Methods and compositions for targeting PD-L1

Abstract

The present disclosure relates to compounds that are 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 pharmaceutically acceptable salt thereof, and uses or methods of using a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of PD-L1 related diseases including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.

Description

[0001] Incorporation by reference into any priority application

[0002] Any and all applications claiming foreign or domestic priority, such as those identified in an application data sheet or request filed with this application, are hereby incorporated by reference at 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 265,510 filed on December 16, 2021. Technical Field

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

[0004] In activated CD4 + and CD8 + The programmed cell death 1 (PD-1) immune checkpoint expressed on the surface of T cells controls the inhibitory mechanism to prevent autoimmunity. The engagement of PD-1 with programmed death ligand 1 (PD-L1) expressed on a variety of cell types (including macrophages, dendritic cells, mast cells and cancer cells) induces T cell exhaustion, resulting in a reduction or loss of effector cytokine production (such as IL-2, TNF-α, IFN-γ) and other inhibitory receptors and immune checkpoints (such as CTLA-4, LAG-3 and BTLA) Upregulation or T cell apoptosis. Many types of cancer show high expression of PD-L1 to escape tumor immune surveillance and are associated with poor prognosis. PD-1-mediated immunosuppression is also associated with some viral infections (such as hepatitis B). There is a continuous need for PD-1 / PD-L1 therapy and its improvement for treating diseases. Summary of the invention

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

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

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

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

[0009] These are further embodiments described in more detail below. DETAILED DESCRIPTION

[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. Inflammation, fibrosis, and cirrhosis associated with these conditions can induce malignancies in the affected liver cells. HCC has a relatively poor prognosis, with a five-year survival rate of about 30%, depending on whether complete surgical resection of the tumor is possible.

[0011] For early stage disease, surgical resection is used. However, due to diagnostic difficulties, most HCCs are identified in the later stage. At the time of late diagnosis, the tumor is unresectable, and most patients are given systemic treatment. The current standard of care for the front line is a multikinase inhibitor (including, for example, sorafenib and / or lenvatinib). Most patients are refractory or recurrent for these treatments, and experience a second-line therapy with an anti-angiogenic agent (including, for example, Regorafinib, Cabozantinib and / or Ramicirumab) or an immune checkpoint inhibitor (including, for example, nivolumab and / or pembrolizumab). However, most patients do not respond to the first and second therapies, and the clinical benefit is poor, with an overall survival of no more than one year. In addition, there is a lack of biomarker-driven therapy. Therefore, it is necessary to develop a more tolerated and effective therapy for the treatment of HCC and related liver diseases.

[0012] HBV is a partially double-stranded circular DNA of about 3.2 kilobase (kb) pairs, and is classified into eight genotypes, i.e., A to H. The HBV replication pathway has been studied in more detail. A portion of the replication includes the formation of a covalently closed circular DNA (cccDNA) form. The presence of cccDNA causes the risk of the virus reappearing during the entire life span of the host organism. HBV carriers can spread the disease for many years. An estimated 300 million people are infected with hepatitis B virus, and it is estimated that more than 750,000 people die of hepatitis B each year worldwide. In addition, immunosuppressed individuals or individuals undergoing chemotherapy are particularly at risk of HBV infection reactivation. HBV can be acute and / or chronic. Acute HBV infection can be asymptomatic or there is symptomatic acute hepatitis.

[0013] HBV can be transmitted by blood, semen, and / or another body fluid. This can occur through direct blood-to-blood contact, unprotected sexual intercourse, shared needles, and from an infected mother to her baby during the birthing process. HBV surface antigen (HBsAg) is most commonly used to screen for the presence of this infection. Currently available drugs cannot cure HBV and / or HDV infection. Instead, the drugs inhibit the replication of the virus.

[0014] Hepatitis D virus (HDV) is also a DNA virus in the Hepadnaviridae family. HDV can only reproduce when HBV is present. The transmission routes of HDV are similar to those of HBV. The spread of HDV can occur via simultaneous infection with HBV (co-infection) or in addition to chronic hepatitis B or hepatitis B carrier status (superinfection). Compared with HBV infection alone, superinfection and co-infection of HDV both lead to more serious complications. These complications include a greater likelihood of experiencing rapid development of liver failure and cirrhosis in acute infection, with an increased risk of developing liver cancer in chronic infection. Combined with hepatitis B, hepatitis D has the highest mortality rate of 20% among all hepatitis infections. There is currently no treatment 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 is used to negatively regulate immune responses to prevent autoimmune disorders. PD-1 protein (NCBI accession number NP_005009.2) is expressed by the cluster of differentiation 279 (CD279) gene (NCBI accession number NG_012110.1) or mRNA transcript (NCBI accession number NM_005018.3). In some preferred embodiments, PD-1 is human PD-1 protein, and CD279 is a human CD279 transcript or gene on chromosome 2. It should be understood that when considering nucleic acids (DNA or RNA) or corresponding translated proteins or their sequences, those of ordinary skill in the art will consider that the terms PD-1 and CD279 are generally nominally interchangeable.

[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 main ligand of PD-1 and leads to 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 anti-tumor immunity of proximal T cells. Viruses have also been observed to regulate the PD-1 / PD-L1 pathway to suppress host immune responses. Hepatitis B virus has been shown to upregulate PD-L1 in infected hepatocytes and PD-1 in associated T cells. PD-L1 protein (NCBI accession number NP_054862.1) is expressed by cluster of differentiation 274 (CD274) transcripts (NCBI accession number NM_014143.4). In some preferred embodiments, PD-L1 is a human PD-L1 protein and CD274 is a human CD274 transcript or gene on chromosome 9. It should be understood that when considering nucleic acids (DNA or RNA) or corresponding translated proteins or their sequences, one of ordinary skill in the art will consider the terms PD-L1 and CD274 to be generally nominally interchangeable.

[0017] definition

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. Unless otherwise indicated, all patents, applications, published applications and other disclosures cited herein are incorporated by reference in their entirety. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosures contained in this specification, this specification is intended to replace and / or take precedence over any such conflicting materials. In the event that there are multiple definitions for a term herein, the definitions in that section shall prevail unless otherwise indicated.

[0019] Whenever a group is described as "optionally substituted", the group may be unsubstituted or substituted by one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the one or more substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted by one or more groups (such as 1, 2 or 3 groups) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-amino The invention also includes but is not limited to the following: alkyl groups, such as alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups, alkyl groups,

[0020] As used herein, "C" wherein "a" and "b" are integers a To 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 ring in a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, a “C1 to C4 alkyl” or “C1-C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If “a” and “b” are not specified with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described in these definitions should be assumed.

[0021] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bond) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in a given range; for example, "1 to 20 carbon atoms" means that the alkyl group may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition of the present invention also encompasses the term "alkyl" that appears without specifying a numerical range). The alkyl group may also be a medium-sized alkyl group with 1 to 10 carbon atoms. The alkyl group may also be a low alkyl group with 1 to 6 carbon atoms. The alkyl group of the compound may be named "C1-C4 alkyl" or similar naming. By way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.Alkyl groups may be substituted or unsubstituted.

[0022] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The length of the alkenyl group can vary. For example, the alkenyl group can be C 2-4 Alkenyl, C 2-6 Alkenyl or C 2-8 Alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and vinyl. Alkenyl groups can be unsubstituted or substituted.

[0023] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The length of the alkynyl group can vary. For example, the alkynyl group can be C 2-4 Alkynyl, C 2-6 Alkynyl or C 2-8 Alkynyl. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0024] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be joined together in a fused form. The cycloalkyl group can contain 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. The cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0025] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if there is more than one double bond, the double bond cannot form a completely delocalized π electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). When composed of two or more rings, the rings may be linked together in a fused form. The cycloalkenyl group may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. The cycloalkenyl group may be unsubstituted or substituted.

[0026] 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 π electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C 14 Aryl group, C6 to C 10 An aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0027] As used herein, "heteroaryl" refers to monocyclic, bicyclic and tricyclic aromatic ring systems (ring systems with a completely delocalized π electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), which are elements other than carbon, including but not limited to nitrogen, oxygen and sulfur. The number of atoms in the ring of the heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. In addition, the term "heteroaryl" includes a fused ring system in which two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0028] As used herein, "heterocyclic group" refers to monocyclic, bicyclic and tricyclic ring systems, wherein carbon atoms together with 1 to 5 heteroatoms constitute the ring system. The heterocyclic ring may optionally contain one or more unsaturated bonds positioned in such a way that a completely delocalized π electron system does not occur throughout all rings. The number of atoms in the ring of the heterocyclic group may vary. For example, the heterocyclic group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. The heterocyclic ring may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo-systems and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, these rings may be joined together in a fused form. In addition, any nitrogen in the heterocyclic group may be quaternized. The heterocyclic group may be unsubstituted or substituted. Examples of such "heterocyclyl" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiinane, 1,4-oxathiinene, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dithiocarboxylate ...

[00136] In some embodiments, the present invention relates to benzopyrrolidine, benzoimidazoline, benzothiophene, benzofuran, benzothiophene-1, benzothiophene-2, benzothiophene-3, benzothiophene-4, benzothiophene-5, benzothiophene-6, benzothiophene-7, benzothiophene-8, benzothiophene-9, benzothiophene-10, benzothiophene-11, benzothiophene-12, benzothiophene-13, benzothiophene-14, benzothiophene-15, benzothiophene-16, benzothiophene-17, benzothiophene-18, benzothiophene-19, benzothiophene-21, benzothiophene-23, benzothiophene-24, benzothiophene-25

[0029] As used herein, "aryl(alkyl)" refers to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0030] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group attached as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of the heteroaryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furanyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and benzo-fused analogs thereof.

[0031] "Heterocyclyl(alkyl)" refers to a heterocyclic group attached as a substituent via a lower alkylene group. The lower alkylene and heterocyclic groups 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-thiazin-4-yl(methyl).

[0032] A "lower alkylene group" is a straight-chain -CH2-tethered group that forms a bond to connect molecular fragments via its terminal carbon atom. In some embodiments, the lower alkylene group may include 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). The lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group with one or more substituents listed according to the definition of "substituted".

[0033] 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, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. In some cases, the alkoxy group may be -OR, where R is an unsubstituted C 1-4 Alkyl. Alkoxy may be substituted or unsubstituted.

[0034] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) attached as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl groups may 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 a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.

[0036] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0037] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some cases, the haloalkoxy group can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1-4 Alkyl. The haloalkoxy group may be substituted or unsubstituted.

[0038] A "sulfenyl" group refers to a "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl group can be substituted or unsubstituted.

[0039] A "sulfinyl" group refers to a "-S(=O)-R" group in which R is the same as defined with respect to sulfenyl. A sulfinyl group can be substituted or unsubstituted.

[0040] A "sulfonyl" group refers to an "S(=O)2R" group in which R is the same as defined with respect to sulfenyl. A sulfonyl group may be substituted or unsubstituted.

[0041] An "O-carboxyl" group refers to an "RC(=O)O-" group wherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0042] The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group in which R is the same as defined with respect to O-carboxy. Esters and C-carboxy may be substituted or unsubstituted.

[0043] A "thiocarbonyl" group refers to a "-C(=S)R" group in which R is the same as defined with respect to O-carboxy. The thiocarbonyl group may be substituted or unsubstituted.

[0044] A "trihalomethanesulfonyl" group refers to a "X3CS(=O)2-" group wherein each X is a halogen.

[0045] A "trihalomethanesulfonylamino" group is one in which each X is a halogen and R A "X3CS(=O)2N(R)" is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A )-” group.

[0046] As used herein, the term "amino" refers to a -NH2 group.

[0047] As used herein, the term "hydroxy" refers to an -OH group.

[0048] A "cyano" group refers to a "-CN" group.

[0049] As used herein, the term "azido" refers to a -N3 group.

[0050] An "isocyanate" group refers to a "-NCO" group.

[0051] A "thiocyanate" group refers to a "-SCN" group.

[0052] An "isothiocyanate" group refers to a "-NCS" group.

[0053] A "mercapto" group refers to a "-SH" group.

[0054] A "carbonyl" group refers to a -C(=O)- group.

[0055] An "S-sulfonylamino" group refers to a group in which R A and R B "-S(=O)2N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B The S-sulfonylamino group may be substituted or unsubstituted.

[0056] An "N-sulfonylamino" group is one in which R and R A "RS(=O)2N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) AThe N-sulfonylamino group may be substituted or unsubstituted.

[0057] An "O-carbamyl" group is one in which R A and R B "-OC(=O)N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B The O-carbamyl group may be substituted or unsubstituted.

[0058] An "N-carbamyl" group is one in which R and R A "ROC(=O)N(R)" which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A The N-carbamoyl group may be substituted or unsubstituted.

[0059] An "O-thiocarbamyl" group is one in which R A and R B "-OC(=S)-N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B The O-thiocarbamoyl group may be substituted or unsubstituted.

[0060] An "N-thiocarbamyl" group is one in which R and R A "ROC(=S)N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A The N-thiocarbamoyl group may be substituted or unsubstituted.

[0061] A "C-amido" group is one in which R A and R B "-C(=O)N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B The C-acylamino group may be substituted or unsubstituted.

[0062] An "N-amido" group is one in which R and R A"RC(=O)N(R)" may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A The N-acylamino group may be substituted or unsubstituted.

[0063] A "monosubstituted amine" is one in which R A "-NHR" which may independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A ". The monosubstituted amine may be substituted or unsubstituted. In some cases, the monosubstituted amine may be -NHR A , where R A Can be unsubstituted C 1-6 alkyl or unsubstituted or substituted benzyl.

[0064] A "disubstituted amine" is one in which R A and R B "-NR" may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) A R B The monosubstituted amine may be substituted or unsubstituted. In some cases, the monosubstituted amine may be -NR A R B , where R A and R B may be independently unsubstituted C 1-6 alkyl or unsubstituted or substituted benzyl.

[0065] As used herein, the term "halogen atom" or "halogen" means any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0066] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens. For another example, "C1 to C3 alkoxyphenyl" may contain one or more of the same or different alkoxy groups containing one, two or three atoms.

[0067] As used herein, unless otherwise indicated, abbreviations for any protecting groups, amino acids, and other compounds are in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission (see, Biochem. 11:942-944 (1972)).

[0068] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant stimulation to the organism to which it is applied and does not eliminate the biological activity and characteristics 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 an inorganic acid (such as, a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid). Pharmaceutical salts can also be obtained by reacting the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid (e.g., formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid). Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salts (e.g., ammonium salts or triethylammonium salts), alkali metal salts (such as lithium, sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), salts with organic bases (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reaction with amino acids (such as arginine and lysine).

[0069] For the terms and phrases used in this application, especially in the appended claims and their variations, unless otherwise expressly stated, they should be understood as open-ended and not restrictive. For the aforementioned examples, the term "including" should be understood as "including but not limited to", "including but not limited to", etc.; as used herein, the term "including" is synonymous with "including", "containing" or "characterized as" and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term "having" should be interpreted as "at least having"; the term "including" should be interpreted as "including but not limited to"; the term "example" is used to provide an illustrative example of the item being discussed, rather than an exhaustive or limiting list thereof. In addition, the term "including" should be interpreted as synonymous with the phrase "at least having" or "at least including". When used in the context of a compound or composition, the term "including" means that the compound or composition includes at least the described features or components, but may also include additional features or components.

[0070] For substantially any plural and / or singular terms used herein, those skilled in the art may convert from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. For clarity, the various singular / plural permutations may be expressly stated herein. The indefinite article "a" or "an" does not exclude a plurality.

[0071] It should be understood that in any compound with one or more chiral centers described herein, if absolute stereochemistry is not clearly indicated, each center can independently be (R) configuration or (S) configuration or a mixture thereof. Therefore, the compound provided herein can be a racemic mixture of enantiomerically pure enantiomerically enriched or a stereoisomeric mixture of diastereomerically pure diastereomerically enriched. In addition, it should be understood that in any compound with one or more double bonds that generate geometric isomers that can be defined as E or Z as described herein, each double bond can independently be E or Z or a mixture thereof. Similarly, it should be understood that in any compound described, all tautomeric forms are also intended to be included.

[0072] It is understood that where compounds disclosed herein have unfilled valencies, these are filled with hydrogen or its isotopes (eg, hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0073] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from improved metabolic stability, such as, for example, increased half-life in vivo or reduced dosage requirements. Each chemical element as represented in the compound structure may include any isotope of the element. For example, in the compound structure, it may be explicitly disclosed or understood that hydrogen atoms are present in the compound. At any position of the compound where hydrogen atoms may be present, the hydrogen atoms may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless otherwise expressly specified in the context, the compounds mentioned herein encompass all possible isotopic forms.

[0074] Where a range of values ​​is provided, it should be understood that the upper and lower limits and every intermediate value between the upper and lower limits of the range are encompassed within the embodiments.

[0075] Compound

[0076] Examples of implementations of the present application include the following:

[0077] Implementation 1

[0078] A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0079]

[0080] Where: R 1a Can be selected from -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6-CH2(4- to 6-membered monocyclic heterocyclyl) and -CH2(5- to 6-membered monocyclic heteroaryl); R 1b Can be selected from hydrogen, -C 1-4 Alkyl and -C 1-4 Haloalkyl; R 1c Can be selected from -N(R m1 )R n1 and -R x1 ; R 2a , R 2b , R 2c , R 2e , R 2g , R 2h R may be independently selected from hydrogen and halogen; 2d and R 2f R may be independently selected from hydrogen, halogen, cyano, -CH3, -CH2CH3, -CH2OH, -OCH3 and -SCH3; 3a may be selected from hydrogen, -CH3, -CF3 and -CHF2; R 3b can be selected from hydrogen, halogen, cyano, -CH3, -CF3, -CHF2, -CH2CH3, -CH2OH, -OH, -OCH3 and -SCH3; Y 1a can be selected from N (nitrogen) and -CH; Y 1b Can be selected from N (nitrogen) and C (R 4 );Y 2a Can be selected from N (nitrogen) and C (R 5 );Y 2b Can be selected from N (nitrogen) and C (R 1d ), R 1d may be selected from hydrogen and halogen; R 4 may be selected from hydrogen, halogen and -CH3; R 5 may be selected from hydrogen, halogen and -CH3; R m1 Can be selected from hydrogen, -C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 5-membered or 6-membered monocyclic heteroaryl, 4-membered to 7-membered monocyclic heterocyclyl, 8-membered to 11-membered fused bicyclic heteroaryl and 8-membered to 11-membered fused bicyclic heterocyclyl; wherein the 5-membered or 6-membered monocyclic heteroaryl, the bicyclic heteroaryl, the 4-membered to 7-membered monocyclic heterocyclyl and the bicyclic heterocyclyl contain at least one atom or atomic group independently selected from O (oxygen), S (sulfur), C (=O), S (=O), S (=O) 2 and N (nitrogen); wherein the -C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, 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 Z2 )R Z3 and -N(R Z1 )S(=O)N(R Z2 )R Z3 ; Among them, the C 3-6 Monocyclic cycloalkyl, the C 5-12 The bicyclic cycloalkyl, the 5-membered or 6-membered monocyclic heteroaryl, the 4-membered to 7-membered monocyclic heterocyclyl, the 8-membered to 11-membered fused bicyclic heteroaryl and the 8-membered to 11-membered fused bicyclic heterocyclyl may be optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, -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 ; and R n1 It can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C3-6 Monocyclic cycloalkyl (CH2)- or -C(=O)OR Z4 ; R x1 You can choose from:

[0081] Where R x1 may be optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, -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 Z1 )R Z3 and -N(R Z1 )S(=O)2N(R Z2 )R Z3 ; 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; each R X3 may be independently selected from 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 ; R Z1 and R Z2 may be independently selected from hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; or R Z1and R Z2 When attached to the same nitrogen, they may be joined together to form a monocyclic heterocyclic group; R Z3 Can be selected from hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; and R Z4 Can be selected from hydrogen, -C 1-4 Alkyl and optionally -C 1-4 Alkyl-substituted 5- to 6-membered monocyclic heterocyclyl (CH2)-. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following structure:

[0082]

[0083] Where: R 1a Can be selected from -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 -CH2(4- to 6-membered monocyclic heterocyclyl) and -CH2(5- to 6-membered monocyclic heteroaryl); R 1b Can be selected from hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl; R 1c Can be selected from -N(R m1 )R n1 and -R x1 ; R 1d may be selected from hydrogen and halogen; R 2a , R 2b , R 2c , R 2e , R 2g , R 2h R may be independently selected from hydrogen and halogen; 2d and R 2f R may be independently selected from hydrogen, halogen, cyano, -CH3, -CH2CH3, -CH2OH, -OCH3 and -SCH3; 3a may be selected from hydrogen, -CH3, -CF3 and -CHF2; R 3b can be selected from hydrogen, halogen, cyano, -CH3, -CF3, -CHF2, -CH2CH3, -CH2OH, -OCH3 and -SCH3; Y 1a can be selected from N (nitrogen) and -CH; Y 1b Can be selected from N (nitrogen) and C (R 4 );Y 2a Can be selected from N (nitrogen) and C (R 5 );R 4 may be selected from hydrogen, halogen and -CH3; R 5 may be selected from hydrogen, halogen and -CH3; R m1 Can be selected from hydrogen, -C1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 5-membered or 6-membered monocyclic heteroaryl, 4-membered to 7-membered monocyclic heterocyclyl, 8-membered to 11-membered fused heteroaryl, 8-membered to 11-membered fused heterocyclyl, and -R x2 wherein the monocyclic heteroaryl, the bicyclic heteroaryl, the monocyclic heterocyclic group and the bicyclic heterocyclic group contain at least one atom or atomic group independently selected from O (oxygen), S (sulfur), C (=O), S (=O), S (=O) 2 and N (nitrogen); wherein the -C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from the group consisting of 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 ; Among them, the C 3-6 Monocyclic cycloalkyl, the C 5-12 The bicyclic cycloalkyl, the 5-membered or 6-membered monocyclic heteroaryl, the 4-membered to 7-membered monocyclic heterocyclyl, the 8-membered to 11-membered fused heteroaryl and the 8-membered to 11-membered fused heterocyclyl may be optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, -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 )RZ2 、-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 n1 It can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic cycloalkyl (CH2)- or -C(=O)OR Z4 ; R x1 Can be selected from the group consisting of:

[0084]

[0085] Where R x1 may be optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, -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 Z1 )R Z3 and -N(R Z1 )S(=O)2N(R Z2 )R Z3 ; R x2 Can be selected from

[0086] 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; each RX3 may be independently selected from 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 ; R Z1 and R Z2 may be independently selected from hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; or R Z1 and R Z2 When attached to the same nitrogen, they may be joined together to form a monocyclic heterocyclic group; R Z3 Can be selected from hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; and R Z4 Can be selected from hydrogen, -C 1-4 Alkyl and optionally -C 1-4 Alkyl-substituted 5- to 6-membered monocyclic heterocyclyl (CH2)-. Some exemplary structures of formula (I) or pharmaceutically acceptable salts thereof include those of formula (Ia) to (Ih):

[0087]

[0088]

[0089] (including pharmaceutically acceptable salts of any of the aforementioned compounds).

[0090] Implementation 2

[0091] A compound according to embodiment 1, wherein Y 2a It may be N (nitrogen).

[0092] Implementation 3

[0093] A compound according to embodiment 1, wherein Y 2a It can be C(R 5 ).

[0094] Implementation 4

[0095] The compound according to embodiment 3, wherein R 5 It may be hydrogen.

[0096] Implementation 5

[0097] The compound according to embodiment 3, wherein R 5 It may be a halogen such as fluorine or chlorine.

[0098] Implementation 6

[0099] The compound according to embodiment 3, wherein R 5 It can be -CH3.

[0100] Implementation Plan 7

[0101] A compound according to any one of embodiments 1 to 6, wherein R 3a It may be hydrogen.

[0102] Implementation 8

[0103] A compound according to any one of embodiments 1 to 6, wherein R 3a It can be -CH3.

[0104] Implementation Plan 9

[0105] A compound according to any one of embodiments 1 to 6, wherein R 3a It can be -CF3.

[0106] Implementation 10

[0107] A compound according to any one of embodiments 1 to 6, wherein R 3a It can be -CHF2.

[0108] Implementation Plan 11

[0109] A compound according to any one of embodiments 1-10, wherein R 3b It may be hydrogen.

[0110] Implementation 12

[0111] A compound according to any one of embodiments 1 to 10, wherein R 3b It may be a halogen such as fluorine or chlorine.

[0112] Implementation 13

[0113] A compound according to any one of embodiments 1 to 10, wherein R 3b It may be a cyano group.

[0114] Implementation Plan 14

[0115] A compound according to any one of embodiments 1 to 10, wherein R 3b It can be -CH3 or -CH2CH3.

[0116] Implementation Plan 15

[0117] A compound according to any one of embodiments 1 to 10, wherein R 3b It can be -CF3 or -CHF2.

[0118] Implementation Plan 16

[0119] A compound according to any one of embodiments 1 to 10, wherein R 3b It can be -CH2OH, -OH, -OCH3 or -SCH3.

[0120] Implementation Plan 17

[0121] A compound according to any one of embodiments 1 to 16, wherein Y 1a It may be N (nitrogen).

[0122] Implementation Plan 18

[0123] A compound according to any one of embodiments 1 to 16, wherein Y 1a It can be -CH.

[0124] Implementation Plan 19

[0125] A compound according to any one of embodiments 1 to 18, wherein Y 1b It may be N (nitrogen).

[0126] Implementation Plan 20

[0127] A compound according to any one of embodiments 1 to 18, wherein Y 1b It can be C(R 4 ).

[0128] Implementation Plan 21

[0129] The compound according to embodiment 20, wherein R 4 It may be hydrogen.

[0130] Implementation Plan 22

[0131] The compound according to embodiment 20, wherein R 4 It can be a halogen. For example, R 4 It may be fluorine or chlorine.

[0132] Implementation Plan 23

[0133] The compound according to embodiment 20, wherein R 4 It can be -CH3.

[0134] Implementation Plan 24

[0135] A compound according to any one of embodiments 1 to 23, wherein R 1a Can be -C 1-4 Alkyl. C 1-4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0136] Implementation Plan 25

[0137] A compound according to any one of embodiments 1 to 23, wherein R 1a Can be -C 1-4 Haloalkyl such as -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CF3 and -CH2CHF2.

[0138] Implementation Plan 26

[0139] A compound according to any one of embodiments 1 to 23, wherein R 1a Can be selected from -CH2(C 3-6 In some embodiments, the 4- to 6-membered monocyclic heterocyclic group (4- to 6-membered monocyclic heterocyclic group) of the -CH2 and / or the 5- to 6-membered monocyclic heteroaryl (5- to 6-membered monocyclic heteroaryl) of the -CH2 may include one or more ring atoms (such as 1, 2, or 3) selected from N (nitrogen), O (oxygen), and S (sulfur).

[0140] Implementation Plan 27

[0141] A compound according to any one of embodiments 1-26, wherein R 1d It may be hydrogen.

[0142] Implementation Plan 28

[0143] A compound according to any one of embodiments 1 to 26, wherein R 1d It may be a halogen such as fluorine or chlorine.

[0144] Implementation Plan 29

[0145] A compound according to any one of embodiments 1 to 28, wherein R 1c Can be -N(R m1 )R n1 .

[0146] Implementation Plan 30

[0147] The compound according to embodiment 29, wherein R n1 can be hydrogen, so that R 1c It can be -NH(R m1 ).

[0148] Implementation Plan 31

[0149] The compound according to embodiment 29, wherein R n1 Can be -C 1-4 Alkyl. For example, R n1 It may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0150] Implementation Plan 32

[0151] The compound according to embodiment 29, wherein R n1 It can be -C(=O)OR Z4 In some embodiments, R Z4 Can be C 1-4 In other embodiments, R Z4 Can be optionally replaced by -C 1-4 alkyl-substituted 5- to 6-membered monocyclic heterocyclyl (CH2)-. In other embodiments, according to the compound described in Embodiment 29, wherein R n1 Can be C 1-4 In other embodiments, according to the compound described in Embodiment 29, wherein R n1 Can be C 3-6 Monocyclic cycloalkyl (CH2)-, such as cyclopropyl-(CH2)-, cyclobutyl-(CH2)-, cyclopentyl-(CH2)- and cyclohexyl-(CH2)-.

[0152] Implementation Plan 33

[0153] A compound according to any one of embodiments 29 to 32, wherein R m1 It may be tetrahydrofuran or tetrahydro-2H-pyran, each of which is optionally substituted with hydroxyl groups.

[0154] Implementation Plan 34

[0155] A compound according to embodiment 33, wherein R m1 Can be

[0156] Implementation Plan 35

[0157] A compound according to any one of embodiments 29 to 32, wherein R m1 Can be selected from

[0158]

[0159] Implementation Plan 36

[0160] A compound according to Embodiment 35, wherein -R m1 Can be Implementation Plan 37

[0161] A compound according to any one of embodiments 1 to 28, wherein R 1c Can be –R x1 .

[0162] Implementation Plan 38

[0163] A compound according to Embodiment 37, wherein -R x1 Can be Implementation Plan 39

[0164] A compound according to embodiment 37, wherein -R x1 You can choose from:

[0165] Implementation Plan 40

[0166] A compound according to embodiment 37, wherein -R x1 You can choose from:

[0167] Implementation Plan 41

[0168] A compound according to any one of embodiments 1 to 40, wherein R 2a , R 2b , R 2c , R 2e , R 2g and R 2h Each may be hydrogen.

[0169] Implementation Plan 42

[0170] A compound according to any one of embodiments 1 to 40, wherein R 2a , R 2c , R 2e , R 2g and R 2h may each be hydrogen; and R 2b It may be a halogen.

[0171] Implementation Plan 43

[0172] A compound according to any one of embodiments 1 to 40, wherein R 2b , R 2c , R 2e , R 2g and R 2h may each be hydrogen; and R 2a It may be a halogen.

[0173] Implementation Plan 44

[0174] A compound according to any one of embodiments 1 to 43, wherein R 2d and R 2f In some embodiments, R 2d and R 2f In other embodiments, R 2d and R 2f Each may be chlorine.

[0175] Implementation Plan 45

[0176] A compound according to any one of embodiments 1 to 43, wherein R 2d and R 2f Each may be -CH3.

[0177] Implementation Plan 46

[0178] A compound according to any one of embodiments 1 to 43, wherein R 2d may be halogen; and R 2f It can be -CH3.

[0179] Implementation Plan 47

[0180] A compound according to any one of embodiments 1 to 43, wherein R 2d may be -CH3; and R 2f It may be a halogen.

[0181] Implementation Plan 48

[0182] A compound according to any one of embodiments 1 to 43, wherein R 2d may be cyano; and R 2f It may be a halogen.

[0183] Implementation Plan 49

[0184] A compound according to any one of embodiments 1 to 43, wherein R 2d may be -OCH3; and R 2f It may be a halogen.

[0185] Implementation Plan 50

[0186] A compound according to any one of embodiments 42 to 44 or 46 to 49, wherein the halogen may be chlorine or fluorine.

[0187] Implementation Plan 51

[0188] A compound according to embodiment 1, wherein -R m1 You can choose from:

[0189] In other embodiments, -R m1 Can be selected from

[0190] In other embodiments, -R m1 Can be selected from

[0191] Implementation Plan 52

[0192] A compound according to embodiment 1, wherein the compound is selected from:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] Or a pharmaceutically acceptable salt of any one of the foregoing.

[0209] Implementation Plan 53

[0210] A compound according to embodiment 1, wherein the compound is selected from:

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222] Or a pharmaceutically acceptable salt of any one of the foregoing.

[0223] Implementation Plan 54

[0224] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof cannot be a compound or a pharmaceutically acceptable salt thereof provided in WO 2021 / 076691.

[0225] Implementation Plan 55

[0226] A pharmaceutical composition may comprise an effective amount of a compound according to any one of Embodiments 1 to 54 or a pharmaceutically acceptable salt thereof and an excipient.

[0227] Implementation Plan 56

[0228] A method for treating hepatitis B in a subject, which may comprise administering to a subject in need thereof an effective amount of a compound according to any one of Embodiments 1 to 54, or a pharmaceutically acceptable salt thereof.

[0229] Implementation Plan 57

[0230] A method for treating hepatocellular carcinoma (HCC) in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of Embodiments 1 to 54, or a pharmaceutically acceptable salt thereof.

[0231] Implementation Plan 58

[0232] According to any one of embodiments 56 to 57, the method may further include administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

[0233] Implementation Plan 59

[0234] According to any one of embodiments 1 to 54, the compound or a pharmaceutically acceptable salt thereof is used for treating hepatitis B.

[0235] Implementation Plan 60

[0236] According to any one of embodiments 1 to 54, the compound or a pharmaceutically acceptable salt thereof is used for treating hepatocellular carcinoma (HCC).

[0237] Implementation Plan 61

[0238] According to the compound of any one of embodiments 59 to 60, the method may further include administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

[0239] Implementation Plan 62

[0240] Use of a compound according to any one of Embodiments 1 to 54 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatitis B.

[0241] Implementation Plan 63

[0242] Use of a compound according to any one of Embodiments 1 to 54 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatocellular carcinoma (HCC).

[0243] Implementation Plan 64

[0244] According to the use of any one of embodiments 62 to 63, the method may further include administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy or antiviral therapy.

[0245] Preparation method

[0246] In this section, as in all other sections, unless the context indicates otherwise, references to formula (I) and pharmaceutically acceptable salts thereof include all other subgroups and examples thereof as provided herein. The general preparation of some representative examples of compounds of formula (I) is described herein, and they are generally prepared from starting materials that are commercially available or prepared by standard synthetic techniques used by those skilled in the art.

[0247] Unless otherwise indicated or obvious from the context, all variables shown in the schemes are defined as referred to herein.

[0248] Solution 1

[0249]

[0250] In general, compounds of formula (I) (including pharmaceutically 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 apply: (1) the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) in a suitable solvent (such as a mixture of 1,4-dioxane and water) with a suitable base (e.g., K2CO3) at a suitable temperature (e.g., 100°C); 2) the presence of a suitable base (e.g., DIPEA) in a suitable solvent (such as DCM) at a suitable temperature (e.g., 100°C); 3) the presence of a suitable catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) in a suitable solvent (such as 1,4-dioxane) The invention relates to a process for preparing an alkyl cyclohexane-diocyanate-containing cyclopentane or cyclopentane-containing cyclopentane. The process comprises the following steps: 1) in the presence of a suitable base (e.g., KOAc) in a mixture of 1,4-dioxane and water at a suitable temperature (e.g., 90°C); 2) 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) at a suitable temperature (e.g., 100°C); and 3) in the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole) in a suitable solvent (e.g., acetonitrile) at a suitable temperature (e.g., 50°C).

[0251] Solution 2

[0252]

[0253] 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 apply: 1) 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., K2CO3) at a suitable temperature (e.g., 100°C); 2) the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate and N-methylimidazole); 3) 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., (e.g., 1,4-dioxane and water) in the presence of a suitable base (e.g., KCO) at a suitable temperature (e.g., 100°C); and 5) in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) in a suitable solvent (e.g., DCM or MeOH) at a suitable temperature (e.g., about 20°C).

[0254] Pharmaceutical composition

[0255] 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 pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and / or veterinary use.

[0256] As used herein, the terms "function" and "functional" refer to a biological, enzymatic or therapeutic function.

[0257] The term "effective amount" or "effective dose" is used to indicate the amount of an active compound or agent that causes the indicated biological or pharmaceutical response. For example, the effective amount of a compound may be the amount required to reduce or alleviate the symptoms of a disease or prolong the survival of a subject being treated. The response may occur in a tissue, system, animal or human and include a reduction in the signs or symptoms of the disease being treated. Based on the disclosure provided herein, the determination of an effective amount is well within the capabilities of those skilled in the art. The effective amount of a compound disclosed herein required as a dose will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal under consideration. The dose can be modulated to achieve the desired effect, but the dose will depend on factors such as body weight, diet, concurrent medications, and other factors that will be recognized by those skilled in the medical field.

[0258] The term "pharmaceutically acceptable salt" includes relatively non-toxic inorganic and organic acid or base addition salts of compositions, including but not limited to analgesics, therapeutic agents, other substances, etc. Examples of pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid and sulfuric acid, and those derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Examples of suitable inorganic bases for forming salts include hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, etc. Salts may also be formed from suitable organic bases, including those that are non-toxic and strong enough to form such salts. For example, the class of such organic bases may include, but are not limited to, monoalkylamines, dialkylamines, and trialkylamines, including methylamine, dimethylamine, and triethylamine; monohydroxyalkylamines, dihydroxyalkylamines, or trihydroxyalkylamines, including monoethanolamine, diethanolamine, and triethanolamine; amino acids, including glycine, arginine, and lysine; guanidine; N-methylglucamine; N-methylglucosamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; and trishydroxymethylaminoethane.

[0259]

[00136] "Formulation," "pharmaceutical composition," and "composition" as used interchangeably herein are equivalent terms referring to a composition of matter for administration to a subject.

[0260] The term "pharmaceutically acceptable" means compatible with treatment of subjects, and particularly humans.

[0261] The term "agent" refers to an active agent that is biologically active and can be used for treatment. In addition, "agent" can be synonymous with "at least one agent", "compound" or "at least one compound", and can refer to any form of the agent, such as its derivatives, analogs, salts or prodrugs. The agent can exist in various forms, components of molecular complexes and pharmaceutically acceptable salts (e.g., hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates and salicylates). The term "agent" can also refer to any drug molecule or compound, therapeutic molecule or compound, matrix-forming molecule or compound, polymer, synthetic molecule and compound, natural molecule and compound, and any combination thereof.

[0262] As used herein, the term "subject" has its ordinary meaning as understood in accordance with this specification, and refers to an animal that is the object of treatment, inhibition or improvement, observation or experiment. "Animal" has its ordinary meaning as understood in accordance with this specification, and includes cold-blooded and warm-blooded vertebrates and / or invertebrates, such as fish, shellfish or reptiles, and particularly mammals. "Mammal" has its ordinary meaning as understood in accordance with this specification, and includes but is not limited to mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates such as humans, monkeys, chimpanzees or apes. In some embodiments, the subject is a human.

[0263] The correct formulation depends on the selected route of administration. The technology for preparing and administering the compounds described herein is known to those skilled in the art. There are various technologies for administering compounds in the art, including but not limited to enteral, oral, rectal, topical, sublingual, oral, intraauricular, epidural, epidermal, aerosol, parenteral delivery (including intramuscular, subcutaneous, intraarterial, intravenous injection, intraportal vein, intraarticular, intradermal, intraperitoneal, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection). Pharmaceutical compositions are usually modulated according to specific expected routes of administration. Pharmaceutical compositions can also be applied to cells separated from patients or individuals, such as T cells, natural killer cells, B cells, macrophages, lymphocytes, stem cells, bone marrow cells or hematopoietic stem cells.

[0264] The drug compound may also be administered in a local rather than systemic manner, for example, by direct injection of the compound into an organ, tissue, cancer, tumor, or area of ​​infection, usually in the form of a depot or slow-release formulation. In addition, the compound may be administered in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposome may be targeted to and selectively taken up by an organ, tissue, cancer, tumor, or area of ​​infection.

[0265] The pharmaceutical compositions disclosed herein can be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, embedding or tableting processes. As described herein, the compounds used in the pharmaceutical compositions can be provided as salts with pharmaceutically compatible counterions.

[0266] As used herein, "carrier" refers to a compound, particle, solid, semisolid, liquid or diluent that facilitates the passage, delivery and / or binding of a compound to cells, tissues and / or body organs. For example, but not limited to, lipid nanoparticles (LNPs) are one type of carrier that can encapsulate a compound as described herein or a pharmaceutically acceptable salt thereof, thereby protecting the compound as described herein or a pharmaceutically acceptable salt thereof from degradation during passage through the bloodstream and / or facilitating delivery to a desired organ, such as the liver.

[0267] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmaceutically active but may be necessary or desirable pharmaceutically. For example, a diluent can be used to increase the volume of a potent drug whose mass is too small to manufacture and / or administer. It can also be a liquid used to dissolve 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.

[0268] The term "excipient" has its ordinary meaning as understood in accordance with this specification, and refers to an inert substance, compound or material added to a pharmaceutical composition to provide, but not limited to, bulk, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. Excipients having desired properties include, but are not limited to, preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizers, detergents, surfactants, chelating agents, antioxidants, alcohols, ketones, aldehydes, ethylenediaminetetraacetic acid (EDTA), citric acid, salts, sodium chloride, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, potassium chloride, potassium phosphate, magnesium sulfate, sugars, dextrose, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, serum, amino acids, polysorbate 20, polysorbate 80, sodium deoxycholate, taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea or vitamins, or any combination thereof. The amount of excipient can be present in the pharmaceutical composition as 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% w / w, or any weight percentage within the range defined by any two of the foregoing numbers.

[0269] As used herein, the term "adjuvant" refers to a substance, compound or material that stimulates the immune response and increases the efficacy of protective immunity and is administered in conjunction with an immunogenic antigen, epitope or composition. Adjuvants are used to improve the immune response by enabling sustained release of antigens, upregulation of cytokines and chemokines, cell recruitment at the site of administration, increased antigen uptake and presentation in antigen-presenting cells, or activation of antigen-presenting cells and inflammasomes. Commonly used adjuvants include, but are not limited to: alum, aluminum salts, aluminum sulfate, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, potassium aluminum sulfate, oil, mineral oil, paraffin oil, oil-in-water emulsions, detergents, Squalene, AS03, alpha-tocopherol, polysorbate 80, AS04, monophosphoryl lipid A, polysorbate, virosomes, nucleic acids, polyinosinic:polycytidylic acid, saponin, QS-21, proteins, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21, imidazoquinoline, CpG oligonucleotides, lipids, phospholipids, dioleoylphosphatidylcholine (DOPC), trehalose dimycolate, peptidoglycan, bacterial extracts, lipopolysaccharide or Freund's adjuvant, or any combination thereof.

[0270] As used herein, the term "purity" of any given substance, compound, or material refers to the actual abundance of the substance, compound, or material relative to the expected abundance. For example, a substance, compound, or material may be at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure, including all decimals therebetween. Purity may be affected by unwanted impurities, including but not limited to by-products, isomers, enantiomers, degradation products, solvents, carriers, vehicles, or contaminants, or any combination thereof. Techniques that can measure purity include but are not limited to chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-visible spectroscopy, infrared spectroscopy, mass spectrometry, nuclear magnetic resonance, gravimetric analysis, or titration, or any combination thereof.

[0271] How to use

[0272] Some embodiments disclosed herein relate to selecting a subject or patient in need. In some embodiments, a patient who needs to treat, inhibit, improve, prevent or mitigate a disease or condition associated with PD-L1 disorder is selected. In some embodiments, such diseases or conditions associated with PD-L1 disorder may include, for example, cancer, HCC, viral infection or HBV. In some embodiments, a subject who has previously been treated for a disease or condition described herein may be selected. In some embodiments, a subject who has previously been treated for a disease or condition described herein may be selected. In some embodiments, a subject who has developed a recurrence of a disease or condition described herein may be selected. In some embodiments, a subject who has developed resistance to a therapy for a disease or condition described herein may be selected. In some embodiments, a subject who may have any combination of the aforementioned selection criteria may be selected.

[0273] The efficacy and toxicity of the compounds disclosed herein and their pharmaceutically acceptable salts can be evaluated using known methods. A non-limiting list of potential advantages of the compounds described herein or their pharmaceutically acceptable salts include improved stability, increased safety profile, increased efficacy, increased binding to a target, increased specificity to a target (e.g., a cancer cell or a virus-infected cell).

[0274] As used herein, the terms "treating", "treatment", "therapeutic" or "therapy" have their ordinary meanings as understood in accordance with this specification, and do not necessarily mean complete cure or elimination of a disease or condition. As used herein, the terms "treating" or "treatment" (and as fully understood in the art) also mean methods of obtaining beneficial or desired results (including clinical results) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviating or improving one or more symptoms or conditions, alleviating the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread or spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing the recurrence and relief of the disease, whether partial or complete, and whether detectable or undetectable. As used herein, "treating" and "treatment" also include preventive treatment. Methods of treatment include administering a therapeutically effective amount of an active agent to a subject. The administration step may consist of a single administration, or may include a series of administrations. The composition is administered to a subject in an amount and duration sufficient to treat the subject. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age and genetic characteristics of the subject, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention can be increased or decreased over the course of a particular treatment or prevention regimen. Changes in dosage can be produced and become apparent by standard diagnostic assays known in the art. In some cases, long-term administration may be required.

[0275] Some embodiments described herein relate to methods for treating, inhibiting, improving, preventing or slowing down a disease or condition described herein. In some embodiments, the method comprises administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof to a subject identified as suffering from a disease or condition described herein. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, inhibiting, improving, preventing or slowing down a disease or condition described herein. Yet other embodiments described herein relate to a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof for treating, inhibiting, improving, preventing or slowing down a disease or condition described herein.

[0276] Some embodiments described herein relate to methods for inhibiting cancer cell or virus replication, which may include contacting cells or viruses with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject identified as having cancer or viral infection. Other embodiments described herein relate to the use of an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for inhibiting cancer cell or virus replication. Yet other embodiments described herein relate to an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting cancer cell or virus replication. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus is hepatitis B.

[0277] Some embodiments described herein relate to methods for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or cells infected with viruses, which may include administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof to a subject identified as having a disease in which cell proliferation needs to be inhibited. Other embodiments described herein relate to the use of an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or cells infected with viruses. Yet other embodiments described herein relate to an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or cells infected with viruses. In some embodiments, cancer cells are HCC cells. In some embodiments, cells infected with viruses are infected with hepatitis B virus.

[0278] Some embodiments described herein relate to methods for inducing apoptosis of cells (e.g., cancer cells or cells infected with viruses), which may include contacting cells with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for inducing apoptosis of cells such as cancer cells or cells infected with viruses. Yet other embodiments described herein relate to the use of an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof for inducing apoptosis of cells such as cancer cells or cells infected with viruses. In some embodiments, cancer cells are HCC cells. In some embodiments, cells infected with viruses are infected with hepatitis B virus.

[0279] Some embodiments described herein relate to methods for reducing the viability of cells (e.g., cancer cells or cells infected with viruses), which may include contacting the cells with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using a compound as described herein or a pharmaceutically acceptable salt thereof in a medicament for manufacturing a cell such as a cancer cell or a cell infected with a virus for reducing the viability of a cell such as a cancer cell or a cell infected with a virus. Yet other embodiments described herein relate to the use of a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof for reducing 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.

[0280] Those skilled in the art of treating such diseases can determine the effective therapeutic daily dose from the test results. The effective therapeutic daily dose will be about 0.005 mg / kg to 50 mg / kg, 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, most preferably about 0.05 mg / kg to about 1 mg / kg body weight.

[0281] In some embodiments, an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof is administered more than once. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is administered every 1, 2, 3, 4, 5, 6, 7 days or 1, 2, 3, 4 weeks or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or 1, 2, 3, 4, 5 years or any time period or combination thereof within the range defined by any two of the aforementioned times. In some embodiments, at least one loading dose and at least one maintenance dose are administered to a subject, wherein at least one loading dose is a higher dose of a compound described herein or a pharmaceutically acceptable salt thereof than at least one maintenance dose.

[0282] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more drug compounds / agents or therapies. Therefore, the use of "combination therapy", "combination" and compound / agent "combination" mentioned in this application may refer to compounds / agents administered as part of the same overall treatment regimen. Therefore, the dosage or timing of each of the two or more compounds / agents may be different: each may be administered simultaneously or at different times. Therefore, the combined compound / agent may be administered sequentially (e.g., before or after) or simultaneously in the same pharmaceutical preparation (i.e., together) or in different pharmaceutical preparations (i.e., alone). Each of the two or more compounds / agents in the combination therapy may also be different relative to the route of administration.

[0283] As used herein, the term "inhibitor" refers to an enzyme inhibitor or a receptor inhibitor, which is a molecule that binds to an enzyme or receptor and reduces and / or blocks its activity. The term may refer to a reversible or irreversible inhibitor.

[0284] Cancer can be treated with surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy or hormone therapy. Any of these mentioned therapies can be used as a combination therapy in combination with another therapy. Chemotherapy compounds include but are not limited to alemtuzumab, altretamine, azacitidine, bendamustine, bleomycin, bortezomib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, chlorambucil, il), chlormethine, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denosumab, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gemcitabine, gemtuzumab, hydroxyurea, ibritumomab, idarubicin, ifosfamide, irinotecan, ixabepilone, lomustine, melphalan melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, ofatumumab, oxaliplatin, paclitaxel, pemetrexed, pentostatin, pertuzumab, procarbazine, raltitrexed,Streptozotocin, tegafur, temozolomide, temsirolimus, teniposide, thioguanine, topotecan, tositumomab, valrubicin, vinblastine, vincristine, vindesine, vinflunine or vinorelbine, or any combination thereof.

[0285] As used herein, the term "protein kinase inhibitor" refers to an inhibitor of a protein kinase, serine / threonine kinase, tyrosine kinase, or dual specificity kinase for the treatment of cancer or other diseases. In some embodiments, the protein kinase 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, protein kinase inhibitors include but are not limited to acalabrutinib, adavosertib, afatinib, alectinib, axitinib, binimetinib, bosutinib, brigatinib, cediranib, ceritinib, cetuximab, cobimetinib, crizotinib, Crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erdafitinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, lortatinib, Marseille 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.

[0286] 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 a 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, PD-L1 checkpoint inhibitors include but are not limited to atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170 or BMS-986189, or any combination thereof. In some embodiments, the immune checkpoint is a CTLA-4 checkpoint. In some embodiments, CTLA-4 checkpoint inhibitors include but are not limited to ipilimumab or tremilimumab, or any combination thereof.

[0287] 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 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, VEGF inhibitors include but are not limited to aflibercept, axitinib, bevacizumab, brivanib, cabozantinib, cediranib, lenvatinib, linifanib, nintedanib, pazopanib, ponatinib, ramucirumab, regorafenib, semasanib, sorafenib, sunitinib, tivozanib, toranib or vandetanib, or any combination thereof.

[0288] As used herein, the term "antiviral drug" 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), Friedman virus, Hanta virus, 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, varicella-zoster virus.

[0289] In some embodiments, the antiviral drug 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 antiviral drug is an interferon, a capsid assembly regulator, a sequence-specific oligonucleotide, an entry inhibitor, or a small molecule immunomodulator. In some embodiments, the antiviral drug includes but is not limited to AB-423, AB-506, ABI-H2158, vebicorvir (ABI-HO731), acyclovir, adapromine, adefovir, adefovir dipivoxil, alafenamide, amantadine, asunaprevir, baloxavir marboxil), beclabuvir, boceprevir, brivudine, cidofovir, ciluprevir, clevudine, cytarabine, daclatasvir, danoprevir, dasabuvir, deleobuvir, dipivoxil, edoxudine, elbasvir, entecavir entecavir, faldaprevir, famciclovir, favipiravir, filibuvir, fomivirsen, foscarnet, galidesivir, ganciclovir, glecaprevir, GLS4, grazoprevir, idoxuridine, imiquimod, IFN-α, interferon alfa2b2b), JNJ-440, JNJ-6379 (JNJ-56136379), lamivudine, laninamivir, ledipasvir, mericitabine, methisazone, MK-608, moroxydine, narlaprevir, NITD008, NZ-4, odalasvir, ombitasvir, oseltamivir, paritaprevir, peginterferon α-2a alfa-2a), penciclovir, peramivir, pibrentasvir, pimodivir, pleconaril, podophyllotoxin, presatovir, radalbuvir, ravidasvir, remdesivir, REP 2139, REP 2165, resiquimod, R07049389 (RG7907), ribavirin, rifampicin, rimantadine, ruzasvir, samatasvir, setrobuvir, simeprevir, sofosbuvir, sorivudine, sovaprevir, taribavirin, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tenofoviralfenamide, triazavirin, trifluridine, tromantadine, umifenovir, uprifosbuvir, valaciclovir, valgancicovir, vaniprevir, vedroprevir, velpatasvir, vidarabine rabine), voxilaprevir, zanamivir, cledvudine, ANA-380 / LB80380, thymalfasin (Zadaxin), ATI-2173, VIR-2218, RG6346, JNJ-73763989 (JNJ-3989), AB-729, BB-103, Hepcludex (Bulevirtide, formerly Myrcludex B), hzVSF, morphothiadin, JNJ-56136379, EDP-514, QL-007, ABI-H3733, ZM-H1505R, B-836, VNRX-9945, GLP-26, ABI-4334, IONIS-HBVRx (GSK 3228836), EBT107, NASVAC, GS-4774, HepTcell, VBI-2601 (BRII-179), VVX001, VTP-300, CVI-HBV-002, AIC-649, HB- 110. JNJ-64300535, CARG-201, PRGN-2013, SA104, VRON-0200, selgantolimod, RG7854, SBT-8230, YS-HBV -002, lenvervimab, Vir-3434, IMC-I109V, LTCR-H2-1, APG-1387, ASC42, EYP001, EDP-721, ENOB-HB-01, GV1001, CP101, DF-006, ALG-000184, ALG-010133, ALG-125097, ALG-020572, ALG-125755, zanamivir, or any combination thereof.

[0290] As used herein, the term "% w / w" or "% wt / wt" has its ordinary meaning as understood in accordance with the present specification, and refers to the percentage expressed as the weight of an ingredient or agent relative to the total weight of a composition multiplied by 100. As used herein, the term "% v / v" or "% vol / vol" has its ordinary meaning as understood in accordance with the present specification, and refers to the percentage expressed as the liquid volume of a compound, substance, ingredient or agent relative to the total liquid volume of a composition multiplied by 100.

[0291] Example

[0292] Some aspects of the embodiments discussed above are disclosed in more detail in the following examples, which are not intended to limit the scope of the present disclosure in any way. It will be appreciated by those skilled in the art that many other embodiments also fall within the scope of the present disclosure, as described above and in the claims.

[0293] Hereinafter, the terms "rt", "rt" or "RT" mean room temperature; "h" means hour; "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 dimethylacetyl amine; "Pd(dppf)Cl2." means [1.1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II); "Pin2B2" means bis(pinacol)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; "preparative HPLC" means preparative high performance liquid chromatography; "TFA" means trifluoroacetic acid; "RP" means reverse phase; "min" means minute; "h" means hour; "PE" means petroleum ether; "v / v" means volume ratio; means diatomaceous earth; “DMSO” means dimethyl sulfoxide; “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; “KOAc” means potassium acetate.

[0294] For intermediates used in the next reaction step in crude form or as partially purified intermediates, estimated molar amounts (indicated by ~ in some cases) or, alternatively, theoretical molar amounts are indicated in the following reaction schemes.

[0295] The meanings of the abbreviations used in the NMR spectra are provided below: s = singlet, d = doublet, dd = double of doublets, dt = double of triplets, ddd = doublet of doublets of doublets, Sept = septet, t = triplet, m = multiplet, br = broad, brs = broad singlet, q = quartet.

[0296] Example A1

[0297] Intermediate 4

[0298]

[0299] 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 minutes, and then NaBH(OAc)3 (161 g, 0.76 mol) was added at 0 ° C. The mixture was stirred at 15 ° C for 1 hour. The reactions were run in parallel for 2 minutes. TLC (DCM:MeOH=10:1, R f=0.4) shows that the reaction is complete. The mixture is diluted with DCM (800mL) and saturated NH3OH solution (800mL). The aqueous phase is separated and extracted with (CHCl3: i-PrOH=3:1). The combined organic layer is washed with brine (1000mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a residue. The crude product is purified by recrystallization from EtOAc (300mL) at 25°C to obtain intermediate 1 (120g, 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).

[0300] 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 hour. The mixture was poured into H2O (1000 mL) and extracted with ethyl acetate (3×1000 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 ( 330g Purification by silica gel flash column, eluting with 0% to 5% MeOH / DCM at 100 mL / min) gave Intermediate 2 as a brown solid (123 g, 97% yield). 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).

[0301] At 15 ° C, DIEA (127g, 984mmol, 171mL) was added dropwise to a mixture of intermediate 2 (123g, 328mmol) and N-phenyl-bis(trifluoromethanesulfonyl imide) (123g, 344mmol) in DCM (2260mL). The brown mixture was stirred at 15 ° C for 16 hours. The residue was diluted with ice water (2000mL) and extracted with DCM (2×1000mL). The combined organic layer was washed with brine (2×1000mL), dried over MgSO4, filtered and concentrated under reduced pressure to obtain a residue. The crude product was ground with EtOAc (600mL) for 2 hours, and filtered to obtain intermediate 3 (136g, 81% yield) as a yellow solid. 1 HNMR: (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).

[0302] 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 Pin2B2 (37.6 g, 148 mmol). The yellow mixture was stirred at 90 °C for 16 hours. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography to give intermediate 4 (27 g, 70% purity) as a brown solid. 24 H 31 BClN4O4[M+H] + The MS:ES m / z calculated value is [M+H] + 485.2, the measured value is 485.0.

[0303] Example A2

[0304] Intermediate 5

[0305]

[0306] A mixture of intermediate 4 (2.50 g, 5.6 mmol), 3-bromo-2-chloroaniline (1.38 g, 6.70 mmol), Pd(dppf)Cl (377 mg, 516 μmol) and KCO (2.14 g, 15.5 mmol) in dioxane (25 mL) and H0 (2.5 mL) was degassed and purged with N (3 times), and then the mixture was stirred at 110°C under N for 2 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography and repurified by preparative HPLC to give intermediate 5 (687 mg, 98% purity) as a yellow oil. 24 H 24 MS:ES m / z calculated for Cl2N5O2 is [M+H] + 484.1, the actual measured value is 484.1.

[0307] Example A3

[0308] Intermediate 6-1

[0309]

[0310] 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) in DCM (10 mL) was stirred at 25 ° C for 3 hours. After adding NaBH (OAc) 3 (1.17 g, 5.53 mmol) to the mixture, the mixture was stirred at 25 ° C for 1 hour. The reaction was quenched by adding water (50 mL) and then extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography to obtain intermediate 6-1 (600 mg) as a yellow liquid. C 11 H 16 MS:ES m / z calculated for BrN4O2 is [M+H] + 315.0, the actual measured value is 315.0.

[0311] The intermediates shown in Table A-1 were prepared by similar reaction schemes as used for the preparation of intermediate 6-1 using appropriate starting materials.

[0312] Table A-1

[0313]

[0314] Example A4

[0315] Intermediate 6A

[0316]

[0317] 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 hours to obtain 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 (3×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography to obtain intermediate 6A-2 (1.66 g, 95% purity) as a white solid. MS:ES m / z calculated for C7H8ClN2O3 is [M+H] + 203.0, the actual measured value is 203.0.

[0318] A mixture of intermediate 6A-2 (700.00 mg, 3.46 mmol) and LiOH·H2O (290 mg, 6.91 mmol) in THF (4.2 mL) and H2O (1.26 mL) was stirred at 40°C for 2 hours. 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 is [M+H] + 189.0, the measured value is 188.9.

[0319] 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 hours. The reaction was quenched with 1N HCl aqueous solution (10 mL), and the mixture was extracted with DCM (20 mL). The organic phase was washed with 1N HCl aqueous solution (2×10 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue, which was purified by flash silica gel chromatography to obtain intermediate 6A (215 mg, 65% purity) as a yellow solid. The MS:ES m / z calculated value for C7H9N2O4 is [M+H] + 185.1, the measured value is 185.0.

[0320] Example A5

[0321] Intermediate 7-1

[0322]

[0323] 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) in dioxane (25 mL) and H2O (2.5 mL) was degassed and purged with N2 (3x). After the mixture was stirred at 100 °C under N2 atmosphere for 2 hours, the reaction was quenched with H2O (30 mL). The mixture was extracted with EtOAc (3×30 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. C 12 MS:ES m / z calculated for H9BrCl2N is [M+H] + 315.9, the measured value is 316.0.

[0324] The intermediates shown in Table A-2 were prepared by similar reaction schemes as used for the preparation of intermediate 7-1 using appropriate starting materials.

[0325] Table A-2

[0326]

[0327] Example A6

[0328] Intermediate 8-1

[0329]

[0330] 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 hours. The mixture was filtered to give a 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. 18 H13 MS:ES m / z calculated for BrCl2N3O2 is [M+H] + 552.0, the measured value is 551.8.

[0331] The intermediates shown in Table A-3 were prepared by similar reaction schemes as used for the preparation of intermediate 8-1 using appropriate starting materials.

[0332] Table A-3

[0333]

[0334]

[0335] Example A7

[0336] Intermediate 9-1

[0337]

[0338] A mixture of intermediate 8-1 (1.55 g, 3.42 mmol), Pin2B2 (955.52 mg, 3.76 mmol), Pd(dppf)Cl2 (250 mg, 342 μmol) and AcOK (1.01 g, 10.26 mmol) in dioxane (10 mL) was degassed and purged with N2 (3 times), and then the mixture was stirred at 110° C. under N2 atmosphere for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give intermediate 9-1 (900 mg) as a yellow solid. 24 H 25 MS:ES m / z calculated for BCl2N3O4 is [M+H] + 500.1, the measured value is 500.0.

[0339] The intermediates shown in Table A-4 were prepared by similar reaction schemes as used for the preparation of intermediate 9-1 using appropriate starting materials.

[0340] Table A-4

[0341]

[0342] Example A8

[0343] Intermediate 10-1

[0344]

[0345] 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-carboxaldehyde (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), and then the mixture was stirred at 110°C under N2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give intermediate 10-1 (720 mg) as a yellow solid. 25 H 19 MS:ES m / z calculated for Cl2N4O4 is [M+H] + 509.1, the actual measured value is 509.1.

[0346] The compounds shown in Table A-5 were prepared by similar reaction schemes as used for the preparation of Intermediate 10-1 using appropriate starting materials.

[0347] Table A-5

[0348]

[0349]

[0350] Example 1

[0351] Compound A-1

[0352]

[0353] 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'-tetramethylformamidine hexafluorophosphate (TCFH) (58 mg, 206 μmol) and N-methylimidazole (NMI) (21 mg, 258 μmol) in MeCN (1.5 mL) was stirred at 50 ° C for 16 hours. The same amount of raw materials were used to repeat the reaction. The combined reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue, which was purified by preparative HPLC to obtain compound A-1 (44 mg, 96% purity) as a yellow solid. 1H 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).

[0354] The compounds shown in Table B-1 were prepared by similar reaction schemes as used for the preparation of compound A-1 using appropriate starting materials.

[0355] Table B-1

[0356]

[0357] Example 2

[0358] Compound B-1

[0359]

[0360] 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 (3x). The mixture was stirred at 110 ° C for 2 hours under N2 atmosphere. The mixture was filtered and then concentrated to obtain a residue, which was purified by preparative HPLC to obtain compound B-1 (36 mg, 99% purity) as a yellow solid.

[0361] The compounds shown in Table B-2 were prepared by similar reaction schemes as used for the preparation of compound B-1 using appropriate starting materials.

[0362] Table B-2

[0363]

[0364]

[0365] Example 3 Compound C-1

[0366] 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 hours. NaBH (OAc) 3 (202 mg, 954 μmol) was added to the mixture. The mixture was stirred at 25 ° C for 12 hours. The reaction was quenched by adding water (0.5 mL). The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain compound C-1 (125 mg, 99% purity) as a white solid.

[0367] The compounds shown in Table B-3 were prepared by similar reaction schemes as used for the preparation of compound C-1 using appropriate starting materials.

[0368] Table B-3

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] Example 3

[0389] Compound D-1

[0390]

[0391] 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 at 25° C. for 1 hour. The mixture was concentrated to give a residue, which was purified by preparative HPLC to give compound D-1 (20 mg, 99% purity) as a yellow solid.

[0392] The compounds shown in Table B-4 were prepared by a similar reaction scheme as used for the preparation of compound D-1 using appropriate starting materials.

[0393] Table B-4

[0394]

[0395] Example 4

[0396] Compound E-1

[0397]

[0398] At 0°C, NaH (15.72 mg, 393 μmol, 60% purity) was added to a solution of compound C-1 (80 mg, 131 μmol) in THF (0.5 mL). After the mixture was stirred at 0°C for 0.5 hours, DMAP (1.60 mg, 13.10 μmol, 0.1 eq.) and chloroformic acid (4-nitrophenyl) methyl ester (28.25 mg, 131.04 μmol, 1 eq.) were added to the mixture at 0°C. The mixture was stirred at 25°C for 4 hours. The reaction was quenched by adding water. The mixture was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain compound E-1 (3.6 mg, 95% purity) as a white solid.

[0399] Example 4A

[0400] Compound F-1

[0401]

[0402] To a solution of compound C-94 (448 mg, 734 μmol) and methyl 4-nitrobenzene carbonate (5-methyl-2-oxo-1,3-dioxol-4-yl) (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 minutes, then warmed to 30°C and stirred for 16 hours. The mixture was filtered to obtain a filtrate, which was purified by preparative HPLC to obtain compound F-1 (172 mg, 99% purity) as a white solid. 36 H 34 Cl2N5O 10 The MS:ES m / z calculated value is [M+H] + 766.2, the measured value is 766.1. 1 HNMR (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).

[0403] Example 4B

[0404] Compound G-1

[0405]

[0406] 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 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain compound G-1 as an off-white solid. 30 H 30 The calculated value of MMS:ES m / z for Cl2N5O6 is [M+H] + 626.2, the measured value is 626.1. 1 H 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).

[0407] Example 4C

[0408] Compound H-1

[0409]

[0410] CDI (72 mg, 447 μmol) was added to a mixture of compound G-1 (70 mg, 89 μmol) in THF (1 mL) at 20 ° C. The resulting mixture was stirred at 50 ° C for 16 hours to obtain 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 layer was filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain compound H-1 as a white solid. 1H NMR (400MHz, CDCL3) δ = 12.24 (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).

[0411] Example 5

[0412] Additional compounds

[0413] Other compounds can be prepared using procedures analogous to those described herein.

[0414]

[0415]

[0416]

[0417]

[0418]

[0419] (including pharmaceutically acceptable salts thereof).

[0420] Example A

[0421] LCMS (Liquid Chromatography / Mass Spectrometry)

[0422] High performance liquid chromatography (HPLC) measurements are performed using LC pumps, diode array (DAD) or UV detectors and columns as specified in the corresponding methods. Additional detectors are also included if necessary (see the table of the following methods). The liquid flow from the column is taken to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Tuning parameters (e.g., scan range, residence time) are set so as to obtain ions of the nominal monoisotopic molecular weight (MW) that allow identification of the compound, which is within the knowledge of the technician. Data acquisition is performed with appropriate software. Compounds are described by their experimental retention time (Rt) and ions. If there is no different provision in the data table, the reported molecular ions correspond to [M+H] + (protonated molecules) and / or [MH] -(deprotonated molecule). In cases where the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH4] + 、[M+Na] + 、[M+HCOO] - etc.). For molecules with multiple isotopic patterns (Br, CI), the reported values ​​are those obtained for the lowest isotopic mass. All results are obtained with the experimental uncertainty usually associated with the method used. In the following, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "RT" means room temperature, "BEH" means bridged ethylsiloxane / silica hybrid, "DAD" means diode array detector, "HSS" means high intensity silica, "Q-Tof" means quadrupole time-of-flight mass spectrometer, "CLND" means nitrogen chemiluminescence detector, and "ELSD" means evaporative light scattering detector.

[0423] Table A: LCMS method codes

[0424]

[0425]

[0426]

[0427] Flow rate is expressed in mL / min; column temperature (T) is expressed in °C; run time is expressed in minutes.

[0428] Table B: LCMS

[0429]

[0430]

[0431]

[0432] Retention time (R t ) are expressed in minutes; LC / MS: where not specified, the mass corresponds to [M+H] +

[0433] Example A-1

[0434] NMR (Nuclear Magnetic Resonance)

[0435] Protons were recorded on a Bruker spectrometer operating at 400 MHz using CDCL3 (deuterated chloroform) or DMSO-d6 (deuterated DMSO, dimethyl-d6-sulfoxide) as solvent. 1H) NMR spectra. Chemical shifts (d) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) used as an internal standard.

[0436] 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).

[0437] Compound C-9: 1 H NMR (400MHz, CDCL3) δ12.23 (s, 1H), 8.65 (dd, J = 1.3, 8.3Hz, 1H), 8.34-8.31 (m, 1H), 8.06 (d, J = 4.3Hz, 1H), 7.93 (d, J = 7.6Hz, 1H), 7.65 (dd, J = 1.6, 7.8Hz , 1H), 7.54-7.28 (m, 4H), 7.11 (dd, J=1.4, 7.5Hz, 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=10.3Hz, 1H).

[0438] Compound C-13: 1 H NMR (400MHz, CDCL3) δ12.24 (s, 1H), 8.65 (dd, J = 1.4, 8.3Hz, 1H), 8.33 (d, J = 4.1Hz, 1H),8.06(d,J=4.3Hz,1H),7.72-7.57(m,2H),7.41(td,J=7.8,10.9Hz,2H),7.29( d, J=1.6Hz, 2H), 7.26 (s, 1H), 7.12 (dd, J=1.4, 7.6Hz, 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=7.1Hz, 3H).

[0439] Compound C-81: 1 H-NMR (DMSO-d6, 400MHz): 1.51-1.57 (m, 1H), 1.64-1.72 (m, 1H), 2.44-50 (m, 1H), 2.70-2.7 4(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 = 3.6Hz, 1H), 7.22 (dd, J = 7.6Hz, 1.5Hz, 1H), 7.47-7.57 (m, 3H), 7.8 (dd, J = 7.6H z, 1.7Hz, 1H), 8.26-8.29 (m, 2H), 8.62 (dd, J=8.3Hz, 1.5Hz, 1H), 8.67 (s, 1H), 12.36 (s, 1H).

[0440] Example B

[0441] PDL1 / PD1 binding assay

[0442] The compounds to be tested are serially diluted in DMSO and further diluted in assay buffer (25mM Hepes pH 7.4, 150mM NaCl, 0.005% Tween 20, BSA 0.01%). The diluted compounds are added to the wells, and the final concentration of DMSO is 1%. PDL1-6xHis protein is added to the wells and mixed thoroughly with the compound. The plate is incubated for 30min at room temperature. PD1-Fc-Avi-biotin protein is added to the wells. The final concentrations of PDL1 and PD1 proteins are 0.3nM and 2.5nM, respectively. After a binding time of 30min at room temperature, anti-6xHis receptor beads (final concentration 20ug / ml) are added to the wells, and incubation continues for 1h. Streptavidin donor beads (final concentration 20ug / mL) are added under reduced light. The plate is sealed with foil and incubated in the dark for another 1h or overnight before reading on the Envision microplate reader. IC was determined by fitting the curve using a four-parameter equation in Graphpad Prism 8 50 value.

[0443] Example C

[0444] PD-1 / PD-L1 NFAT reporter assay

[0445] The cellular activity of the compounds was evaluated using a co-culture reporter assay, in which the TCR-mediated NFAT activity of Jurkat T cells was constitutively inhibited by engaging PD-1 through CHO cells expressing PD-L1. Blocking the PD-1 / PD-L1 interaction will release the inhibitory signal and lead to TCR signaling and NFAT-mediated luciferase activity.

[0446] CHO cells expressing surface-bound anti-CD3 antibodies 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 on the monolayer of CHO cells. The co-culture was then incubated at 37°C for 6 hours. Luciferase activity was assessed by adding ONE-Glo reagent and measuring luminescence with a microplate reader. EC was determined by fitting of the dose-response curve. 50 value.

[0447] As illustrated in the Examples, the compounds described herein exhibit EC values ​​in the range 50 or IC 50 Value: 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 >10000 nM; nd = not determined; nr = EC 50 It was not reached within the tested concentration range starting from 1 nM to 5000 nM.

[0448] Table C

[0449]

[0450]

[0451]

[0452]

[0453] In addition, although the foregoing has been described in some detail by way of illustration and example for the purpose of clarity and understanding, it will be appreciated by those skilled in the art that many and various modifications may be made without departing from the essence of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure, but also encompass all modifications and alternatives that are consistent with the true scope and essence of the present disclosure.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: in: R 1a Selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH2(C 3-6 -CH2(4- to 6-membered monocyclic heterocyclyl), and -CH2(5- to 6-membered monocyclic heteroaryl); R 1b Selected from the group consisting of: hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl; R 1c Selected from the group consisting of: -N(R m1 )R n1 and -R x1 ; R 2a , R 2b , R 2c , R 2e , R 2g , R 2h are independently selected from the group consisting of: hydrogen and halogen; R 2d and R 2f are independently selected from hydrogen, halogen, cyano, -CH3, -CH2CH3, -CH2OH, -OCH3 and -SCH3; R 3a Selected from the group consisting of: hydrogen, -CH3, -CF3 and -CHF2; R 3b Selected from the group consisting of hydrogen, halogen, cyano, -CH3, -CF3, -CHF2, -CH2CH3, -CH2OH, -OCH3 and -SCH3; Y 1a selected from the group consisting of: N (nitrogen) and -CH; Y 1b Selected from the group consisting of: N (nitrogen) and C (R 4 ); Y 2a Selected from the group consisting of: N (nitrogen) and C (R 5 ); Y 2b Selected from the group consisting of: N (nitrogen) and C (R 1d ), where R 1d selected from the group consisting of: hydrogen and halogen; R 4 selected from the group consisting of: hydrogen, halogen, and -CH3; R 5 selected from the group consisting of: hydrogen, halogen, and -CH3; R m1 Selected from the group consisting of: hydrogen, -C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 5-membered or 6-membered monocyclic heteroaryl, 4-membered to 7-membered monocyclic heterocyclyl, 8-membered to 11-membered fused bicyclic heteroaryl and 8-membered to 11-membered fused bicyclic heterocyclyl; wherein the 5-membered or 6-membered monocyclic heteroaryl, the bicyclic heteroaryl, the 4-membered to 7-membered monocyclic heterocyclyl and the bicyclic heterocyclyl contain at least one atom or atomic group independently selected from the group consisting of: O (oxygen), S (sulfur), C (=O), S (=O), S (=O) 2 and N (nitrogen); wherein the -C 1-4 The alkyl group is optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, hydroxyl, -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 wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 The bicyclic cycloalkyl, the 5-membered or 6-membered monocyclic heteroaryl, the 4-membered to 7-membered monocyclic heterocyclyl, the 8-membered to 11-membered fused bicyclic heteroaryl and the 8-membered to 11-membered fused bicyclic heterocyclyl are optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, -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 ; and R n1 It is hydrogen, C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic cycloalkyl (CH2)- or -C(=O)OR Z4 ; R x1 Select from the group consisting of: Where R x1 Optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, -C 1-4 Alkyl, hydroxyl, –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 Z1 )R Z3 and –N(R Z1 )S(=O)2N(R Z2 )R Z3 ; m1, m2 and m3 are independently 1 or 2; m4 is 0, 1, or 2; m5 is 1, 2, 3 or 4; Each R X3 are independently selected from the group consisting of 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 ; R Z1 and R Z2 are independently selected from the group consisting of: hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; or R Z1 and R Z2 taken together to form a monocyclic heterocyclyl when attached to the same nitrogen; R Z3 Selected from the group consisting of: hydrogen, -C 1-4 Alkyl and -C 1-4 haloalkyl; and R Z4 Selected from the group consisting of: hydrogen, -C 1-4 Alkyl and optionally -C 1-4 Alkyl-substituted 5- to 6-membered monocyclic heterocyclyl (CH2)-.

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

3. The compound according to claim 1, wherein Y 2a C(R 5 ).

4. The compound according to claim 3, wherein R 5 For hydrogen.

5. The compound according to claim 3, wherein R 5 It is a halogen.

6. The compound according to claim 3, wherein R 5 It is -CH3.

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

8. A compound according to any one of claims 1 to 6, wherein R 3a It is -CH3.

9. A compound according to any one of claims 1 to 6, wherein R 3a It is -CF3.

10. A compound according to any one of claims 1 to 6, wherein R 3a is -CHF2.

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

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

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

14. A compound according to any one of claims 1 to 10, wherein R 3b It is -CH3 or -CH2CH3.

15. A compound according to any one of claims 1 to 10, wherein R 3b It is -CF3 or -CHF2.

16. A compound according to any one of claims 1 to 10, wherein R 3b is -CH2OH, -OH, -OCH3 or -SCH3.

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

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

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

20. A compound according to any one of claims 1 to 18, wherein Y 1b C(R 4 ).

21. The compound according to claim 20, wherein R 4 For hydrogen.

22. The compound according to claim 20, wherein R 4 It is a halogen.

23. The compound according to claim 20, wherein R 4 It is -CH3.

24. A compound according to any one of claims 1 to 23, wherein R 1a For -C 1-4 alkyl.

25. A compound according to any one of claims 1 to 23, wherein R 1a For -C 1-4 Halogenated alkyl.

26. A compound according to any one of claims 1 to 23, wherein R 1a Selected from the group consisting of: -CH2(C 3-6 -CH2(4- to 6-membered monocyclic heterocyclyl), and -CH2(5- to 6-membered monocyclic heteroaryl).

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

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

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

30. The compound according to claim 29, wherein R n1 For hydrogen.

31. The compound according to claim 29, wherein R n1 For -C 1-4 alkyl.

32. The compound according to claim 29, wherein R n1 For -C 1-4 Haloalkyl, C 3-6 Monocyclic cycloalkyl (CH2)- or -C(=O)OR Z4 .

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

34. The compound according to claim 33, wherein R m1 for 35. A compound according to any one of claims 29 to 32, wherein R m1 Select from the group consisting of:

36. The compound according to claim 35, wherein -R m1 for 37. A compound according to any one of claims 1 to 28, wherein R 1c For –R x1 .

38. The compound according to claim 37, wherein -R x1 for 39. The compound according to claim 37, wherein -R x1 Select from the group consisting of:

40. The compound according to claim 37, wherein -R x1 Select from the group consisting of:

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

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

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

44. A compound according to any one of claims 1 to 43, wherein R 2d and R 2f Each is a halogen.

45. A compound according to any one of claims 1 to 43, wherein R 2d and R 2f Each is -CH3.

46. ​​A compound according to any one of claims 1 to 43, wherein R 2d is a halogen; and R 2f It is -CH3.

47. A compound according to any one of claims 1 to 43, wherein R 2d is –CH3; and R 2f It is a halogen.

48. A compound according to any one of claims 1 to 43, wherein R 2d is cyano; and R 2f It is a halogen.

49. A compound according to any one of claims 1 to 43, wherein R 2d is –OCH3; and R 2f It is a halogen.

50. A compound according to any one of claims 42 to 44 or 46 to 49, wherein the halogen is chlorine or fluorine.

51. The compound according to claim 1, wherein -R m1 Select from the group consisting of:

52. The compound of claim 1, selected from the group consisting of: Or a pharmaceutically acceptable salt of any one of the foregoing.

53. The compound of claim 1, selected from the group consisting of: Or a pharmaceutically acceptable salt of any one of the foregoing.

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

55. 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 according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

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

57. The method of any one of claims 55 to 56, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

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

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

60. The compound of any one of claims 58 to 59, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

61. Use of a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatitis B.

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

63. The method of any one of claims 61 to 62, further comprising administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, or antiviral therapy.

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