herein are pharmaceutical compositions of the compounds described herein and uses or methods of using the compounds for the treatment of PD-L1 associated diseases, including, but not limited to, liver disease, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B. [Background technology]

[0003] activated CD4 + and CD8 +The programmed cell death 1 (PD-1) immune checkpoint expressed on the surface of T cells controls inhibitory mechanisms to prevent autoimmunity. Engagement of PD-1 by programmed death-ligand 1 (PD-L1), expressed on many cell types including macrophages, dendritic cells, mast cells, and cancer cells, induces T cell exhaustion or apoptosis, resulting in 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). High expression of PD-L1 is exhibited by many types of cancers that escape tumor immune surveillance and is associated with poor prognosis. PD-1-mediated immune suppression is also associated with some viral infections, such as hepatitis B. Summary of the Invention

[0004] There is a continuing need for and improvements in PD-1 / PD-L1 therapies for the treatment of disease.

[0005] Some embodiments disclosed herein relate to a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0006] Some embodiments disclosed herein relate to pharmaceutical compositions that can include an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

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

[0008] Some embodiments disclosed herein relate to methods of inhibiting HBV and / or HDV replication, which may include contacting a cell infected with HBV and / or HDV with an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, for use in inhibiting HBV and / or HDV replication.

[0009] These and other embodiments are described in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 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 malignancies in affected liver cells. HCC has a relatively poor prognosis, with a 5-year survival rate of approximately 30%, depending on whether complete surgical resection of the tumor is possible.

[0011] For early stage disease, surgical resection is employed. However, most HCCs are identified at a later stage due to the difficulty of diagnosis. At the time of late stage diagnosis, the tumor is unresectable and most patients are given systemic therapy. The current standard of care at the frontline is multi-targeted kinase inhibitors (including, for example, sorafenib and / or lenvatinib). Most patients fail these therapies or relapse and receive suboptimal therapy with angiogenesis inhibitors (including, for example, regorafenib, cabozantinib, and / or lamisillumab) or immune checkpoint inhibitors (including, for example, nivolumab and / or pembrolizumab). However, most patients fail first and second therapies, with little clinical benefit and overall survival not exceeding one year. In addition, biomarker-driven therapy is lacking. Therefore, there is a need to develop more tolerable and effective therapies for the treatment of HCC and associated liver damage.

[0012] HBV is a partially double-stranded circular DNA of approximately 3.2 kilobase (kb) pairs and is classified into eight genotypes, A-H. The HBV replication pathway has been studied in great detail. Part of the replication involves the formation of a covalently closed circular DNA (cccDNA) form. The presence of cccDNA creates a risk of re-emergence of the virus over the lifespan of the host organism. HBV carriers can transmit the disease for many years. An estimated 300 million people live infected with the hepatitis B virus, and it is estimated that more than 750,000 people die from hepatitis B annually worldwide. In addition, immunosuppressed individuals or those undergoing chemotherapy are particularly at risk for reactivation of HBV infection. HBV can be acute and / or chronic. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis.

[0013] HBV can be transmitted by blood, semen, and / or other bodily fluids. This can occur through direct blood-to-blood contact, unprotected sex, sharing needles, and can also occur from an infected mother to her newborn during the birth process. HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available drugs do not cure HBV and / or HDV infections. Rather, these drugs suppress the replication of the virus.

[0014] Hepatitis D virus (HDV) is a DNA virus in the Hepadnaviridae family of viruses. HDV can only be transmitted in the presence of HBV. The route of infection of HDV is similar to that of HBV. Infection of HDV can occur either through simultaneous infection with HBV (co-infection) or in addition to chronic hepatitis B or hepatitis B carriage (superinfection). Both superinfection and co-infection with HDV result in more serious complications compared to infection with HBV alone. These complications include a higher likelihood of undergoing liver failure, rapid progression to cirrhosis in acute infections, and an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B, hepatitis D has the highest case fatality rate of 20% of all hepatitis infections. Currently, there is no cure or vaccine for hepatitis D.

[0015] Programmed cell death 1 or programmed 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 helps to negatively regulate immune responses to prevent autoimmune disorders. PD-1 protein (NCBI accession number NP_005009.2) is expressed from the cluster of differentiation (CD279) gene (NCBI accession number NG_012110.1) or mRNA transcript (NCBI accession number NM_005018.3). In some preferred embodiments, PD-1 is human PD-1 protein and CD279 is human CD279 transcript or gene on chromosome 2. It should be understood that those skilled in the art will often consider the terms PD-1 and CD279 nominally interchangeable, given the nucleic acid (DNA or RNA) or corresponding translated protein, or their sequences.

[0016] Programmed cell death ligand 1, or programmed death ligand 1 (PD-L1), also known as B7 homolog 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 primary ligand for PD-1, resulting in inhibition of T cell cytotoxicity and cytokine production. Cancer cells, such as HCC cells, exploit this immune checkpoint by upregulating PD-L1 expression, resulting in dysfunctional antitumor immunity by proximal T cells. Viruses have also been observed to modulate the PD-1 / PD-L1 pathway to inhibit immune host responses. Hepatitis B virus has been shown to upregulate PD-L1 in infected hepatocytes, and PD-1 is T cell associated. The PD-L1 protein (NCBI accession number NP_054862.1) is expressed from the cluster of differentiation 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 is understood that those of skill in the art will often consider the terms PD-L1 and CD274 nominally interchangeable, given the nucleic acid (DNA or RNA) or corresponding translated protein, or their sequences.

[0017] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise specified. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, this specification is intended to supersede and / or supersede any such conflicting material. In the event that there are multiple definitions for a term herein, the definition in this section shall prevail unless otherwise specified.

[0018] Whenever a group is described as being "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituent(s) can be selected from one or more of the indicated substituents. If no substituents are indicated, it means that the indicated "optionally substituted" or "substituted" group may be individually and independently substituted with one or more group(s) (1, 2, or 3 groups) selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amine, and disubstituted amine.

[0019] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a ~C b " or "C a ~ b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group or a "C1-C4" alkyl group refers to all alkyl groups having one through four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described in those definitions is assumed.

[0020] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that includes a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1-20 carbon atoms (whenever it appears herein, a numerical range such as "1-20" refers to each integer within the given range, e.g., "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also extends to the appearance of the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium-sized alkyl having 1-10 carbon atoms. The alkyl group may also be a lower alkyl having 1-6 carbon atoms. The alkyl group of the compound may be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1-4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. The alkyl group may be substituted or unsubstituted.

[0021] As used herein, "alkenyl" refers to an alkyl group that contains one or more double bonds in the straight or branched hydrocarbon chain. The length of the alkenyl can vary. For example, an alkenyl can be any of the C 2~4 Alkenyl, C 2~6 Alkenyl, or C 2~8 It may be alkenyl. Examples of alkenyl groups include arenyl, vinylmethyl, and ethenyl. Alkenyl groups may be unsubstituted or substituted.

[0022] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. The length of an alkynyl can vary. For example, an alkynyl can be any of the C2~4 Alkynyl, C 2~6 Alkynyl, or C 2~8 It may be alkynyl. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted.

[0023] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be joined by fusion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0024] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if more than one is present, the double bonds cannot form a completely delocalized pi-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). When composed of more than one ring, the rings may be joined by fusion. Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). Cycloalkenyl groups may be unsubstituted or substituted.

[0025] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, aryl groups include C6 to C7 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0026] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1-5 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4-14 atoms in the ring(s), 5-10 atoms in the ring(s), or 5-6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0027] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms together with one to five heteroatoms constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized pi-electron system does not occur throughout all rings. The number of atoms in the rings of a heterocyclyl group may vary. For example, a heterocyclyl group may contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s). The heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functionalities, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined by fusion. Additionally, any nitrogen in a heterocyclyl may be quaternized.A heterocyclyl group may be substituted or unsubstituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxyl aryl, aryl ... These include, but are not limited to, thiazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrroldione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0028] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent through a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0029] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent through a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.

[0030] "(Heterocyclyl)alkyl" refers to a heterocyclic group bonded as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of the heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinane-4-yl(methyl).

[0031] A "lower alkylene group" is a linear -CH2- linking group that forms bonds to connect molecular fragments through their terminal carbon atoms. In some embodiments, a lower alkylene can contain 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent(s) listed in the definition of "substituted."

[0032] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. In some cases, alkoxy can be -OR, where R is an unsubstituted C 1~4 Alkyl. Alkoxy can be substituted or unsubstituted.

[0033] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted or unsubstituted.

[0034] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl can be substituted or unsubstituted.

[0035] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0036] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some cases, the haloalkoxy can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1~4 The haloalkoxy may be substituted or unsubstituted.

[0037] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl can be substituted or unsubstituted.

[0038] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. The sulfinyl can be substituted or unsubstituted.

[0039] A "sulfonyl" group refers to an "S(=O)R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0040] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

[0041] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0042] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0043] A "trihalomethanesulfonyl" group refers to an "X3CS(=O)2-" group where each X is a halogen.

[0044] The "trihalomethanesulfonamide" group is "X3CS(=O)2N(R A )-" group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0045] As used herein, the term "amino" refers to the group --NH.

[0046] As used herein, the term "hydroxy" refers to an --OH group.

[0047] A "cyano" group refers to a "-CN" group.

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

[0049] An "isocyanato" group refers to a "-NCO" group.

[0050] A "thiocyanato" group refers to a "-SCN" group.

[0051] An "isothiocyanato" group refers to a "-NCS" group.

[0052] A "mercapto" group refers to a "-SH" group.

[0053] A "carbonyl" group refers to a -C(=O)- group.

[0054] The "S-sulfonamide" group is defined as "-S(=O)2N(R A R B )" group, where R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides can be substituted or unsubstituted.

[0055] The "N-sulfonamide" group is defined as "RS(=O)2N(R A )-" group, where R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides can be substituted or unsubstituted.

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

[0057] The "N-carbamyl" group is "ROC(=O)N(R A )-" group, where R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl can be substituted or unsubstituted.

[0058] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B )" group, where R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl can be substituted or unsubstituted.

[0059] The "N-thiocarbamyl" group is ROC(=S)N(R A )-" group, where R and R Acan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl can be substituted or unsubstituted.

[0060] A "C-amide" group is a group that is defined as -C(=O)N(R A R B )" group, where R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides can be substituted or unsubstituted.

[0061] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides can be substituted or unsubstituted.

[0062] "Mono-substituted amine" means "-NHR A " In the formula, R A can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines can be substituted or unsubstituted. In some cases, monosubstituted amines can be -NHR A where R A is unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0063] "Disubstituted amine" means "-NR A R B " In the formula, R A and R B can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Mono-substituted amines can be substituted or unsubstituted. In some cases, mono-substituted amines can be -NR A R B where R A and R B are independently unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0064] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0065] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0066] As used herein, the abbreviations of any protecting groups, amino acids, and other compounds are in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)), unless otherwise indicated.

[0067] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting 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 or sulfonic acids, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting the compound with a base to form salts such as ammonium salts (e.g., ammonium or triethylammonium salts), alkali metal salts such as lithium, sodium, or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0068] Terms and phrases used in this application and variations thereof, particularly those in the appended claims, should be construed as open-ended rather than limiting, unless otherwise specified. As examples of the foregoing, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like; as used herein, the term "comprising" is synonymous with "comprising," "containing," or "featuring," is inclusive or open-ended, and does not exclude additional unrecited elements or method steps; the term "having" should be construed as "having at least," the term "including" should be construed as "including but not limited to," and the term "examples" is used to provide illustrative examples of the items under discussion, not an exhaustive or limiting list thereof. In addition, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0069] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate for the context and / or application. The various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality.

[0070] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently in the (R)-configuration or (S)-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bond(s) that generate a geometric isomer that may be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0071] It is understood that where the compounds disclosed herein have unfilled valences, the valences are filled with hydrogen or an isotope thereof, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0072] It is understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0073] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are included within an embodiment.

[0074] compound Example embodiments of the present application include the following.

[0075] EMBODIMENT 1 A compound of formula (I) having the structure:

[0076] [ka] In the formula, R 1a -C 1~4 Alkyl, -C 1~4 Haloalkyl, -CH2(C 3~6 -CH2 (4- to 6-membered monocyclic heteroaryl), -CH2 (4- to 6-membered monocyclic heteroaryl), and R 1b is hydrogen, -C 1~4 Alkyl, and -C 1~4 haloalkyl, R 1c is -N(R m1 )R n1 and -R x1 You can choose from R 2a , R 2b , R 2c , R 2e , R 2g , and R 2h may be independently selected from hydrogen and halogen; R 2d and R 2f can be independently selected from hydrogen, halogen, cyano, -CH, -CHCH, -CHOH, -OCH, and -SCH; R 3a can be selected from hydrogen, -CH3, -CF3, and -CHF2; R 3b can be selected from hydrogen, halogen, cyano, -CH, -CF, -CHF, -CHCH, -CHOH, -OH, -OCH, and -SCH; Y 1a can be selected from N (nitrogen) and -CH, Y 1b is N (nitrogen) and C (R 4 ) can be selected, Y 2ais N (nitrogen) and C (R 5 ) can be selected, Y 2b is N (nitrogen) and C (R 1d ) can be selected, R 1d can be selected from hydrogen and halogen; R 4 can be selected from hydrogen, halogen, and -CH3; R 5 can be selected from hydrogen, halogen, and -CH3; R m1 is hydrogen, -C 1~4 Alkyl, C 3~6 Monocyclic cycloalkyl, C 5~12 Bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, 8- to 11-membered fused bicyclic heteroaryl, and 8- to 11-membered fused bicyclic heterocyclyl, wherein the 5- or 6-membered monocyclic heteroaryl, bicyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and bicyclic heterocyclyl contain at least one atom or group of atoms independently selected from O (oxygen), S (sulfur), C(=O), S(=O), S(=O)2, and N (nitrogen), and -C 1~4 Alkyl is independently halogen, cyano, hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4 Haloalkoxy, -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 Z2 )R Z3 , and -N(R Z1 )S(=O)N(R Z2 )R Z3 and optionally substituted with one, two or three substituents selected from 3~6Monocyclic cycloalkyl, C 5~12 Bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, 8- to 11-membered fused bicyclic heteroaryl, and 8- to 11-membered fused bicyclic heterocyclyl are independently selected from halogen, cyano, -C 1~4 Alkyl, Hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4 Haloalkoxy, -C(=O)OR Z1 , -C(=O)NHS(=O)2R Z3 , -C(=O)N(R Z1 )R Z2 , -C(=O)R Z3 , -CH2C(=O)OR Z3 , -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 n1 is hydrogen, -C 1~4 Alkyl, -C 1~4 Haloalkyl, C 3~6 Monocyclic cycloalkyl(CH2)- or -C(=O)OR Z4 R x1 teeth,

[0077] [ka] You can choose from R x1 are independently halogen, cyano, -C 1~4 Alkyl, Hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4Haloalkoxy, -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 m1, m2, and m3 can independently be 1 or 2; m4 can be 0, 1, or 2; m5 can be 1, 2, 3, or 4; and each R X3 are independently hydrogen, halogen, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C(=O)R Z3 , -C(=O)OR Z1 , -CH2C(=O)OR Z3 , -S(=O)2R Z1 , -C(=O)NHS(=O)2(R Z3 ), -NHC(=O)(R Z3 ), -C(=O)N(R Z1 )R Z2 , and -S(=O)2N(R Z1 )R Z2 You can choose from R Z1 and R Z2 are independently hydrogen, -C 1~4 Alkyl, and -C 1~4 haloalkyl, or R Z1 and R Z2 can be taken together to form a monocyclic heterocyclyl, when attached to the same nitrogen, R Z3 is hydrogen, -C 1~4 Alkyl and -C 1~4 haloalkyl, RZ4 is hydrogen, -C 1~4 Alkyl, and -C 1~4 and 5-6 membered monocyclic heterocyclyl(CH2)-, optionally substituted with alkyl. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, can have the structure:

[0078] [ka] In the formula, R 1a -C 1~4 Alkyl, -C 1~4 Haloalkyl, -CH2(C 3~6 -CH2 (4- to 6-membered monocyclic heteroaryl), -CH2 (4- to 6-membered monocyclic heteroaryl), and R 1b is hydrogen, -C 1~4 Alkyl, -C 1~4 haloalkyl, R 1c is -N(R m1 )R n1 and -R x1 You can choose from R 1d can be selected from hydrogen and halogen; R 2a , R 2b , R 2c , R 2e , R 2g , R 2h may be independently selected from hydrogen and halogen; R 2d and R 2f can be independently selected from hydrogen, halogen, cyano, -CH, -CHCH, -CHOH, -OCH, and -SCH; R 3a can be selected from hydrogen, -CH3, -CF3, and -CHF2; R 3b can be selected from hydrogen, halogen, cyano, -CH, -CF, -CHF, -CHCH, -CHOH, -OCH, and -SCH; Y 1a can be selected from N (nitrogen) and -CH, Y 1b is N (nitrogen) and C (R 4) can be selected, Y 2a is N (nitrogen) and C (R 5 ) can be selected, R 4 can be selected from hydrogen, halogen, and -CH3; R 5 can be selected from hydrogen, halogen, and -CH3; R m1 is hydrogen, -C 1~4 Alkyl, C 3~6 Monocyclic cycloalkyl, C 5~12 Bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, 8- to 11-membered fused heteroaryl, 8- to 11-membered fused heterocyclyl, and -R x2 and wherein monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclyl, and bicyclic heterocyclyl contain at least one atom or group of atoms independently selected from O (oxygen), S (sulfur), C(=O), S(=O), S(=O)2, and N (nitrogen); 1~4 Alkyl is independently halogen, cyano, hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4 Haloalkoxy, -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 Z2 )R Z3 , and -N(R Z1 )S(=O)N(R Z2 )R Z3 and optionally substituted with one, two or three substituents selected from 3~6 Monocyclic cycloalkyl, C 5~12Bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, 8- to 11-membered fused heteroaryl, and 8- to 11-membered fused heterocyclyl are independently selected from halogen, cyano, -C 1~4 Alkyl, Hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4 Haloalkoxy, -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 Z2 )R Z3 , and -N(R Z1 )S(=O)N(R Z2 )R Z3 R n1 is hydrogen, -C 1~4 Alkyl, -C 1~4 Haloalkyl, C 3~6 Monocyclic cycloalkyl(CH2)- or -C(=O)OR Z4 R x1 teeth,

[0079] [ka] R x1 are independently halogen, cyano, -C 1~4 Alkyl, Hydroxy, -C 1~4 Alkoxy, -C 1~4 Haloalkyl, -C 1~4 Haloalkoxy, -C(=O)OR Z1 , -C(=O)NHS(=O)2R Z3 , -C(=O)N(R Z1 )RZ2 , -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 and R x2 teeth,

[0080] [ka] m1, m2, and m3 can be independently 1 or 2; m4 can be 0, 1, or 2; m5 can be 1, 2, 3, or 4; and each R X3 are independently hydrogen, halogen, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C(=O)R Z3 , -C(=O)OR Z1 , -S(=O)2R Z1 , -C(=O)N(R Z1 )R Z2 , and -S(=O)N(R Z1 )R Z2 You can choose from R Z1 and R Z2 are independently hydrogen, -C 1~4 Alkyl, and -C 1~4 haloalkyl, or R Z1 and R Z2 can be taken together to form a monocyclic heterocyclyl, when attached to the same nitrogen, R Z3 is hydrogen, -C 1~4 Alkyl and -C 1~4 haloalkyl, R Z4 is hydrogen, -C 1~4 Alkyl, and -C1~4 5-6 membered monocyclic heterocyclyl (CH2)- optionally substituted with alkyl. Some exemplary structures of formula (I) or pharma- ceutically acceptable salts thereof include those of formulas (Ia)-(Ih):

[0081] [ka]

[0082] [ka] (including pharma- ceutically acceptable salts of any of the foregoing).

[0083] EMBODIMENT 2 Y 2a can be N (nitrogen).

[0084] EMBODIMENT 3 Y 2a is C(R 5 ).

[0085] EMBODIMENT 4 R 5 The compound of embodiment 3, wherein R can be hydrogen.

[0086] EMBODIMENT 5 R 5 The compound of embodiment 3, wherein R can be halogen, such as fluoro or chloro.

[0087] EMBODIMENT 6 The compound of embodiment 3, wherein R5 can be -CH3.

[0088] EMBODIMENT 7 R 3a The compound of any one of embodiments 1-6, wherein may be hydrogen.

[0089] EMBODIMENT 8 R 3aThe compound of any one of embodiments 1-6, wherein may be -CH3.

[0090] EMBODIMENT 9 R 3a The compound of any one of embodiments 1-6, wherein may be -CF3.

[0091] EMBODIMENT 10 R 3a The compound according to any one of embodiments 1-6, wherein may be -CHF2.

[0092] EMBODIMENT 11 R 3b The compound of any one of embodiments 1-10, wherein may be hydrogen.

[0093] EMBODIMENT 12 R 3b The compound of any one of embodiments 1-10, wherein may be halogen, such as fluoro or chloro.

[0094] EMBODIMENT 13 R 3b The compound of any one of embodiments 1-10, wherein may be cyano.

[0095] EMBODIMENT 14 R 3b The compound according to any one of embodiments 1 to 10, wherein may be -CH3 or -CH2CH3.

[0096] EMBODIMENT 15 R 3b The compound according to any one of embodiments 1 to 10, wherein may be -CF3 or -CHF2.

[0097] EMBODIMENT 16 R 3b The compound according to any one of embodiments 1 to 10, wherein may be -CH2OH, -OH, -OCH3, or -SCH3.

[0098] EMBODIMENT 17 Y1a The compound according to any one of embodiments 1 to 16, wherein may be N (nitrogen).

[0099] EMBODIMENT 18 Y 1a The compound of any one of embodiments 1-16, wherein may be —CH.

[0100] EMBODIMENT 19 Y 1b The compound according to any one of embodiments 1 to 18, wherein may be N (nitrogen).

[0101] EMBODIMENT 20 Y 1b is C(R 4 19. The compound of any one of embodiments 1-18, wherein

[0102] EMBODIMENT 21 R 4 The compound of embodiment 20, wherein R can be hydrogen.

[0103] EMBODIMENT 22 R 4 The compound of embodiment 20, wherein R can be halogen. For example, R 4 can be fluoro or chloro.

[0104] EMBODIMENT 23 The compound of embodiment 20, wherein R4 can be -CH3.

[0105] EMBODIMENT 24 R 1a -C 1~4 The compound according to any one of embodiments 1 to 23, which may be alkyl. 1~4 Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[0106] EMBODIMENT 25 R 1ais -C such as -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CF3, and -CH2CHF2. 1~4 The compound according to any one of embodiments 1-23, which may be haloalkyl.

[0107] EMBODIMENT 26 R 1a is -CH2(C 3~6 The compound according to any one of embodiments 1-23, wherein the 4- to 6-membered monocyclic heterocyclyl of -CH2(4- to 6-membered monocyclic heterocyclyl) and the 5- to 6-membered monocyclic heteroaryl of -CH2(5- to 6-membered monocyclic heteroaryl) can include one or more ring atoms (such as 1, 2, or 3) selected from N (nitrogen), O (oxygen), and S (sulfur). Exemplary monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 4- to 6-membered monocyclic heterocyclyl of -CH2(4- to 6-membered monocyclic heterocyclyl) and / or the 5- to 6-membered monocyclic heteroaryl of -CH2(5- to 6-membered monocyclic heteroaryl) can include one or more ring atoms (such as 1, 2, or 3) selected from N (nitrogen), O (oxygen), and S (sulfur).

[0108] EMBODIMENT 27 R 1d The compound of any one of embodiments 1-26, wherein may be hydrogen.

[0109] EMBODIMENT 28 R 1d The compound according to any one of embodiments 1-26, wherein may be halogen, such as fluoro or chloro.

[0110] EMBODIMENT 29 R 1c is -N(R m1 )R n1 The compound according to any one of embodiments 1 to 28, which may be:

[0111] EMBODIMENT 30 R n1 is R 1c -NH(R m1 30. The compound of embodiment 29, wherein R is 0, R is 1, and R is 2.

[0112] EMBODIMENT 31 R n1 -C 1~4 The compound of embodiment 29, which may be alkyl. For example, R n1 can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

[0113] EMBODIMENT 32 R n1 is -C(=O)OR Z4 The compound of embodiment 29, wherein R Z4 is C 1~4 In other embodiments, R Z4 -C 1~4 It can be a 5-6 membered monocyclic heterocyclyl(CH2)-, optionally substituted with alkyl. In other embodiments, R n1 is C 1~4 The compound of embodiment 29, which can be haloalkyl. In still other embodiments, R n1 C such as cyclopropyl-(CH2)-, cyclobutyl-(CH2)-, cyclopentyl-(CH2)-, and cyclohexyl-(CH2)- 3~6 The compound of embodiment 29, which can be a monocyclic cycloalkyl(CH2)-.

[0114] EMBODIMENT 33 R m1 The compound of any one of embodiments 29-32, wherein may be tetrahydrofuran or tetrahydro-2H-pyran, each optionally substituted with hydroxy.

[0115] EMBODIMENT 34 R m1 teeth,

[0116] [ka] The compound of embodiment 33, wherein the compound is

[0117] EMBODIMENT 35 R m1 teeth,

[0118] [ka] The compound according to any one of embodiments 29 to 32, which may be selected from:

[0119] EMBODIMENT 36 -R m1 teeth,

[0120] [ka] The compound of embodiment 35, wherein the compound is

[0121] EMBODIMENT 37 R 1c -R x1 The compound according to any one of embodiments 1 to 28, which may be:

[0122] EMBODIMENT 38 -R x1 teeth,

[0123] [ka] The compound of embodiment 37, wherein the compound is

[0124] EMBODIMENT 39 -R x1 teeth,

[0125] [ka] The compound according to embodiment 37, which may be selected from:

[0126] EMBODIMENT 40 -R x1 teeth,

[0127] [ka] The compound according to embodiment 37, which may be selected from:

[0128] EMBODIMENT 41 R 2a , R 2b , R 2c , R 2e , R 2g , and R 2h The compound of any one of embodiments 1-40, wherein each may be hydrogen.

[0129] EMBODIMENT 42 R 2a , R 2c , R 2e , R 2g , and R 2h may each be hydrogen, R 2b The compound of any one of embodiments 1-40, wherein may be halogen.

[0130] EMBODIMENT 43 R 2b , R 2c , R 2e , R 2g , and R 2h may each be hydrogen, R 2a The compound of any one of embodiments 1-40, wherein may be halogen.

[0131] EMBODIMENT 44 R 2d and R 2f The compound of any one of embodiments 1-43, wherein each R can be halogen. 2d and R 2f Each can be fluoro. In other embodiments, R 2d and R 2f may each be chloro.

[0132] EMBODIMENT 45 R 2d and R 2f The compound of any one of embodiments 1-43, wherein each can be -CH3.

[0133] EMBODIMENT 46 R 2d may be a halogen, R 2f The compound of any one of embodiments 1-43, wherein may be -CH3.

[0134] EMBODIMENT 47 R 2d can be -CH3, R 2f The compound of any one of embodiments 1-43, wherein may be halogen.

[0135] EMBODIMENT 48 R 2d can be cyano, R 2f The compound of any one of embodiments 1-43, wherein may be halogen.

[0136] EMBODIMENT 49 R 2d can be -OCH3, R 2f The compound of any one of embodiments 1-43, wherein may be halogen.

[0137] EMBODIMENT 50 Compounds according to any one of embodiments 42-44 or 46-49, wherein halogen can be chloro or fluoro.

[0138] EMBODIMENT 51 -R m1 teeth,

[0139] [ka] and in other embodiments, -R m1 teeth,

[0140] [ka] In yet another embodiment, the compound of embodiment 1 can be selected from -R m1 teeth,

[0141] [ka] You can choose from.

[0142] EMBODIMENT 52

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] [ka]

[0150] [ka]

[0151] [ka]

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka] or a pharma- ceutically acceptable salt of any of the foregoing.

[0157] EMBODIMENT 53

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka]

[0166] [ka]

[0167] [ka] or a pharma- ceutically acceptable salt of any of the foregoing.

[0168] EMBODIMENT 54 In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof may not be a compound or a pharma- ceutically acceptable salt provided in WO 2021 / 076691.

[0169] EMBODIMENT 55 A pharmaceutical composition, which may include an effective amount of a compound according to any one of embodiments 1 to 54, or a pharma- ceutically acceptable salt thereof, and an excipient.

[0170] EMBODIMENT 56 A method for treating Hepatitis B in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1 to 54.

[0171] EMBODIMENT 57 A method for treating hepatocellular carcinoma (HCC) in a subject, the method may comprise administering to a subject in need thereof an effective amount of a compound, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1 to 54.

[0172] EMBODIMENT 58 58. The method of embodiment 56 or 57, which can further comprise administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

[0173] EMBODIMENT 59 A compound according to any one of embodiments 1-54, or a pharma- ceutically acceptable salt thereof, for use in treating Hepatitis B.

[0174] EMBODIMENT 60 A compound according to any one of embodiments 1-54, or a pharma- ceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC).

[0175] EMBODIMENT 61 The compound according to embodiment 59 or 60, which can further comprise administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

[0176] EMBODIMENT 62 The use of a compound according to any one of embodiments 1 to 54, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for use in treating Hepatitis B.

[0177] EMBODIMENT 63 The use of a compound according to any one of embodiments 1 to 54, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC).

[0178] EMBODIMENT 64 The use according to embodiment 62 or 63, which may further comprise administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

[0179] Methods for preparation In this section, as in all other sections, unless the context dictates otherwise, a reference to formula (I) includes all other subgroups and examples thereof as provided herein, together with pharma- ceutically acceptable salts thereof. The general preparation of some representative examples of compounds of formula (I) is described herein and are generally prepared from starting materials that are either commercially available or prepared by standard synthetic processes used by those skilled in the art.

[0180] All variables shown in the schemes are defined as referenced herein unless otherwise indicated or clear from the context.

[0181] Scheme 1

[0182] [ka]

[0183] In general, compounds of formula (I) (including pharma- ceutically acceptable salts thereof) can be prepared according to Scheme 1. In Scheme 1, LG can be Br or Cl. All other variables in Scheme 1 are according to formula (I) provided herein. In Scheme 1, the following reaction conditions are applied: (1) at a suitable temperature (e.g., 100° C.), with a suitable base (e.g., K2CO3), in a suitable solvent, such as a mixture of 1,4-dioxane and water, in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II)dichloride), (2) at a suitable temperature (e.g., 100° C.), in a suitable solvent, such as a mixture of 1,4-dioxane and water, in the presence of a suitable base (e.g., DCM), (3) at a suitable temperature (e.g., 90° C.), with a suitable base (e.g., KOAc), in a suitable solvent, such as a mixture of 1,4-dioxane and water, in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II)dichloride), , bis(triphenylphosphine)palladium(II) dichloride), 4) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent such as a mixture of 1,4-dioxane and water with a suitable base (e.g., KCO) at a suitable temperature (e.g., 100° C.), and (5) in the presence of a suitable coupling reagent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole) in a suitable solvent (e.g., acetonitrile) at a suitable temperature (e.g., 50° C.).

[0184] Scheme 2

[0185] [ka]

[0186] In general, compounds of formula (I) can be prepared according to Scheme 2. In Scheme 2, LG can be Br or Cl. All other variables in Scheme 2 are according to formula (I) provided herein. In Scheme 2, the following reaction conditions are applied: (1) at a suitable temperature (e.g., 100° C.) with a suitable base (e.g., K2CO3) in a suitable solvent such as a mixture of 1,4-dioxane and water, in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II)dichloride); 2) in the presence of a suitable coupling reagent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole); (3) at a suitable temperature (e.g., 90° C.) with a suitable base (e.g., KOAc) in a suitable solvent such as a mixture of 1,4-dioxane and water, in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II)dichloride); (4) in the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as a mixture of 1,4-dioxane and water, with a suitable base (e.g., KCO) at a suitable temperature (e.g., 100° C.); and (5) in the presence of a suitable reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent, such as DCM or MeOH, at a suitable temperature, such as around 20° C.

[0187] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions comprising, consisting essentially of, or consisting of an effective amount of a compound described herein (such as a compound of formula (I), or a pharma- ceutically acceptable salt thereof) and a pharma- ceutical acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and / or veterinary use.

[0188] As used herein, the terms "function" and "functional" refer to a biological function, an enzymatic function, or a therapeutic function.

[0189] The term "effective amount" or "effective dose" is used to indicate the amount of an active compound or pharmaceutical agent that induces the indicated biological or medical response. For example, an effective amount of a compound may be the amount required to alleviate or ameliorate the symptoms of a disease or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical arts would recognize.

[0190] The term "pharmaceutical acceptable salts" includes, but is not limited to, relatively non-toxic inorganic and organic acid or base addition salts of compositions, including analgesics, therapeutic agents, other materials, and the like. Examples of pharmaceutical acceptable salts include salts derived from mineral acids such as hydrochloric acid and sulfuric acid, and from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of inorganic bases suitable for forming salts include hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Salts may also be formed with suitable organic bases, including those bases that are non-toxic and strong enough to form such salts. For example, classes of such organic bases may include, but are not limited to, mono-, di-, and trialkylamines, including methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines, including monoethanolamine, diethanolamine, and triethanolamine; amino acids, including glycine, arginine, and lysine; guanidine, N-methylglucosamine, N-methylglucamine, L-glutamine, N-methylpiperazine, morpholine, ethylenediamine, N-benzylphenethylamine, trihydroxymethylaminoethane.

[0191] "Formulation," "pharmaceutical composition," and "composition," used interchangeably herein, are equivalent terms that refer to a composition of matter for administration to a subject.

[0192] The term "pharmaceutical acceptable" means compatible with the treatment of a subject, especially a human.

[0193] The term "drug" refers to an active agent that has biological activity and can be used in treatment. Also, "drug" can be synonymous with "at least one drug," "compound," or "at least one compound," and can refer to any form of the drug, such as a derivative, analog, salt, or prodrug thereof. The drug can exist in various forms, components of molecular complexes, and pharma- ceutically acceptable salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate). The term "drug" can also refer to any pharmaceutical 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.

[0194] As used herein, the term "subject" has its ordinary meaning as understood in the context of the present specification and refers to an animal that is the subject of treatment, inhibition or improvement, observation, or experiment. "Animal" has its ordinary meaning as understood in the context of the present specification and includes cold-blooded and warm-blooded vertebrates and / or invertebrates, such as fish, crustaceans, or reptiles, particularly mammals. "Mammal" has its ordinary meaning as understood in the context of the present specification and includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as humans, monkeys, chimpanzees, or apes. In some embodiments, the subject is a human.

[0195] The appropriate formulation depends on the route of administration selected. The techniques for formulating and administering the compounds described herein are known to those skilled in the art. There are multiple techniques for administering compounds in the art, including enteral, oral, rectal, topical, sublingual, buccal, intraaural, epidural, epidermal, aerosol, parenteral administration, including but not limited to intramuscular, subcutaneous, intraarterial, intravenous, intraportal, intraarticular, intradermal, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. Pharmaceutical compositions are generally tailored to the specific intended route of administration. Pharmaceutical compositions can also be administered to cells isolated 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.

[0196] Pharmaceutical compositions can also be administered locally rather than systemically, for example, via direct injection of the compound into an organ, tissue, cancer, tumor, or site of infection, often in a depot or sustained release formulation. Additionally, the compound may be administered in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposome can be targeted to and selectively taken up by the organ, tissue, cancer, tumor, or site of infection.

[0197] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts with pharma- ceutically compatible counterions.

[0198] As used herein, "carrier" refers to a compound, particle, solid, semi-solid, liquid, or diluent that facilitates the passage, delivery, and / or incorporation of a compound into cells, tissues, and / or body organs. For example, but not by way of limitation, lipid nanoparticles (LNPs) are a type of carrier that can encapsulate a compound, or a pharma- ceutically acceptable salt thereof, as described herein, thereby protecting the compound, or a pharma-ceutically acceptable salt thereof, as described herein, from degradation during passage through the bloodstream and / or facilitate delivery to a desired organ, such as the liver.

[0199] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmacologically active, but may be medicamentally necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the composition of human blood.

[0200] The term "excipient" has its ordinary meaning as understood in light of this specification and refers, without limitation, to an inert substance, compound, or material added to a pharmaceutical composition to provide bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. Excipients having desirable 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, sugar, dextrose, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, serum, amino acids, polysorbate 20, polysorbate 80, sodium deoxycholate, sodium taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea, or vitamins, or any combination thereof. The amount of excipient in a pharmaceutical composition can be found at 0% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, 100% by weight, or any weight percentage within a range defined by any two of the foregoing numbers.

[0201] As used herein, the term "adjuvant" refers to a substance, compound, or material that stimulates the immune response and increases the effectiveness of protective immunity, administered in conjunction with an immunogenic antigen, epitope, or composition. Adjuvants help improve the immune response by allowing continuous release of antigens, upregulation of cytokines and chemokines, cell recruitment at the site of administration, increased uptake and presentation of antigens 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, oil, mineral oil, paraffin oil, oil-in-water emulsions, detergents, MF59®, squalene, AS03, α-tocopherol, polysorbate 80, AS04, monophosphoryl lipid A, virosomes, nucleic acids, polyinosinic:polycytidylic acid, saponin, QS-21, proteins, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21, imidazoquinolines, CpG oligonucleotides, lipids, phospholipids, dioleoyl phosphatidylcholine (DOPC), trehalose dimycolate, peptidoglycan, bacterial extracts, lipopolysaccharides, or Freund's adjuvant, or any combination thereof.

[0202] As used herein, the term "purity" of any given substance, compound, or material refers to the actual amount of the substance, compound, or material present relative to the expected amount present. For example, the 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 decimal points therebetween. Purity may be affected by undesirable impurities, including, but not limited to, by-products, isomers, enantiomers, decomposition products, solvents, carriers, vehicles, or contaminants, or any combination thereof. Purity may be measured by techniques including, but not limited to, chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-visible spectroscopy, infrared spectroscopy, mass spectrometry, nuclear magnetic resonance, gravimetry, or titration, or any combination thereof.

[0203] How to use Some embodiments disclosed herein relate to selecting a subject or patient in need. In some embodiments, the patient is selected in need of treatment, inhibition, amelioration, prevention, or slowing of a disease or condition associated with PD-L1 dysregulation. In some embodiments, such disease or condition associated with PD-L1 dysregulation may include, for example, cancer, HCC, viral infection, or HBV. In some embodiments, a subject who has been previously treated for a disease or disorder described herein may be selected. In some embodiments, a subject who has been previously treated for being at risk for a disease or disorder described herein may be selected. In some embodiments, a subject who has developed a recurrence of a disease or disorder described herein may be selected. In some embodiments, a subject who has developed resistance to a treatment for a disease or disorder described herein may be selected. In some embodiments, a subject who may have any combination of the aforementioned selection criteria may be selected.

[0204] The compounds disclosed herein, and their pharma- ceutically acceptable salts, can be evaluated for efficacy and toxicity using known methods.A non-limiting list of potential advantages of the compounds described herein, or their pharma- ceutical acceptable salts, includes improved stability, improved safety profile, improved efficacy, enhanced binding to target, and improved specificity to target (e.g., cancer cells or virus-infected cells).

[0205] As used herein, the terms "treating", "treatment", "therapeutic" or "therapy" have their ordinary meaning as understood in light of the present specification and do not necessarily mean a complete cure or elimination of a disease or condition. As used herein, the terms "treating" or "treatment" (also well understood in the art) also refer to an approach to obtain a beneficial or desired result in a subject's condition, including a clinical result. A beneficial or desired clinical result may include, but is not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization (i.e., not worsening) of the disease state, prevention of disease transmission or spread, delay or slowing of disease progression, improvement or remission of the disease state, reduction in disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. As used herein, "treating" and "treatment" also include prophylactic treatment. The treatment method includes administering a therapeutically effective amount of an active agent to the subject. The administration step may consist of a single administration or may include a series of administrations. The composition is administered to the subject in an amount and duration sufficient to treat the subject. The length of the treatment period depends on various factors, such as the severity of the condition, the age and genetic profile of the subject, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Changes in dosage may occur and be obvious according to standard diagnostic analysis known in the art. In some cases, long-term administration may be required.

[0206] Some embodiments described herein relate to a method of treating, inhibiting, ameliorating, preventing, or slowing a disease or disorder described herein. In some embodiments, the method comprises administering to a subject identified as suffering from a disease or disorder described herein an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating, inhibiting, ameliorating, preventing, or slowing a disease or disorder described herein. Still other embodiments described herein relate to the use of a compound, or a pharma- ceutically acceptable salt thereof, as described herein, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, for treating, inhibiting, ameliorating, preventing, or slowing a disease or disorder described herein.

[0207] Some embodiments described herein relate to a method for inhibiting the replication of cancer cells or viruses, which may include contacting a cell or virus with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or administering to a subject identified as suffering from cancer or a viral infection. Other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically 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 a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of a compound described herein, or a pharma- ceutically 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.

[0208] Some embodiments described herein relate to a method for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or virus-infected cells, which may include administering to a subject identified as suffering from a disease in which it is desirable to inhibit cell proliferation, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or virus-infected cells. Still other embodiments described herein relate to a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, for inhibiting cell proliferation, such as inhibiting cell 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.

[0209] Some embodiments described herein relate to a method of inducing apoptosis in a cell (e.g., a cancer cell or a cell infected with a virus), which may include contacting the cell with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inducing apoptosis in a cell, such as a cancer cell or a cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, to induce apoptosis in a cell, such as a cancer cell or a cell infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus-infected cell is infected with Hepatitis B virus.

[0210] Some embodiments described herein relate to a method of reducing the viability of a cell (e.g., a cancer cell or a cell infected with a virus), which may include contacting the cell with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for reducing the viability of a cell, such as a cancer cell or a cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, to reduce the viability of a cell, such as a cancer cell or a cell infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus-infected cell is infected with Hepatitis B virus.

[0211] Those skilled in the art of treating such diseases can determine the effective therapeutic amount per day from the test results. The effective therapeutic amount per day is about 0.005 mg / kg to 50 mg / kg body weight, particularly 0.01 mg / kg to 50 mg / kg body weight, more particularly 0.01 mg / kg to 25 mg / kg body weight, preferably about 0.01 mg / kg to about 15 mg / kg, more preferably about 0.01 mg / kg to about 10 mg / kg, even more preferably about 0.01 mg / kg to about 1 mg / kg, and most preferably about 0.05 mg / kg to about 1 mg / kg body weight.

[0212] In some embodiments, an effective amount of the compound described herein, or a pharma- ceutically acceptable salt thereof, is administered two or more times. In some embodiments, the compound described herein, or a pharma- ceutically acceptable salt thereof, can be administered every 1, 2, 3, 4, 5, 6, 7 days, or every 1, 2, 3, 4 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or every 1, 2, 3, 4, 5 years, or any period or combination within the range defined by any two of the above. In some embodiments, at least one loading dose and at least one maintenance dose are administered to the subject, and at least one loading dose is a higher dose of the compound described herein, or a pharma- ceutically acceptable salt thereof, than at least one maintenance dose.

[0213] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more pharmaceutical compounds / agents or therapies. Thus, references in this application to the use of "combination therapy," "combination," and compounds / agents "in combination" may refer to compounds / agents that are administered as part of the same overall treatment regimen. Thus, the dosage or timing of each of the two or more compounds / agents may be different, and each may be administered simultaneously or at different times. Thus, the compounds / agents of the combination may be administered in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately), sequentially (e.g., before or after) or simultaneously. Each of the two or more compounds / agents in the combination therapy may also differ with respect to the route of administration.

[0214] 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 can relate to reversible or irreversible inhibitors.

[0215] Cancer may be treated with surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or hormonal therapy. Any of these mentioned therapies may be used in conjunction with another therapy as a combination therapy. Chemotherapeutic compounds include, but are not limited to, alemtuzumab, altretamine, azacitidine, bendamustine, bleomycin, bortezomib, busulfan, cabazitaxel, capecitabine, carboplatin, carmoful, carmustine, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denosumab, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gemcitabine, gemtuzumab, hydroxychloroquine, hydroxylamine ... cicarbamide, ibritumomab, idarubicin, ifosfamide, irinotecan, ixabepilone, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, ofatumumab, oxaliplatin, paclitaxel, pemetrexed, pentostatin, pertuzumab, procarbazine, raltitrexed, streptozotocin, tegafur, temozolomide, temsirolimus, teniposide, thioguanine, topotecan, tositumomab, valrubicin, vinblastine, vincristine, vindesine, vinflunine, or vinorelbine, or any combination thereof.

[0216] As used herein, the term "protein kinase inhibitor" refers to an inhibitor of a protein kinase, a serine / threonine kinase, a tyrosine kinase, or a dual specificity kinase for the treatment of cancer or other diseases. In some embodiments, the protein kinase inhibitor is a small molecule, a chemical compound, a polysaccharide, a lipid, a peptide, a polypeptide, a protein, an antibody, a nucleoside, a nucleoside analog, a nucleotide, a nucleotide analog, a nucleic acid, or an oligonucleotide. In some embodiments, protein kinase inhibitors include, but are not limited to, acalabrutinib, adavosertib, afatinib, alectinib, axitinib, binimetinib, bosutinib, brigatinib, cediranib, ceritinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erdafitinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtine, and the like. nib, lortatinib, masitinib, momelotinib, mubritinib, neratinib, nilotinib, nintedanib, olmutinib, osimertinib, pacritinib, panitumumab, pazopanib, pegaptanib, ponatinib, radotinib, regorafenib, rociletinib, ruxolitinib, selumetinib, semaxanib, sorafenib, sunitinib, SU6656, tivozanib, toceranib, trametinib, trastuzumab, vandetanib, or vemurafenib, or any combination thereof.

[0217] As used herein, the term "checkpoint inhibitor" refers to an immunotherapy that targets immune checkpoints to stimulate immune function. In some embodiments, the checkpoint inhibitor is a small molecule, a compound, a polysaccharide, a lipid, a peptide, a polypeptide, a protein, an antibody, a nucleoside, a nucleoside analog, a nucleotide, a nucleotide analog, a nucleic acid, or an oligonucleotide. In some embodiments, the immune checkpoint is the PD-1 / PD-L1 checkpoint. In some embodiments, the PD-1 checkpoint includes, but is not limited to, nivolumab, pembrolizumab, spartalizumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, or AMP-514, or any combination thereof. In some embodiments, the PD-L1 checkpoint inhibitor includes, but is not limited to, atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170, or BMS-986189, or any combination thereof. In some embodiments, the immune checkpoint is the CTLA-4 checkpoint. In some embodiments, the CTLA-4 checkpoint inhibitor includes, but is not limited to, ipilimumab, or tremilimumab, or any combination thereof.

[0218] 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 is a small molecule, a chemical compound, a polysaccharide, a lipid, a peptide, a polypeptide, a protein, an antibody, a nucleoside, a nucleoside analog, a nucleotide, a nucleotide analog, a nucleic acid, or an oligonucleotide. In some embodiments, the VEGF inhibitor includes, but is not limited to, aflibercept, axitinib, bevacizumab, brivanib, cabozantinib, cediranib, lenvatinib, linfinib, nintedanib, pazopanib, ponatinib, ramucirumab, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, or vandetanib, or any combination thereof.

[0219] As used herein, the term "antiviral agent" refers to a pharmaceutical composition administered to treat a viral infection. In some embodiments, the viral infection is caused by adenovirus, Ebola virus, coronavirus, Epstein-Barr virus (EBV), Friend 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 herpes virus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus, and varicella-zoster virus.

[0220] In some embodiments, the antiviral agent is a small molecule, a chemical compound, a polysaccharide, a lipid, a peptide, a polypeptide, a protein, an antibody, a nucleoside, a nucleoside analog, a nucleotide, a nucleotide analog, a nucleic acid, or an oligonucleotide. In some embodiments, the antiviral agent is an interferon, a capsid assembly modulator, a sequence-specific oligonucleotide, an entry inhibitor, or a small molecule immunomodulator. In some embodiments, the antiviral agent is a drug, including, but not limited to, AB-423, AB-506, ABI-H2158, bevicorvir (ABI-HO731), acyclovir, adapromine, adefovir, adefovir dipivoxil, alafenamide, amantadine, asunaprevir, baloxavir marboxil, beclavuvir, boceprevir, brivudine, cidofovir, cilprevir, clevudine, cytarabine, daclatasvir, danoprevir, daclo ... vir, dasabuvir, deleofvir, dipivoxil, edoxudine, elbasvir, entecavir, faldaprevir, famciclovir, favipiravir, filbubivir, fomivirsen, foscarnet, galidesivir, ganciclovir, glecaprevir, GLS4, grazoprevir, idoxuridine, imiquimod, IFN-α, interferon alpha 2b, JNJ-440, JNJ-6379 (JNJ-56136379), lamivudine, la Ninamivir, ledipasvir, mericitabine, mitisazone, MK-608, moroxydine, narulaprevir, NITD008, NZ-4, odalasvir, ombitasvir, oseltamivir, paritaprevir, peginterferon, alpha-2a, penciclovir, peramivir, pibrentasvir, pimoxivir, pleconaril, podophyllotoxin, presatovir, ladarbuvir, ravidasvir, remdesivir, REP2139, REP2165, resveratrol, serovar ... Siquimod, R07049389 (RG7907), ribavirin, rifampicin, rimantadine, ruzasvir, samatasvir, setrobuvir, simeprevir, sovosbuvir, sorivudine, sovaprevir, taribavirin, telaprevir, telbivudine, tenofovir, tenofovir, disoproxil, tenofovir alfenamide, triazavirine, trifluridine, tromantadine, umifenovir, uplifosbuvir, valacyclovir, valgancicovir,Vaniprevir, vedroprevir, velpatasvir, vidarabine, voxilaprevir, zanamivir, cledovudine, ANA-380 / LB80380, thymalfasin (Zadaxin), ATI-2173, VIR-2218, RG6346, JNJ-73763989 (JNJ-3989), AB-729, BB-103, hepcludex (Brevirtivir), , formerly Myrcludex B), hzVSF, morphothiazine, JNJ-56136379, EDP-514, QL-007, ABI-H3733, ZM-H1505R, B-836, VNRX-9945, GLP-26, ABI-4334, IONIS-HBVRx (GSK3228836), EBT107, NASVAC, GS-4774, HepTcel l, VBI-2601(BRII-179), VVX001, VTP-300, CVI-HBV-002, AIC-649, HB-110, JNJ-64300535, CARG- 201, PRGN-2013, SA104, VRON-0200, Cergantolimod, RG7854, SBT-8230, YS-HBV-002, Lembervimab, Vir-343 4, 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, ALG-125755, zanamivir, or any combination thereof.

[0221] As used herein, the terms "% w / w" or "% wt / wt" have their ordinary meaning as understood in the context of this specification and refer to the percentage of the weight of a component or agent relative to the total weight of the composition, multiplied by 100. As used herein, "% v / v" or "% vol / vol" have their ordinary meaning as understood in the context of this specification and refer to the percentage of the liquid volume of a compound, substance, component, or agent relative to the total liquid volume of the composition, multiplied by 100. EXAMPLES

[0222] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not intended to limit the scope of the disclosure in any way. Those skilled in the art will appreciate that many other embodiments are also within the scope of the disclosure, as described above and in the claims.

[0223] Hereinafter, the terms "rt", "rt" or "RT" mean room temperature, "h" means time, "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, "EtOAc" means ethyl acetate, "TEA" or "Et3N" means triethylamine, "DCM" means dichloromethane, "MeCN" or "ACN" means acetonitrile, "DMF" means dimethylformamide, "CDI" means 1,1'-carbonyldiimidazole, "DMA" means dimethylacetamide, and "Pd(dppf)Cl2" means [1."Pin 2B2" means 1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), "Pin 2B2" means bis(pinacolato)diboron, "THF" means tetrahydrofuran, "i-PrOH" or "iPrOH" means 2-propanol, "LC" means liquid chromatography, "LCMS" means liquid chromatography / mass spectrometry, "HPLC" means high performance liquid chromatography, "prep HPLC" means preparative high performance liquid chromatography, "TFA" means trifluoroacetic acid, "RP" means reverse phase, "min" means minute(s), "h" means hour(s), "PE" means petroleum ether, "v / v" means volume per volume, "Celite® " means diatomaceous earth, "DMSO" means dimethylsulfoxide, "SFC" means supercritical fluid chromatography, "DIPE" means diisopropyl ether, "DIPEA" or "DIEA" means N,N-diisopropylethylamine, "Pd2(dba)3" means tris(dibenzylideneacetone)-dipalladium, "Pd(OAc)2" means palladium(II) acetate, "AcOH" means acetic acid, "DMAP" means 4-(dimethylamino)pyridine, "t-BuOK", "BuO", or "KOtBu" means potassium tert-butoxide, "TLC" means thin layer chromatography, "prep-TLC" means preparative TLC, and "KOAc" means potassium acetate.

[0224] For intermediates that were used in subsequent reaction steps as crude or partially purified intermediates, estimated molar amounts (in some cases indicated by ~) are given in the reaction protocols described below, or alternatively theoretical molar amounts are given.

[0225] The meanings of abbreviations in nuclear magnetic resonance spectroscopy are provided as follows: s=singlet, d=doublet, dd=double doublet, dt=double triplet, ddd=triple doublet, Sept=septet, t=triplet, m=multiplet, br=broad, brs=broad singlet, q=quartet.

[0226] Example A1 Intermediate 4

[0227] [ka]

[0228] To a solution of 5-bromo-3-methoxypyrazine-2-carbaldehyde (55.0 g, 0.25 mol) and 2,5-diazaspiro[3.4]octan-6-one TFA salt (89.2 g, 0.28 mol) in DCM (800 mL) was added MgSO4 (122 g, 1.01 mol) and Et3N (51.3 g, 0.51 mol, 70.5 mL). The mixture was stirred at 15° C. for 30 min, then NaBH(OAc)3 (161 g, 0.76 mol) was added at 0° C. The mixture was stirred at 15° C. for 1 h. The reaction was run in parallel twice. TLC (DCM:MeOH=10:1, R f =0.4) indicated the reaction was complete. The mixture was diluted with DCM (800 mL) and saturated NaHCO3 solution (800 mL). The aqueous phase was separated and extracted with CHCl3:i-PrOH=3:1. The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The crude product was purified by recrystallization from EtOAc (300 mL) at 25 °C to give intermediate 1 (120 g, 69% yield) as a white solid. 1 H NMR:(400MHz,CDCl3)δ8.24-8.17(m,1H),6.52(br s,1H),4.06-3.97(m,3H),3.81-3.71(m,2H),3.58(d,J=8.6Hz,2H),3.39(d,J=8.6Hz,2H),2.47-2.32(m,4H).

[0229] To a mixture of compound 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (94.1 g, 370 mmol), intermediate 1 (110 g, 336 mmol) and K2CO3 (139 g, 1.01 mol) in dioxane (1100 mL) and H2O (220 mL) was added Pd(dppf)Cl2 (24.6 g, 33.6 mmol). The brown mixture was purged with N2 (3 times) and stirred at 100 °C for 1 h. The mixture was poured into H2O (1000 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluent of 0-5% MeOH / DCM @ 100 mL / min) to give intermediate 2 (123 g, 97% yield) as a brown solid. 1 H NMR:(400MHz,DMSO-d6)δ10.38(br s,1H),8.33(s,1H),8.14(s,1H),7.39-7.17(m,1H),7.06(br dd,J=7.8,13.7Hz,2H),3.94(s,3H),3.72(s,2H),3.44(br d,J=7.1Hz,2H),3.25(br d,J=7.1Hz,2H),2.28-2.07(m,4H).

[0230] To a mixture of intermediate 2 (123 g, 328 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (123 g, 344 mmol) in DCM (2260 mL) was added DIEA (127 g, 984 mmol, 171 mL) dropwise at 15° C. The brown mixture was stirred at 15° C. for 16 h. The residue was diluted with cold water (2000 mL) and extracted with DCM (2×1000 mL). The combined organic layers were washed with brine (2×1000 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (600 mL) for 2 h and filtered to give intermediate 3 (136 g, 81% yield) as a yellow solid. 1H NMR:(400MHz,DMSO-d6)δ8.54-8.39(m,1H),8.15(s,1H),7.90-7.60(m,3H),3.96(s ,3H),3.75(s,2H),3.45(d,J=8.1Hz,2H),3.25(d,J=8.0Hz,2H),2.30-2.06(m,4H).

[0231] To a mixture of intermediate 3 (50 g, 98.6 mmol), KOAc (29.0 g, 295 mmol), and dioxane (1000 mL) was added Pd(dppf)Cl2 (7.22 g, 9.86 mmol) and pin 2B2 (37.6 g, 148 mmol). The yellow mixture was stirred at 90 °C for 16 h. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography to give intermediate 4 (27 g, 70% pure) as a brown solid. MS:ES C 24 H 31 m / z calculated for BClNO4: 485.2 [M+H] + , actual value 485.0.

[0232] Example A2 Intermediate 5

[0233] [ka]

[0234] A mixture of intermediate 4 (2.50 g, 5.6 mmol), 3-bromo-2-chloroaniline (1.38 g, 6.70 mmol), Pd(dppf)Cl2 (377 mg, 516 μmol), and K2CO3 (2.14 g, 15.5 mmol) was degassed in dioxane (25 mL) and HO (2.5 mL) and purged with N2 (3 times), then the mixture was stirred under N2 atmosphere at 110 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography and repurified by preparative HPLC to give intermediate 5 (687 mg, 98% pure) as a yellow oil. MS:ES C 24 H 24 m / z calculated for Cl2N5O2: 484.1 [M+H] +, actual value 484.1.

[0235] Example A3 Intermediate 6-1

[0236] [ka]

[0237] A mixture of 5-bromo-3-methoxy-pyrazine-2-carbaldehyde (400 mg, 1.84 mmol), (5S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (416 mg, 2.76 mmol), and TEA (769.63 μL, 5.53 mmol) was stirred in DCM (10 mL) at 25° C. for 3 h. After NaBH(OAc)3 (1.17 g, 5.53 mmol) was added to the mixture, the mixture was stirred at 25° C. for 1 h. The reaction was quenched by the addition of water (50 mL) and then extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give intermediate 6-1 (600 mg) as a yellow liquid. MS:ES C 11 H 16 Calculated m / z for BrN4O2: 315.0 [M+H] + , actual value 315.0.

[0238] Using the appropriate starting materials, the intermediates shown in Table A-1 were prepared by reaction protocols similar to those used to prepare intermediate 6-1.

[0239] [Table 1]

[0240] Example A4 Intermediate 6A

[0241] [ka]

[0242] To a mixture of methyl 6-chloro-2,3-dihydro-3-oxo-4-pyridazinecarboxylate (2.00 g, 10.6 mmol) in DMF (20 mL) was added K2CO3 (2.93 g, 21.2 mmol) and MeI (3.01 g, 21.2 mmol, 1.32 mL) at room temperature. The mixture was stirred at 25 °C for 12 h to give a yellow suspension. The mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H2O (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give intermediate 6A-2 (1.66 g, 95% pure) as a white solid. MS: ES m / z calculated for C7H8ClN2O3 203.0 [M+H] + , actual value 203.0.

[0243] A mixture of intermediate 6A-2 (700.00 mg, 3.46 mmol) and LiOH·HO (290 mg, 6.91 mmol) in THF (4.2 mL) and HO (1.26 mL) was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to remove THF. The residue was purified by preparative HPLC to give intermediate 6A-1 (451.00 mg, 90% purity) as an off-white solid. MS: ES m / z calculated for C6H6ClN2O3 189.0 [M+H] + , actual value 188.9.

[0244] To a solution of intermediate 6A-1 (451 mg) in MeOH (10 mL) was added t-BuOK (671 mg, 5.98 mmol) at room temperature. The mixture was stirred at 160° C. for 6 h. The reaction was quenched with 1N aqueous hydrochloric acid (10 mL) and the mixture was extracted with DCM (20 mL). The organic phase was washed with 1N aqueous hydrochloric acid (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography to give intermediate 6A (215 mg, 65% pure) as a yellow solid. MS: ES m / z calculated for C7H9N2O4 185.1 [M+H] +, actual value 185.0.

[0245] Example A5 Intermediate 7-1

[0246] [ka]

[0247] A mixture of 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.1 g, 8.28 mmol), 1,3-dibromo-2-chlorobenzene (4.48 g, 16.6 mmol), Pd(dppf)Cl2 (606 mg, 828 μmol) and K2CO3 (3.43 g, 24.9 mmol) was degassed in dioxane (25 mL) and H2O (2.5 mL) and purged with N2 (3 times). After the mixture was stirred at 100 °C under N2 atmosphere for 2 h, the reaction was quenched with H2O (30 mL). The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give intermediate 7-1 (1.4 g) as a yellow solid. MS:ES C 12 m / z calculated for H9BrCl2: 315.9N [M+H] + , actual value 316.0.

[0248] Using the appropriate starting materials, the intermediates shown in Table A-2 were prepared by reaction protocols similar to those used to prepare intermediate 7-1.

[0249] [Table 2]

[0250] Example A6 Intermediate 8-1

[0251] [ka]

[0252] A mixture of intermediate 7-1 (1.26 g, 3.98 mmol), 2-methyl-3-oxo-pyridazine-4-carboxylic acid (737 mg, 4.78 mmol), TCFH (2.24 g, 7.97 mmol), and NMI (818 mg, 9.96 mmol) in MeCN (12 mL) was stirred at 50° C. for 21 h. The mixture was filtered to give the crude product, which was triturated with EtOAc (2×15 mL) and dried to give intermediate 8-1 (1.55 g, 96% purity) as a yellow solid. MS:ES C 18 H 13 Calculated m / z for BrCl2N3O2: 552.0 [M+H] + , actual value 551.8.

[0253] Using the appropriate starting materials, the intermediate shown in A-3 was prepared by a reaction protocol similar to that used to prepare intermediate 8-1.

[0254] [Table 3]

[0255] Example A7 Intermediate 9-1

[0256] [ka]

[0257] A mixture of intermediate 8-1 (1.55 g, 3.42 mmol), pin 2B2 (955.52 mg, 3.76 mmol), Pd(dppf)Cl2 (250 mg, 342 μmol), and AcOK (1.01 g, 10.26 mmol) was degassed in dioxane (10 mL) and purged with N2 (3 times), then the mixture was stirred under N2 atmosphere at 110 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give intermediate 9-1 (900 mg) as a yellow solid. MS:ES C 24 H 25m / z calculated for BCl2N3O4: 500.1 [M+H] + , actual value 500.0.

[0258] Using the appropriate starting materials, the intermediates shown in Table A-4 were prepared by reaction protocols similar to those used to prepare intermediate 9-1.

[0259] [Table 4]

[0260] Example A8 Intermediate 10-1

[0261] [ka]

[0262] To a solvent mixture of dioxane (8 mL) and H2O (0.8 mL) was added intermediate 9-1 (850 mg, 1.70 mmol), 6-chloro-2-methoxy-pyridine-3-carbaldehyde (321 mg, 1.87 mmol), Pd(dppf)Cl2 (124 mg, 170 μmol), and K2CO3 (705 mg, 5.10 mmol). The mixture was degassed and purged with N2 (3 times), then the mixture was stirred under N2 atmosphere at 110 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give intermediate 10-1 (720 mg) as a yellow solid. MS: ES C 25 H 19 m / z calculated for Cl2N4O4: 509.1 [M+H] + , actual value 509.1.

[0263] Using the appropriate starting materials, the compounds shown in Table A-5 were prepared by reaction protocols similar to those used to prepare intermediate 10-1.

[0264] [Table 5-1]

[0265] [Table 5-2]

[0266] Example 1 Compound A-1

[0267] [ka]

[0268] A mixture of intermediate 5 (50 mg, 103 μmol), 2-methyl-3-oxo-pyridazine-4-carboxylic acid (19 mg, 124 μmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (58 mg, 206 μmol), and N-methyl imidazole (NMI) (21 mg, 258 μmol) in MeCN (1.5 mL) was stirred at 50 °C for 16 h. This reaction was repeated using the same amount of starting material. The combined reaction mixture was diluted with HO (10 mL) and extracted with DCM (3x5 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give a residue which was purified twice by preparative HPLC to give compound A-1 (44 mg, 96% purity) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ12.23(br s,1H),8.66(dd,J=1.4,8.3Hz,1H),8.48(s,1H),8.33(d,J=4.3Hz,1H),8.06(d,J=4.3Hz, 1H),7.64(dd,J=1.7,7.7Hz,1H),7.52-7.33(m,3H),7.13(dd,J=1.5,7.6Hz,1H),6.40(br s,1H),4.05(s,3H),3.97(s,3H),3.92(s,2H),3.69(br d,J=8.0Hz,2H),3.61-3.53(m,2H),2.45-2.33(m,4H).

[0269] Using the appropriate starting materials, the compounds shown in Table B-1 were prepared by reaction protocols similar to those used to prepare compound A-1.

[0270] [Table 6]

[0271] Example 2 Compound B-1

[0272] [ka]

[0273] To a solvent mixture of 1,4-dioxane (2 mL) and H2O (0.2 mL) was added intermediate 6-1 (50 mg, 159 μmol), intermediate 9-1 (87 mg, 1751 μmol), Pd-118 (10 mg, 16 μmol), and K2CO3 (66 mg, 476 μmol). The mixture was degassed and purged with N2 (3 times). The mixture was stirred at 110 °C under N2 atmosphere for 2 h. The mixture was filtered and then concentrated to give a residue that was purified by preparative HPLC to give compound B-1 (36 mg, 99% pure) as a yellow solid.

[0274] Using the appropriate starting materials, the compounds shown in Table B-2 were prepared by reaction protocols similar to those used to prepare compound B-1.

[0275] [Table 7-1]

[0276] [Table 7-2]

[0277] Example 3 Compound C-1

[0278] [ka]

[0279] A mixture of (3R,4R)-4-aminotetrahydropyran-3-ol HCl (74 mg, 485 μmol) and intermediate 10-1 (170 mg, 334 μmol) in DCM (3 mL) was stirred at 25° C. for 2 h. To the mixture was added NaBH(OAc)3 (202 mg, 954 μmol). The mixture was stirred at 25° C. for 12 h. The reaction was quenched by adding water (0.5 mL). The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give compound C-1 (125 mg, 99% pure) as a white solid.

[0280] Using the appropriate starting materials, the compounds shown in Table B-3 were prepared by reaction protocols similar to those used to prepare compound C-1.

[0281] [Table 8-1]

[0282] [Table 8-2]

[0283] [Table 8-3]

[0284] [Table 8-4]

[0285] [Table 8-5]

[0286]

Table 8-6

[0287]

Table 8-7

[0288]

Table 8-8

[0289]

Table 8-9

[0290]

Table 8-10

[0291]

Table 8-11

[0292]

Table 8-12

[0293]

Table 8-13

[0294]

Table 8-14

[0295]

Table 8-15

[0296]

Table 8-16

[0297] [Table 8-17]

[0298] Example 3 Compound D-1

[0299] [ka]

[0300] A mixture of compound B-1 (55 mg, 90 μmol), ethyl chloroformate (18 μl, 181 μmol), and K2CO3 (37 mg, 271 μmol) in THF (2 mL) was stirred for 1 h at 25° C. The mixture was concentrated to give a residue, which was purified by preparative HPLC to give compound D-1 (20 mg, 99% pure) as a yellow solid.

[0301] Using the appropriate starting materials, the compounds shown in Table B-4 were prepared by reaction protocols similar to those used to prepare compound D-1.

[0302] [Table 9]

[0303] Example 4 Compound E-1

[0304] [ka]

[0305] To a solution of compound C-1 (80 mg, 131 μmol) in THF (0.5 mL) was added NaH (15.72 mg, 393 μmol, 60% purity) at 0° C. After the mixture was stirred at 0° C. for 0.5 h, DMAP (1.60 mg, 13.10 umol, 0.1 eq.) and (4-nitrophenyl)methyl chloroformate (28.25 mg, 131.04 umol, 1 eq.) were added to the mixture at 0° C. The mixture was stirred at 25° C. for 4 h. The reaction was quenched by adding water. The mixture was extracted with EtOAc (2×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound E-1 (3.6 mg, 95% purity) as a white solid.

[0306] Example 4A Compound F-1

[0307] [ka]

[0308] To a solution of compound C-94 (448 mg, 734 μmol) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (267.60 mg, 771 μmol) in DMF (5 mL) was added DIEA (383 μL, 2.20 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then warmed to 30° C. and stirred for 16 h. The mixture was filtered to obtain a filtrate, which was purified by preparative HPLC to obtain compound F-1 (172 mg, 99% pure) as a white solid. M:ES C 36 H 34 Cl2NO 10 Calculated m / z value: 766.2 [M+H] + , actual value 766.1. 1H NMR(400MHz,CDCL3)δ12.24(s,1H),8.65(dd,J=1.4,8.3Hz,1H),8.33(d,J=4.3Hz,1H),8.06(d,J =4.1Hz,1H),7.69-7.64(m,1H),7.54-7.54(m,1H),7.54-7.37(m,3H),7.31-7.28(m,1H),7.13(br d,J=7.6Hz,1H),4.89(d,J=17.0Hz,2H),4.51(d,J=10.6Hz,2H),4.13(q,J=7.2Hz,2H),4.03(s,3H),3 .97(s,3H),3.70-3.61(m,2H),2.68-2.57(m,2H),2.18(d,J=14.1Hz,3H),1.26(dt,J=2.8,7.1Hz,3H).

[0309] Example 4B Compound G-1

[0310] [ka]

[0311] A mixture of compound C-38 (410 mg, 686 μmol) and 4-methylbenzenesulfonic acid, hydrate (300.24 mg, 1.58 mmol) in EtOH (8 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give compound G-1 as an off-white solid. MS:ES C 30 H 30 m / z calculated for Cl2N5O6: 626.2 [M+H] + , actual value 626.1. 1H NMR(400MHz,CDCL3)δ12.27-12.20(m,1H),8.65(dd,J=1.5,8.3Hz,1H),8.33(d,J=4.3Hz,1H),8.06 (d,J=4.3Hz,1H),7.70-7.62(m,2H),7.42(td,J=7.8,14.4Hz,2H),7.32-7.27(m,2H),7.13(dd,J=1. 5,7.6Hz,1H),4.42-4.35(m,1H),4.27(q,J=7.1Hz,2H),4.04(s,3H),3.97(s,3H),3.96-3.95(m,1H ),3.95-3.82(m,2H),3.12(dd,J=3.8,12.3Hz,1H),2.96(dd,J=6.3,12.4Hz,1H),1.34-1.29(m,3H).

[0312] Example 4C Compound H-1

[0313] [ka]

[0314] To a mixture of compound G-1 (70 mg, 89 μmol) in THF (1 mL) was added CDI (72 mg, 447 μmol) at 20° C. The resulting mixture was stirred at 50° C. for 16 h to give a yellow solution. The yellow reaction solution was cooled to 20° C. The resulting mixture was diluted with DCM (10 mL) and then washed with H2O (5 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic layers were filtered and concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give compound H-1 as a white solid. 1H NMR(400MHz,CDCl3)δ12.24(br s,1H),8.81-8.53(m,1H),8.45-8.22(m,1H),8.06(br s,1H),7.65(br s,2H),7.51-7.37(m,2H),7.30(br s,2H),7.13(br s,1H),5.02-4.82(m,1H),4.49(br s,2H),4.36-4.22(m,2H),4.03(br s,3H),3.97(br s,3H),3.85(br s,1H),3.67(br s,1H),1.36-1.24(m,3H).

[0315] Example 5 Further compounds Other compounds that can be prepared applying procedures similar to those described herein include:

[0316] [ka]

[0317] [ka]

[0318] [ka]

[0319] [ka]

[0320] [ka] (including pharma- ceutically acceptable salts thereof).

[0321] Example A LCMS (Liquid Chromatography / Mass Spectrometry) High Performance Liquid Chromatography (HPLC) measurements were performed using an LC pump, a diode-array (DAD) or UV detector, and a column as specified in each method. Additional detectors were included if necessary (see methods table below). The flow from the column was sent to a Mass Spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, residence time) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data acquisition was performed with appropriate software. Compounds are described by their experimental retention time (Rt) and ion. If not specified differently in the data tables, the reported molecular ions are [M+H] + (protonated molecule) and / or [MH] - (deprotonated molecule). If the compound was not directly ionizable, the type of adduct was identified (i.e., [M+NH4] + , [M+Na] + , [M+HCOO] - etc.). For molecules with multiple isotopic patterns (Br, Cl), the values ​​reported are those obtained for the lowest isotopic mass. All results were obtained with experimental uncertainties typically associated with the method used. In the following, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "RT" means room temperature, "BEH" means crosslinked ethylsiloxane / silica hybrid, "DAD" means diode array detector, "HSS" means high strength silica, "QT" means quadrupole time-of-flight mass spectrometer, "CLND" means chemiluminescence nitrogen detector, and "ELSD" means evaporative optical scanning detector.

[0322] [Table 10-1]

[0323] [Table 10-2] Flow rates are expressed in mL / min, column temperatures (T) are expressed in °C, and run times are expressed in minutes.

[0324] [Table 11-1]

[0325] [Table 11-2] Retention time (R t ) (min), LC / MS: not indicated, mass is [M+H] + Supports

[0326] Example A-1 NMR (nuclear magnetic resonance) Proton ( 1 H NMR spectra were recorded and chemical shifts (d) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) used as internal standard.

[0327] Compound C-7: 1 H NMR(400MHz,CDCL3)δ12.32-12.08(m,1H),8.65(dd,J=1.4,8.3Hz,1H),8.33(d,J=4.3Hz,1H),8.06(d,J=4.1Hz,1H),7.74-7.61(m,2H),7.41(t d,J=7.8,12.9Hz,2H),7.31-7.28(m,2H),7.13(dd,J=1.4,7.6Hz,1H),4 .60-4.49(m,1H),4.03(s,3H),3.97(s,3H),3.94-3.77(m,4H),3.35(br s,2H).

[0328] Compound C-9: 11H NMR (400 MHz, CDCl3) δ 12.23 (s, 1H), 8.65 (dd, J = 1.3, 8.3 Hz, 1H), 8.34 - 8.31 (m, 1H), 8.06 (d, J = 4.3 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 1.6, 7.8 Hz, 1H), 7.54 - 7.28 (m, 4H), 7.11 (dd, J = 1.4, 7.5 Hz, 1H), 4.70 - 4.33 (m, 2H), 4.27 (s, 2H), 4.23 - 4.09 (m, 2H), 4.08 - 4.02 (m, 3H), 3.99 - 3.94 (m, 3H), 3.55 (br d, J = 10.3 Hz, 1H).

[0329] Compound C-13: 1 1H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 8.65 (dd, J = 1.4, 8.3 Hz, 1H), 8.33 (d, J = 4.1 Hz, 1H), 8.06 (d, J = 4.3 Hz, 1H), 7.72 - 7.57 (m, 2H), 7.41 (td, J = 7.8, 10.9 Hz, 2H), 7.29 (d, J = 1.6 Hz, 2H), 7.26 (s, 1H), 7.12 (dd, J = 1.4, 7.6 Hz, 1H), 4.23 - 4.14 (m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.69 - 3.61 (m, 4H), 3.46 - 3.32 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0330] Compound C-81: 1 1H-NMR (DMSO-d6, 400 MHz): 1.51~1.57 (m, 1H), 1.64~1.72 (m, 1H), 2.44~50 (m, 1H), 2.70~2.74 (m, 1H), 3.24~3.36 (m, 2H), 3.66~3.70 (m, 2H), 3.73~3.78 (m, 3H), 3.86 (s, 3H), 3.99 (s, 3H), 4.65 (d, J = 3.6 Hz, 1H), 7.22 (dd, J = 7.6 Hz, 1.5 Hz, 1H), 7.47~7.57 (m, 3H), 7.8 (dd, J = 7.6 Hz, 1.7 Hz, 1H), 8.26~8.29 (m, 2H), 8.62 (dd, J = 8.3 Hz, 1.5 Hz, 1H), 8.67 (s, 1H), 12.36 (s, 1H).

[0331] Example B PDL1 / PD1 binding assay Compounds to be tested were serially diluted in DMSO and further diluted in assay buffer (25 mM Hepes pH 7.4, 150 mM NaCl, 0.005% Tween 20, 0.01% BSA). The diluted compounds were added to the wells, with a final concentration of 1% DMSO. PDL1-6xHis protein was added to the wells and mixed well with the compounds. The plate was incubated for 30 minutes at room temperature. PD1-Fc-Avi-biotin protein was added to the wells. The final concentrations of PDL1 and PD1 proteins are 0.3 nM and 2.5 nM, respectively. After 30 minutes of binding time at room temperature, anti-6xHis acceptor beads (final concentration 20 μg / mL) were added to the wells and incubation continued for 1 hour. Streptavidin donor beads (final concentration 20 μg / mL) were added under reduced light. Plates were sealed with foil and incubated in the dark for an additional hour or overnight before being read on an Envision reader. 50 Values ​​were determined by curve fitting using a four parameter equation in Graphpad Prism8.

[0332] Example C PD-1 / PD-L1 NFAT reporter assay The cellular activity of the compounds was assessed using a co-culture reporter assay in which TCR-mediated NFAT activity in Jurkat T cells was constitutively inhibited by engagement of PD-1 by PD-L1-expressing CHO cells. Blockade of the PD-1 / PD-L1 interaction releases an inhibitory signal, resulting in TCR signaling and NFAT-mediated luciferase activity.

[0333] CHO cells expressing surface-bound anti-CD3 antibody and PD-L1 were first seeded overnight and treated with compounds. Jurkat cells overexpressing PD-1 and luciferase constructs under the NFAT promoter were then immediately seeded onto the monolayer of CHO cells. The co-cultures were then incubated at 37°C for 6 hours. Luciferase activity was assessed by adding ONE-Glo reagent and measuring luminescence with a plate reader. EC 50 Values ​​were determined from fitting of dose-response curves.

[0334] The compounds described herein have EC values ​​in the following ranges, as illustrated in the Examples: 50 Value or IC 50 The values ​​are shown. A:IC 50 or EC 50 ≦10nM, B:10nM <IC 50 or EC 50 ≦100nM, C:100nM <IC 50 or EC 50 ≦1000nM, D:1000nM <IC 50 or EC 50 ≦10000nM, E:IC 50 or EC 50 >10000nM, nd=not determined, nr=EC not reached in the range of tested concentrations starting from 1nM to 5000nM 50 .

[0335] [Table 12-1]

[0336] [Table 12-2]

[0337] Although the foregoing has been described in some detail with reference to the figures and examples for clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It is therefore to be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present disclosure.

Claims

1. A compound of formula (I) having the structure: 【Chemistry 1】 During the ceremony, R １ａ is -C １～４ Alkyl, -C １～４ Haloalkyl, -CH ２ (C ３～６ monocyclic cycloalkyl), -CH ２ (4- to 6-membered monocyclic heterocyclyl), and -CH ２ (5-6 membered monocyclic heteroaryl); R １ｂ is hydrogen, -C １～４ Alkyl, and -C １～４ haloalkyl; R １ｃ is -N(R ｍ１ ) R ｎ１ and -R ｘ１ is selected from the group consisting of R ２ａ , R ２ｂ , R ２ｃ , R ２ｅ , R ２ｇ , R ２ｈ is independently selected from the group consisting of hydrogen and halogen; R ２ｄ and R ２ｆ are independently hydrogen, halogen, cyano, -CH ３ , -CH ２ CH ３ , -CH ２ OH, -OCH ３ , and -SCH ３ is selected from R ３ａ is hydrogen, -CH ３ , -CF ３ , and -CHF ２ is selected from the group consisting of R ３ｂ is hydrogen, halogen, cyano, -CH ３ , -CF ３ , -CHF ２， -CH ２ CH ３ , -CH ２ OH, -OCH ３ , and -SCH ３ is selected from the group consisting of Y １ａ is selected from the group consisting of N (nitrogen) and -CH; Y １ｂ is N (nitrogen) and C (R ４ ) selected from the group consisting of Y ２ａ is N (nitrogen) and C (R ５ ) selected from the group consisting of Y ２ｂ is N (nitrogen) and C (R １ｄ ) selected from the group consisting of R １ｄ is selected from the group consisting of hydrogen and halogen; R ４ is hydrogen, halogen and -CH ３ is selected from the group consisting of R ５ is hydrogen, halogen and -CH ３ is selected from the group consisting of R ｍ１ is hydrogen, -C １～４ Alkyl, C ３～６ Monocyclic cycloalkyl, C ５～１２ bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, 8- to 11-membered fused bicyclic heteroaryl, and 8- to 11-membered fused bicyclic heterocyclyl, wherein the 5- or 6-membered monocyclic heteroaryl, bicyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and bicyclic heterocyclyl are independently selected from O (oxygen), S (sulfur), C(═O), S(═O), S(═O), ２ and N (nitrogen), １～４ Alkyl is independently halogen, cyano, hydroxy, -C １～４ Alkoxy, -C １～４ Haloalkyl, -C １～４ Haloalkoxy, -C(=O)OR Ｚ１ , -C(=O)NHS(=O) ２ R Ｚ３ , -C(=O)N(R Ｚ１ ) R Ｚ２ , -S(=O) ２ R Ｚ３ , -S(=O) ２ 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)N(R Ｚ２ ) R Ｚ３ and optionally substituted with one, two or three substituents selected from the group consisting of ３～６ Monocyclic cycloalkyl, ５～１２ The bicyclic cycloalkyl, the 5- or 6-membered monocyclic heteroaryl, the 4- to 7-membered monocyclic heterocyclyl, the 8- to 11-membered fused bicyclic heteroaryl, and the 8- to 11-membered fused bicyclic heterocyclyl are independently selected from halogen, cyano, -C １～４ Alkyl, hydroxy, -C １～４ Alkoxy, -C １～４ Haloalkyl, -C １～４ Haloalkoxy, -C(=O)OR Ｚ１ , -C(=O)NHS(=O) ２ R Ｚ３ , -C(=O)N(R Ｚ１ ) R Ｚ２ , -C(=O)R Ｚ３ , -CH ２ C(=O)OR Ｚ３ , -S(=O) ２ R Ｚ３ , -S(=O) ２ 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)N(R Ｚ２ ) R Ｚ３ and R is optionally substituted with one or two or three substituents selected from the group consisting of ｎ１ is hydrogen, -C １～４ Alkyl, -C １～４ Haloalkyl, C ３～６ Monocyclic cycloalkyl (CH ２ )-, or -C(=O)OR Ｚ４ and R ｘ１ teeth, 【Chemistry 2】 R ｘ１ are independently halogen, cyano, -C １～４ Alkyl, hydroxy, -C １～４ Alkoxy, -C １～４ Haloalkyl, -C １～４ Haloalkoxy, -C(=O)OR Ｚ１ , -C(=O)NHS(=O) ２ R Ｚ３ , -C(=O)N(R Ｚ１ ) R Ｚ２ , -S(=O) ２ R Ｚ３ , -S(=O) ２ 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 Ｚ１ ) R Ｚ３ , and -N(R Ｚ１ ) S(=O) ２ N (R Ｚ２ ) R Ｚ３ and optionally substituted with one or two substituents selected from the group consisting of: m １ , m ２ , and m ３ is independently 1 or 2; m ４ is 0, 1, or 2, m ５ is 1, 2, 3, or 4, Each R Ｘ３ are independently hydrogen, halogen, -C １～４ Alkyl, -C １～４ Haloalkyl, -C(=O)R Ｚ３ , -C(=O)OR Ｚ１ , -CH ２ C(=O)OR Ｚ３ , -S(=O) ２ R Ｚ１ , -C(=O)NHS(=O) ２ (R Ｚ３ ), -NHC(=O)(R Ｚ３ ), -C(=O)N(R Ｚ１ ) R Ｚ２ , and -S(=O) ２ N (R Ｚ１ ) R Ｚ２ is selected from the group consisting of R Ｚ１ and R Ｚ２ are independently hydrogen, -C １～４ Alkyl, and -C １～４ haloalkyl; or R Ｚ１ and R Ｚ２ when attached to the same nitrogen, are taken together to form a monocyclic heterocyclyl, R Ｚ３ is hydrogen, -C １～４ Alkyl, and -C １～４ haloalkyl; R Ｚ４ is hydrogen, -C １～４ Alkyl, and -C １～４ 5-6 membered monocyclic heterocyclyl optionally substituted with alkyl (CH ２ )-, or a pharma- ceutically acceptable salt thereof.

2. Y ２ａ The compound of claim 1 , wherein is N.

3. Y ２ａ is C(R ５ 2. The compound of claim 1, wherein

4. R ５ The compound of claim 3 , wherein is hydrogen.

5. R ５ The compound of claim 3 , wherein is a halogen.

6. R ５ is -CH ３ 4. The compound of claim 3,

7. R ３ａ The compound according to any one of claims 1 to 6, wherein is hydrogen.

8. R ３ａ is -CH ３ The compound according to any one of claims 1 to 6,

9. R ３ａ is -CF ３ The compound according to any one of claims 1 to 6,

10. R ３ａ is -CHF ２ The compound according to any one of claims 1 to 6,

11. R ３ｂ The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. R ３ｂ The compound according to any one of claims 1 to 10, wherein is a halogen.

13. R ３ｂ The compound according to any one of claims 1 to 10, wherein is cyano.

14. R ３ｂ is -CH ３ or -CH ２ CH ３ The compound according to any one of claims 1 to 10,

15. R ３ｂ is -CF ３ or -CHF ２ The compound according to any one of claims 1 to 10,

16. R ３ｂ is -CH ２ OH, -OH, -OCH ３ , or -SCH ３ The compound according to any one of claims 1 to 10,

17. Y １ａ The compound according to any one of claims 1 to 16, wherein is N.

18. Y １ａ The compound according to any one of claims 1 to 16, wherein is -CH.

19. Y １ｂ The compound according to any one of claims 1 to 18, wherein is N.

20. Y １ｂ is C(R ４ 19. The compound according to any one of claims 1 to 18, wherein

21. R ４ The compound of claim 20 , wherein is hydrogen.

22. R ４ The compound of claim 20 , wherein is a halogen.

23. R ４ is -CH ３ 21. The compound of claim 20,

24. R １ａ is -C １～４ The compound of any one of claims 1 to 23, which is alkyl.

25. R １ａ is -C １～４ The compound of any one of claims 1 to 23, which is haloalkyl.

26. R １ａ is -CH ２ (C ３～６ monocyclic cycloalkyl), -CH ２ (4- to 6-membered monocyclic heterocyclyl), and -CH ２ 24. The compound according to any one of claims 1 to 23, selected from the group consisting of (5-6 membered monocyclic heteroaryl).

27. R １ｄ The compound according to any one of claims 1 to 26, wherein is hydrogen.

28. R １ｄ The compound according to any one of claims 1 to 26, wherein is halogen.

29. R １ｃ is -N(R ｍ１ ) R ｎ１ The compound according to any one of claims 1 to 28,

30. R ｎ１ is hydrogen.

31. R ｎ１ is -C １～４ 30. The compound of claim 29, which is alkyl.

32. R ｎ１ is -C １～４ Haloalkyl, C ３～６ Monocyclic cycloalkyl (CH ２ )-, or -C(=O)OR Ｚ４ 30. The compound of claim 29,

33. R ｍ１ A compound according to any one of claims 29 to 32, wherein is tetrahydrofuran or tetrahydro-2H-pyran, each optionally substituted by hydroxy.

34. R ｍ１ teeth, 【Chemistry 3】 34. The compound of claim 33, wherein

35. R ｍ１ teeth, 【Chemistry 4】 The compound according to any one of claims 29 to 32, selected from the group consisting of:

36. -R ｍ１ teeth, 【Chemistry 5】 36. The compound of claim 35,

37. R １ｃ is -R ｘ１ The compound according to any one of claims 1 to 28,

38. -R ｘ１ teeth, 【Chemistry 6】 38. The compound of claim 37, wherein:

39. -R ｘ１ teeth, 【Chemistry 7】 38. The compound of claim 37, selected from the group consisting of:

40. -R ｘ１ teeth, 【Chemistry 8】 38. The compound of claim 37, selected from the group consisting of:

41. R ２ａ , R ２ｂ , R ２ｃ , R ２ｅ , R ２ｇ , and R ２ｈ The compound of any one of claims 1 to 40, wherein each is hydrogen.

42. R ２ａ , R ２ｃ , R ２ｅ , R ２ｇ , and R ２ｈ are each hydrogen, R ２ｂ The compound according to any one of claims 1 to 40, wherein is halogen.

43. R ２ｂ , R ２ｃ , R ２ｅ , R ２ｇ , and R ２ｈ are each hydrogen, R ２ａ The compound according to any one of claims 1 to 40, wherein is halogen.

44. R ２ｄ and R ２ｆ The compound of any one of claims 1 to 43, wherein each is halogen.

45. R ２ｄ and R ２ｆ are each -CH ３ The compound according to any one of claims 1 to 43,

46. R ２ｄ is a halogen, R ２ｆ is -CH ３ The compound according to any one of claims 1 to 43,

47. R ２ｄ is -CH ３ and R ２ｆ The compound according to any one of claims 1 to 43, wherein is halogen.

48. R ２ｄ is cyano, R ２ｆ The compound according to any one of claims 1 to 43, wherein is halogen.

49. R ２ｄ is -OCH ３ and R ２ｆ The compound according to any one of claims 1 to 43, wherein is halogen.

50. 50. The compound of any one of claims 42-44 or 46-49, wherein the halogen is chloro or fluoro.

51. -R ｍ１ teeth, 【Chemistry 9】 2. The compound of claim 1 selected from the group consisting of:

52. 【Catalog 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 2. The compound of claim 1 selected from the group consisting of:

53. 【Catalogue 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 ​ 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 2. The compound of claim 1 selected from the group consisting of:

54. 54. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, and an excipient.

55. 54. A method for treating Hepatitis B in a subject, comprising administering to the subject in need thereof an effective amount of a compound, or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 53.

56. 54. A method for treating hepatocellular carcinoma (HCC) in a subject, comprising administering to the subject in need thereof an effective amount of a compound, or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 53.

57. 57. The method of claim 55 or 56, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

58. 54. A compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, for use in treating hepatitis B.

59. 54. A compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC).

60. 60. The compound of claim 58 or 59, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

61. 54. Use of a compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for use in treating Hepatitis B.

62. 54. Use of a compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC).

63. 63. The use of claim 61 or 62, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

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