Methods and compositions for targeting PD-l1

Abstract

The present disclosure related to compounds that can be useful as inhibitors of PD-1, PD-L1 or the PD-1 / PD-L1 interaction. Also disclosed herein are pharmaceutical compositions of that can include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and uses of 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

METHODS AND COMPOSITIONS FOR TARGETING PD-L1 INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference in their entireties under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 513,518, filed July 13, 2023. The present application claims priority to U.S. Provisional Application No.63 / 513,518, filed July 13, 2023. FIELD

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

[0003] The programmed cell death 1 (PD-1) immune checkpoint expressed on the surface of activated CD4+and CD8+T cells controls an inhibitory mechanism to prevent autoimmunity. Engagement of PD-1 by programmed death-ligand 1 (PD-L1) expressed on the multitude of cell types, including macrophages, dendritic cells, mast cells as well as cancer cells induces T cell exhaustion resulting in reduction or loss of effector cytokine production (e.g. IL-2, TNF-Į, IFN-Ȗ) and upregulation of other inhibitory receptors and immune checkpoints (e.g. CTLA-4, LAG-3, and BTLA), or T cell apoptosis. High expression of PD- L1 is exhibited by many types of cancers to escape tumor immune surveillance and has been associated with poorer prognosis. PD-1-mediated immunosuppression is also linked to some viral infections, such as hepatitis B. There is an ongoing need for PD-1 / PD-L1 therapies and improvements thereof for the treatment of disease.SUMMARY

[0004] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to a method of treating an HBV and / or HDV infection that can include administering to a subject identified as suffering from the HBV and / or HDV infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating an HBV and / or HDV infection.

[0007] Some embodiments disclosed herein relate to a method of inhibiting replication of HBV and / or HDV that can include contacting a cell infected with the HBV and / or HDV with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication of HBV and / or HDV.

[0008] These are other embodiments are described in greater detail below. DETAILED DESCRIPTION

[0009] Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC can be caused by a variety of conditions, such as alcohol consumption, cirrhosis, and viral infections that cause hepatitis, such as hepatitis B virus, hepatitis C virus, and hepatitis D virus. The inflammation, fibrosis, and cirrhosis linked with these conditions can inducemalignancies in affected liver cells. HCC has relatively poor prognosis, with a five-year survival rate of about 30%, depending on if full surgical resection of the tumor is possible.

[0010] For early disease, surgical resection is used. However, most HCC are identified at later stages because of difficulties in diagnosing. Upon late-stage diagnosis, the tumors are unresectable, and most patients are given systemic therapies. The current standard of care in front line are multi-kinase inhibitors (including, for example, sorafenib and / or lenvatinib). Most patients are refractory or relapse from these treatments and undergo second line therapies that have anti-angiogenic agents (including, for example, Regorafinib, Cabozantinib, and / or Ramicirumab) or immune checkpoint inhibitors (including, for example, nivolumab and / or pembrolizumab). However, most patients do not respond to first and second therapies, and the clinical benefit is poor, with overall survival not exceeding one year. In addition, biomarker driven therapies are lacking. Thus, there is a need to develop more tolerable and efficacious therapies for the treatment of HCC and related liver disorders.

[0011] HBV is a partially double-stranded circular DNA of about 3.2 kilobase (kb) pairs, and is classified into eight genotypes, A to H. The HBV replication pathway has been studied in great detail. One part of replication includes the formation of the covalently closed circular DNA (cccDNA) form. The presence of the cccDNA gives rise to the risk of viral reemergence throughout the life of the host organism. HBV carriers can transmit the disease for many years. An estimated 300 million people are living with hepatitis B virus infection, and it is estimated that over 750,000 people worldwide die of hepatitis B each year. In addition, immunosuppressed individuals or individuals undergoing chemotherapy are especially at risk for reactivation of an HBV infection. HBV can be acute and / or chronic. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis.

[0012] HBV can be transmitted by blood, semen, and / or another body fluid. This can occur through direct blood-to-blood contact, unprotected sex, sharing of needles, and from an infected mother to her baby during the delivery process. The HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available medications do not cure HBV and / or HDV infection. Rather, the medications suppress replication of the virus.

[0013] The hepatitis D virus (HDV) is a DNA virus, also in the Hepadnaviridae family of viruses. HDV can propagate only in the presence of HBV. The routes of transmissionof HDV are similar to those for HBV. Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. There is currently no cure or vaccine for hepatitis D.

[0014] 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 serves to negatively regulate immune responses to prevent autoimmune disorder. PD-1 protein (NCBI accession number NP_005009.2) is expressed from 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 the human PD-1 protein, and CD279 is the human CD279 transcript or gene on chromosome 2. It should be understood that a person with ordinary skill in the art would view the terms PD-1 and CD279 as often nominally interchangeable when considering the nucleic acid (DNA or RNA) or corresponding translated protein, or the sequences thereof.

[0015] Programmed cell death-ligand 1, or programmed death-ligand 1 (PD-L1), also known as B7 homolog 1 (B7-H1) is 272 amino acid long type I transmembrane protein found as a surface marker on many different cell types. PD-L1 is a major ligand of PD-1 and results in inhibition of T cell cytotoxicity and cytokine production. Cancer cells such as HCC cells take advantage of this immune checkpoint by upregulating PD-L1 expression, resulting in dysfunctional anti-tumor immunity by proximal T cells. Viruses also have been observed to modulate the PD-1 / PD-L1 pathway to inhibit immune host response. 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 from the cluster of differentiation 274 (CD274) transcript (NCBI accession number NM_014143.4). In some preferred embodiments, PD-L1 is the human PD-L1 protein, and CD274 is the human CD274 transcript or gene on chromosome 9. It should be understood that a person with ordinary skillin the art would view the terms PD-L1 and CD274 as often nominally interchangeable when considering the nucleic acid (DNA or RNA) or corresponding translated protein, or the sequences thereof. Definitions

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0017] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) 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 with one or more group(s) (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-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amine and a di-substituted amine.

[0018] As used herein, “Ca to Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbonatoms. Thus, for example, a “C1to C4alkyl” or a “C1-C4alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.

[0019] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4alkyl” or similar designations. By way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

[0020] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. The length of an alkenyl can vary. For example, the alkenyl can be a C2-4alkenyl, C2-6alkenyl or C2-8alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.

[0021] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The length of an alkynyl can vary. For example, the alkynyl can be a C2-4 alkynyl, C2-6 alkynyl or C2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.

[0022] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or morerings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0023] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.

[0024] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14aryl group, a C6-C10aryl group, or a C6aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0025] As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where 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, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0026] As used herein, “heterocyclyl” refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary. For example, the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5- triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2- oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

[0027] As used herein, “aryl(alkyl)” refers to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0028] As used herein, “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group ofheteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.

[0029] A “(heterocyclyl)alkyl” refer to a heterocyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro- 2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).

[0030] “Lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. In some embodiments, a lower alkylene can 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-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.”

[0031] As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. In some instances, an alkoxy can be –OR wherein R is an unsubstituted C1-4 alkyl. An alkoxy may be substituted or unsubstituted.

[0032] As used herein, “acyl” refers to a hydrogen an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0033] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2- dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0034] 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., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0035] As used herein, “haloalkoxy” refers to a O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. In some instances, a haloalkoxy can be –OR, wherein R is a C1-4alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted.

[0036] A “sulfenyl” group refers to an “–SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0037] A “sulfinyl” group refers to an “–S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0038] A “sulfonyl” group refers to an “S(=O)2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0039] An “O-carboxy” group refers to a “RC(=O)O–” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0040] The terms “ester” and “C-carboxy” refer to a “–C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0041] A “thiocarbonyl” group refers to a “–C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0042] A “trihalomethanesulfonyl” group refers to an “X3CS(=O)2–” group wherein each X is a halogen.

[0043] A “trihalomethanesulfonamido” group refers to an “X3CS(=O)2N(RA)–” group wherein each X is a halogen, and RAis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0044] The term “amino” as used herein refers to a –NH2 group.

[0045] As used herein, the term “hydroxy” refers to a –OH group.

[0046] A “cyano” group refers to a “–CN” group.

[0047] The term “azido” as used herein refers to a –N3group.

[0048] An “isocyanato” group refers to a “–NCO” group.

[0049] A “thiocyanato” group refers to a “–SCN” group.

[0050] An “isothiocyanato” group refers to an “–NCS” group.

[0051] A “mercapto” group refers to an “–SH” group.

[0052] A “carbonyl” group refers to a –C(=O)– group.

[0053] An “S-sulfonamido” group refers to a “–S(=O)2N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0054] An “N-sulfonamido” group refers to a “RS(=O)2N(RA)–” group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0055] An “O-carbamyl” group refers to a “–OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0056] An “N-carbamyl” group refers to an “ROC(=O)N(RA)–” group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0057] An “O-thiocarbamyl” group refers to a “–OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0058] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)–” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0059] A “C-amido” group refers to a “–C(=O)N(RARB)” group in which RA and RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0060] An “N-amido” group refers to a “RC(=O)N(RA)–” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0061] A “mono-substituted amine” refers to a “–NHRA” in which RA can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be –NHRA, wherein RAcan be an unsubstituted C1-6alkyl or an unsubstituted or a substituted benzyl.

[0062] A “di-substituted amine” refers to a “–NRARB” in which RA and RB can be independently can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be –NRARB, wherein RAand RBcan be independently an unsubstituted C1-6alkyl or an unsubstituted or a substituted benzyl.

[0063] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0064] Where the number of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0065] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.11:942-944 (1972)).

[0066] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt (for example, ammonium or triethylammonium salt), an alkali metal salt, such as a lithium, a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0067] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound orcomposition, the term "comprising" means that the compound or composition includes at least the recited features or components but may also include additional features or components.

[0068] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality.

[0069] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0070] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0071] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0072] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Compounds

[0073] Examples of embodiments of the present application include the following: Embodiment 1

[0074] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:; X1can be selected from CH and N (nitrogen); X2can be selected from C(R5) and N (nitrogen); Y1and Y2can each independently be selected from N (nitrogen) and CH; R1acan be selected from –C1-4 alkyl, –C1-4 haloalkyl, –CH2(C3-6 monocyclic cycloalkyl), –CH2(4-6 membered monocyclic heterocyclyl) and –CH2(5-6 membered monocyclic heteroaryl); R1band R1ccan each independently be selected from hydrogen, halogen –C1-2alkyl, –C1-2haloalkyl, –OH, –OC1-2alkyl and –OC1-2haloalkyl; R1dand R1ecan each independently be selected from hydrogen, –C1-2alkyl and –C1-2haloalkyl; R1fand R1gcan each independently be selected from hydrogen, –C1-2 alkyl and –C1-2 haloalkyl; R2a, R2b, R2c, R2e, R2gand R2hcan each independently be selected from hydrogen and halogen; R2dand R2fcan each independently beselected from halogen, cyano, –CH3, –CH2CH3, –OCH3and –SCH3; R3aand R3bcan each independently be selected from hydrogen, –C1-4 alkyl and –C2-4 haloalkyl; R4acan be selected from the hydrogen, –C1-4 alkyl and –C2-4 haloalkyl; R4bcan be selected from hydrogen, halogen, –OH, –CN, –C1-4 alkyl and –C2-4 haloalkyl; R5can be selected from hydrogen and halogen; Rx1can be selected from hydrogen, –C1-4 alkyl and –Ry1, wherein the –C1-4 alkyl can be optionally substituted with one or two substituents independently selected from halogen, cyano, amino, hydroxy, –C alkoxy, –C haZ11-4 1-4loalkyl, –C1-4haloalkoxy, –C(=O)OR , –C(=O)NHS(=O)2RZ3, –C(=O)N(RZ1)RZ2, –S(=O)2RZ3, –S(=O)2N(RZ1)RZ2, –N(RZ1)C(=O)RZ3, –N(RZ1)C(=O)ORZ3, –N(RZ1)S(=O)RZ3, –N(RZ1)C(=O)N(RZ1)RZ3and –N(RZ1)S(=O)2N(RZ2)RZ3; Ry1can be selected from: , , ,1can be optionally substituted with one or two substituents independently selected from halogen, cyano, amino, hydroxy, –CZ11-4alkoxy, –C1-4haloalkyl, –C1-4haloalkoxy, –C(=O)OR , ,–N(RZ1)S(=O)2N(RZ2)RZ3; m1, m2and m3can each independently be 1 or 2; n1can be 0, 1 or 2; RZ1, RZ2and RZ3can each independently be selected from hydrogen, –C1-4 alkyl and –C1-4 haloalkyl; Rx2can be selected from hydrogen, halogen, –C1-4 alkyl, –C1-4 haloalkyl, –C(=O)RW3, –C(=O)ORW3, –S(=O)2RW3, –C(=O)N(RW1)RW2and –S(=O)N(RW1)RW2; and RW1, RW2and RW3can each independently be selected from hydrogen, –C1-4 alkyl and –C1-4 haloalkyl. Embodiment 2

[0075] The compound of Embodiment 1, where X1can be CH. Embodiment 3

[0076] The compound of Embodiment 1, wherein X1can be N (nitrogen). Embodiment 4

[0077] The compound of any one of Embodiments 1-3, wherein X2can be C(R5). Embodiment 5

[0078] The compound of Embodiment 4, wherein R5can be H. Embodiment 6

[0079] The compound of Embodiment 4, wherein R5can be halogen, such as fluoro or chloro. Embodiment 7

[0080] The compound of any one of Embodiments 1-3, wherein X2can be N (nitrogen). Embodiment 8

[0081] The compound of any one of Embodiments 1-7, wherein R1acan be –C1-4alkyl. For example, R1acan be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert- butyl. In some embodiments, R1acan be methyl. Embodiment 9

[0082] The compound of any one of Embodiments 1-7, wherein R1acan be –C1-4 haloalkyl, such as –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3 and –CH2CHF2. Embodiment 10

[0083] The compound of any one of Embodiments 1-7, wherein R1acan be –CH2(monocyclic C3-6cycloalkyl). Exemplary monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Embodiment 11

[0084] The compound of any one of Embodiments 1-7, wherein R1acan be –CH2(4- 6 membered monocyclic heterocyclyl). In some embodiments, the 4-6 membered monocyclic heterocyclyl can include one or more ring atoms (such as 1, 2 or 3) selected from N (nitrogen), O (oxygen) and S (sulfur). Embodiment 12

[0085] The compound of any one of Embodiments 1-7, wherein R1acan be –CH2(5- 6 membered monocyclic heteroaryl). In some embodiments, the 5-6 membered monocyclic heteroaryl can include one or more ring atoms (such as 1, 2 or 3) selected from N (nitrogen), O (oxygen) and S (sulfur). Embodiment 13

[0086] The compound of any one of Embodiments 1-12, wherein Rx1can be hydrogen. Embodiment 14

[0087] The compound of any one of Embodiments 1-12, wherein Rx1can be –C1-4alkyl. Examples of C1-4alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In some embodiments, Rx1can be –C1-4alkyl optionally substituted with one or two substituents independently selected from halogen, cyano, amino, hydroxy, –C1-4alkoxy (e.g., –O-(C1-4 alkyl)), –C1-4 haloalkyl, –C1-4haloalkoxy (e.g., –O-(C1-4 haloalkyl)), –C(=O)ORZ1, –C(=O)NHS(=O)2RZ3, –C(=O)N(RZ1)RZ2, –S(=O)2RZ3, –S(=O)2N(RZ1)RZ2, –N(RZ1)C(=O)RZ3, –N(RZ1)C(=O)ORZ3, –N(RZ1)S(=O)RZ3, –N(RZ1)C(=O)N(RZ1)RZ3and –N(RZ1)S(=O)2N(RZ2)RZ3. In some embodiments, Rx1can be – C1-4 alkyl optionally substituted with one substituent selected from halogen, cyano, amino, hydroxy, –C1-4alkoxy (e.g., –O-(C1-4 alkyl)), –C1-4 haloalkyl, –C1-4haloalkoxy (e.g., –O-(C1-4 haloalkyl)), , –S(=O)2N(, –N(RZ1)C(=O)N(RZ1)RZ3and –N(RZ1)S(=O)2N(RZ2)RZ3. In some embodiments, Rx1can be – C1-4 alkyl optionally substituted with two substituents independently selected from halogen,cyano, amino hydroxy, –C1-4alkoxy (e.g., –O-(C1-4 alkyl)), –C1-4 haloalkyl, –C1-4haloalkoxy(e.g., –O-(C1-4 haloalkyl)), ,–S(=O)2RZ3, –S(=O)2N(RZ1)RZ,–N(RZ1)C(=O)N(RZ1)RZ3and –N(RZ1)S(=O)2N(RZ2)RZ3. In some embodiments of this paragraph, RZ1can be hydrogen. In some embodiments of this paragraph, RZ2can be hydrogen. In some embodiments of this paragraph, RZ3can be –C1-4 alkyl. Embodiment 15

[0088] The compound of Embodiment 14, wherein Rx1can be –C1-4 alkyl substituted by amino (–NH2). Embodiment 16

[0089] The compound of Embodiment 14, wherein Rx1can be –C1-4alkyl substituted by –OH (hydroxy). The compound of Embodiment 13, wherein Rx1can be –C1-4alkyl substituted by –OH (hydroxy) and –C(=O)ORZ1. Embodiment 17

[0090] The compound of Embodiment 14, wherein Rx1can be –C1-4 alkyl substituted by –C(=O)ORZ1, wherein RZ1can be selected from hydrogen, –C1-4 alkyl and –C1-4haloalkyl. For example, RZ1can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2. Embodiment 18

[0091] The compound of Embodiment 17, wherein RZ1can be hydrogen. Embodiment 19

[0092] The compound of Embodiment 14, wherein Rx1can be –C1-4 alkyl substituted by –N(RZ1)C(=O)RZ3, wherein RZ1and RZ3can independently be selected from hydrogen, –C1-4alkyl and –C1-4haloalkyl. The compound of Embodiment 13, wherein Rx1can be –C1-4alkyl substituted by –N(RZ1)C(=O)ORZ3, wherein RZ1and RZ3can independently be selected from hydrogen, –C1-4alkyl and –C1-4haloalkyl. In some embodiments of this paragraph, RZ1can be hydrogen. In some embodiments of this paragraph, RZ3can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl. In other embodiments of this paragraph, RZ3can be –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3 or –CH2CHF2.Embodiment 20

[0093] The compound of Embodiment 19, wherein RZ1can be hydrogen (H) and RZ3can be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert- butyl. Embodiment 21

[0094] The compound of Embodiment 20, wherein RZ3can be –CH3(methyl). Embodiment 22

[0095] The compound of Embodiment 20, wherein RZ3can be tert-butyl. Embodiment 23

[0096] The compound of Embodiment 14, wherein Rx1can be –C1-4 alkyl substituted by –N(RZ1)C(=O)N(RZ1)RZ3, wherein each RZ1and RZ3can independently be selected from hydrogen, –C1-4 alkyl and –C1-4 haloalkyl. In some embodiments of this paragraph, RZ1can be hydrogen. In some embodiments of this paragraph, RZ3can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl. In other embodiments of this paragraph, RZ3can be –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2. Embodiment 24

[0097] The compound of Embodiment 23, wherein RZ1can be hydrogen (H); and RZ3can be –C1-4 alkyl. For example, RZ3can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 25

[0098] The compound of Embodiment 24, wherein RZ3can be –CH3(methyl). Embodiment 26

[0099] The compound of any one of Embodiments 1-12, wherein Rx1can be –Ry1.Embodiment 27

[0100] The compound of Embodiment 26, wherein –Ry1can be selected from: , e. Embodiment 28

[0101] The compound of Embodiment 27, wherein n1can be 0. Embodiment 29

[0102] The compound of Embodiment 27, wherein n1can be 1. Embodiment 30

[0103] The compound of Embodiment 27, wherein n1 can be 2. Embodiment 31

[0104] The compound of any one of Embodiments 27-30, wherein RZ1can be hydrogen (H).Embodiment 32

[0105] The compound of any one of Embodiments 27-30, wherein RZ1can be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 33

[0106] The compound of Embodiment 32, wherein RZ1can be –CH3 (methyl). Embodiment 34

[0107] The compound of any one of Embodiments 27-30, wherein RZ1can be –C1-4haloalkyl. For example, RZ1can be –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2. Embodiment 35

[0108] The compound of Embodiment 26, wherein –Ry1can be selected from: , .. Embodiment 36

[0109] The compound of Embodiment 35, wherein m1 can be 1. Embodiment 37

[0110] The compound of Embodiment 35, wherein m1can be 2. Embodiment 38

[0111] The compound of any one of Embodiments 35-37, wherein m2and m3can each be 1.Embodiment 39

[0112] The compound of any one of Embodiments 35-38, wherein RZ1can be hydrogen (H). Embodiment 40

[0113] The compound of any one of Embodiments 35-38, wherein RZ1can be –C1-4alkyl. For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 41

[0114] The compound of Embodiment 40, wherein RZ1can be –CH3(methyl). Embodiment 42

[0115] The compound of any one of Embodiments 35-38, wherein RZ1can be –C1-4 haloalkyl, such as –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3 or –CH2CHF2. Embodiment 43

[0116] The compound of Embodiment 26, wherein –Ry1can be selected from. Embodiment 44

[0117] The compound of Embodiment 43, wherein m1 can be 1. Embodiment 45

[0118] The compound of Embodiment 43, wherein m1 can be 2. Embodiment 46

[0119] The compound of any one of Embodiments 43-45, wherein m2and m3can each be 1. Embodiment 47

[0120] The compound of any one of Embodiments 43-46, wherein RZ1can be hydrogen (H). Embodiment 48

[0121] The compound of any one of Embodiments 43-46, wherein RZ1can be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.Embodiment 49

[0122] The compound of Embodiment 48, wherein RZ1can be –CH3 (methyl). Embodiment 50

[0123] The compound of any one of Embodiments 43-46, wherein RZ1can be –C1-4 haloalkyl, such as –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3 or –CH2CHF2. Embodiment 51

[0124] The compound of Embodiment 26, wherein –Ry1can be. Embodiment 52

[0125] The compound of Embodiment 51, wherein m1can be 1. Embodiment 53

[0126] The compound of Embodiment 51, wherein m1can be 2. Embodiment 54

[0127] The compound of any one of Embodiments 51-53, wherein m2 and m3 are each 1. Embodiment 55

[0128] The compound of any one of Embodiments 51-54, wherein RZ1can be hydrogen (H). Embodiment 56

[0129] The compound of any one of Embodiments 51-54, wherein RZ1can be –C1-4alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 57

[0130] The compound of Embodiment 56, wherein RZ1can be –CH3 (methyl). Embodiment 58

[0131] The compound of any one of Embodiments 51-54, wherein RZ1can be –C1-4haloalkyl, such as –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2.Embodiment 59 e. Embodiment 60

[0133] The compound of Embodiment 59, wherein n1can be 0. Embodiment 61

[0134] The compound of Embodiment 59, wherein n1 can be 1. Embodiment 62

[0135] The compound of Embodiment 59, wherein n1 can be 2. Embodiment 63

[0136] The compound of any one of Embodiments 59-62, wherein m1and m2each can be 1. Embodiment 64

[0137] The compound of any one of Embodiments 59-62, wherein m1can be 1 and m2 can be 2. Embodiment 65

[0138] The compound of any one of Embodiments 59-62, wherein m1 and m2 each can be 2. Embodiment 66

[0139] The compound of any one of Embodiments 59-65, wherein Rx2can be hydrogen (H). Embodiment 67

[0140] The compound of any one of Embodiments 59-65, wherein Rx2can be –C1-4 alkyl. For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.Embodiment 68

[0141] The compound of Embodiment 67, wherein Rx2can be –CH3 (methyl). Embodiment 69

[0142] The compound of any one of Embodiments 59-65, wherein Rx2can be –C(=O)RW3, wherein RW3can be selected from hydrogen, –C1-4 alkyl and –C1-4 haloalkyl. For example, RW3can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2. In some embodiments of this paragraph, RW3can be –C1-4alkyl. In other embodiments of this paragraph, RW3can be –C1-4haloalkyl. Embodiment 70

[0143] The compound of any one of Embodiments 59-65, wherein Rx2can be –C(=O)ORW3, wherein RW3can be selected from hydrogen, –C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) and –C1-4 haloalkyl (for example, –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2). Embodiment 71

[0144] The compound of Embodiment 69 or Embodiment 70, wherein RW3can be hydrogen (H). Embodiment 72

[0145] The compound of Embodiment 69 or Embodiment 70, wherein RW3can be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 73

[0146] The compound of Embodiment 72, wherein RW3can be –CH3(methyl). Embodiment 74

[0147] The compound of Embodiment 69 or Embodiment 70, wherein RW3can be –C1-4haloalkyl, such as –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3or –CH2CHF2. Embodiment 75

[0148] The compound of any one of Embodiments 59-65, wherein Rx2can be C(=O)N(RW1)RW2, wherein RW1and RW2can be independently selected from hydrogen, –C1-4 alkyl and –C1-4haloalkyl. For example, RW1and RW2can each independently be methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, –CF3, –CHF2, –CH2F, –CCl3, –CHCl2, –CH2Cl, –CH2CF3 or –CH2CHF2. Embodiment 76

[0149] The compound of Embodiment 75, wherein RW1is H; and RW2can be –C1-4 alkyl. For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 77

[0150] The compound of Embodiment 76, wherein RW2can be –CH3(methyl). Embodiment 78

[0151] The compound of any one of Embodiments 1-77, wherein R1band R1ccan each be hydrogen. Embodiment 79

[0152] The compound of any one of Embodiments 1-12, wherein Rx1can be , , ,,,Embodiment 80

[0153] The compound of any one of Embodiments 1-79, wherein R1dand R1ecan each be hydrogen (H). Embodiment 81

[0154] The compound of any one of Embodiments 1-80, wherein R1fand R1gcan each be hydrogen. Embodiment 82

[0155] The compound of any one of Embodiments 1-81, wherein B1can be. Embodiment 83

[0156] The compound of Embodiment 82, wherein Y1can be nitrogen (N). Embodiment 84

[0157] The compound of Embodiment 82, wherein Y1can be CH. Embodiment 85

[0158] The compound of any one of Embodiments 82-84, wherein R3acan be hydrogen. Embodiment 86

[0159] The compound of any one of Embodiments 82-84, wherein R3acan be –C1-4alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.Embodiment 87

[0160] The compound of Embodiment 86, wherein R3acan be –CH3 (methyl). Embodiment 88

[0161] The compound of any one of Embodiments 82-84, wherein R3acan be –C2-4 haloalkyl. For example, R3acan be –CH2CF3 or –CH2CHF2. Embodiment 89

[0162] The compound of any one of Embodiments 82-88, wherein R3bcan be hydrogen (H). Embodiment 90

[0163] The compound of any one of Embodiments 82-88, wherein R3bcan be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 91

[0164] The compound of Embodiment 90, wherein R3bcan be –CH3 (methyl). Embodiment 92

[0165] The compound any one of Embodiments 82-88, wherein R3bcan be –C2-4haloalkyl. For example, R3bcan be –CH2CF3or –CH2CHF2. Embodiment 93

[0166] The compound of any one of Embodiments 1-81, wherein B1can be. Embodiment 94

[0167] The compound of Embodiment 93, wherein Y2can be nitrogen (N). Embodiment 95

[0168] The compound of Embodiment 93, wherein Y2can be CH. Embodiment 96

[0169] The compound of any one of Embodiments 93-95, wherein R4acan be hydrogen (H).Embodiment 97

[0170] The compound of any one of Embodiments 93-95, wherein R4acan be –C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 98

[0171] The compound of Embodiment 97, wherein R4acan be –CH3 (methyl). Embodiment 99

[0172] The compound of any one of Embodiments 93-95, wherein R4acan be –C2-4haloalkyl, such as –CH2CF3or –CH2CHF2. Embodiment 100

[0173] The compound of any one of Embodiments 93-99, wherein R4bcan be hydrogen. Embodiment 101

[0174] The compound of any one of Embodiments 93-99, wherein R4bcan be halogen, such as fluoro or chloro. Embodiment 102

[0175] The compound of any one of Embodiments 93-99, wherein R4bcan be –OH (hydroxy). Embodiment 103

[0176] The compound of any one of Embodiments 93-99, wherein R4bcan be CN (cyano). Embodiment 104

[0177] The compound of any one of Embodiments 93-99, wherein R4bcan be –C1-4alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. Embodiment 105

[0178] The compound of Embodiment 104, wherein R4bcan be –CH3(methyl). Embodiment 106

[0179] The compound of any one of Embodiments 93-99, wherein R4bcan be –C2-4 haloalkyl, such as –CH2CF3 or –CH2CHF2. Embodiment 107

[0180] The compound of any one of Embodiments 1-106, wherein R2a, R2b, R2c, R2e, R2gand R2hcan each be hydrogen.Embodiment 108

[0181] The compound of any one of Embodiments 1-106, wherein R2a, R2c, R2e, R2gand R2hcan each be hydrogen; and R2bcan be halogen. Embodiment 109

[0182] The compound of any one of Embodiments 1-106, wherein R2b, R2c, R2e, R2gand R2hcan each be hydrogen; and R2acan be halogen. Embodiment 110

[0183] The compound of any one of Embodiments 1-106, wherein R2a, R2b, R2c, R2gand R2hcan each be hydrogen; and R2ecan be halogen. Embodiment 111

[0184] The compound of any one of Embodiments 1-106, wherein R2a, R2b, R2e, R2gand R2hcan each be hydrogen; and R2ccan be halogen. Embodiment 112

[0185] The compound of any one of Embodiments 1-111, wherein R2dcan be halogen. Embodiment 113

[0186] The compound of any one of Embodiments 1-111, wherein R2dcan be cyano. Embodiment 114

[0187] The compound of any one of Embodiments 1-111, wherein R2dcan be –CH3 (methyl). Embodiment 115

[0188] The compound of any one of Embodiments 1-111, wherein R2dcan be –CH2CH3. Embodiment 116

[0189] The compound of any one of Embodiments 1-111, wherein R2dcan be –OCH3. Embodiment 117

[0190] The compound of any one of Embodiments 1-111, wherein R2dcan be –SCH3.Embodiment 118

[0191] The compound of any one of Embodiments 1-117, wherein R2fcan be halogen. Embodiment 119

[0192] The compound of any one of Embodiments 1-117, wherein R2fcan be cyano. Embodiment 120

[0193] The compound of any one of Embodiments 1-117, wherein R2fcan be –CH3(methyl). Embodiment 121

[0194] The compound of any one of Embodiments 1-117, wherein R2fcan be –CH2CH3. Embodiment 122

[0195] The compound of any one of Embodiments 1-117, wherein R2fcan be –OCH3. Embodiment 123

[0196] The compound of any one of Embodiments 1-117, wherein R2fcan be –SCH3. Embodiment 124

[0197] The compound of Embodiments 108-112 or 118, wherein the halogen can be chloro or fluoro.Embodiment 125

[0198] The compound of Embodiment 1, wherein a compound of Formula (I) can be selected from: , ,,,,,d, y acceptable salt of any of the foregoing. In some embodiments, a compound of Formula (I) can , dy acceptable salt of any of the foregoing.Embodiment 126

[0199] A pharmaceutical composition that can include an effective amount of a compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof, and excipient. Embodiment 127

[0200] A method for treating hepatitis B in a subject that can include administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof. Embodiment 128

[0201] A method for treating hepatocellular carcinoma (HCC) in a subject that can include administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof. Embodiment 129

[0202] The method of any one of Embodiments 127-128, that can further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy. Embodiment 130

[0203] A compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis B. Embodiment 131

[0204] A compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC). Embodiment 132

[0205] The compound of any one of Embodiments 130-131, that can further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy. Embodiment 133

[0206] Use of a compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatitis B.Embodiment 134

[0207] Use of a compound of any one of Embodiments 1-125, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC). Embodiment 135

[0208] The use of any one of Embodiments 133-134, that can further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy. Methods for the Preparation

[0209] In this section, as in all other sections unless the context indicates otherwise, references to Formula (I), along with pharmaceutical acceptable salts thereof, include all other sub-groups and examples thereof as provided herein. The general preparations of some representative examples of compounds of Formula (I) are described herein, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes used by those skilled in the art.

[0210] All variables shown in the schemes are defined as mentioned herein, unless otherwise is indicated or is clear from the context.Scheme 1

[0211] In general, compounds of Formula (I) (including pharmaceutically acceptable salts thereof) can be prepared according to Scheme 1. All variables in Scheme 1 are according to Formula (I) provided herein. In Scheme 1, the following reaction conditions apply: 1) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, K2CO3) at a suitable temperature (for example, 90 °C); 2) In the presence of suitable coupling reagents (for example, N,N,Nƍ,Nƍ- tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole) in a suitable solvent (for example, acetonitrile) at a suitable temperature (for example, 60 °C); 3) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, KOAc) at a suitable temperature (for example, 100 °C); and 4) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, K2CO3) at a suitable temperature (for example, 90 °C).Scheme 2

[0212] In general, compounds of Formula (I) can be prepared according to Scheme 2. In Scheme 2, LG is a leaving group, such as Cl, Br, OMs (mesylate), OTos (tosylate), or OTf (triflate). All other variables in Scheme 2 are according to Formula (I) provided herein. In Scheme 2, the following reaction conditions apply: 1) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, K2CO3) at a suitable temperature (for example, 90 °C); 2) In the presence of suitable acid (for example, trifluoroacetic acid ) in a suitable solvent, such as dichloromethane, at a suitable temperature (for example, 25 °C); 3) In the presence of suitable reductant (for example, sodium cyanoborohydride) in a suitable solvent, such as MeOH, at a suitable temperature (for example, 30 °C); and 4) In the presence of suitable base (for example, di-isopropylethylamine) in a suitable solvent, such as dimethylsulfoxide, at a suitable temperature (for example, 40 °C).Scheme 3

[0213] In general, compounds of Formula (I) can be prepared according to Scheme 2. In Scheme 2, LG is a leaving group, such as Cl, Br, OMs (mesylate), OTos (tosylate), or OTf (triflate). In Scheme 3, the following reaction conditions apply: 1) In the presence of suitable catalyst (for example, 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, K2CO3) at a suitable temperature (for example, 90 °C); 2) In the presence of suitable base(for example, triethylamine ) in a suitable solvent, such as methanol, at a suitable temperature (for example, 25 - 70°C); 3) In the presence of suitable acid (for example, trifluoroacetic acid ) in a suitable solvent, such as dichloromethane, at a suitable temperature (for example, 25 °C); and 4) In the presence of suitable reductant (for example, sodium cyanoborohydride) in a suitable solvent, such as MeOH, at a suitable temperature (for example, 30 °C); (5) In the presence of suitable base (for example, di-isopropylethylamine) in a suitable solvent, such as dimethylsulfoxide, at a suitable temperature (for example, 40 °C).Pharmaceutical Compositions

[0214] Some embodiments described herein relate to pharmaceutical compositions that comprise, consist essentially of, or consist 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. A pharmaceutical composition described herein is suitable for human and / or veterinary applications.

[0215] The terms “function” and “functional” as used herein refer to a biological, enzymatic, or therapeutic function.

[0216] The terms “effective amount” or “effective dose” is used to indicate an amount of an active compound, or pharmaceutical agent, which elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0217] The term “pharmaceutically acceptable salts” includes relatively non-toxic, inorganic and organic acid, or base addition salts of compositions, including without limitation, analgesic agents, therapeutic agents, other materials, and the like. Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of suitable inorganic bases for the formation of salts include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Salts may also be formed with suitable organic bases, including those that are non-toxic and strong enough to form such salts. For example, the class of such organic basesmay include but are not limited to mono-, di-, and trialkylamines, including methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines including mono-, di-, and triethanolamine; amino acids, including glycine, arginine and lysine; guanidine; N- methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; trihydroxymethyl aminoethane.

[0218] “Formulation”, “pharmaceutical composition”, and “composition” as used interchangeably herein are equivalent terms referring to a composition of matter for administration to a subject.

[0219] The term “pharmaceutically acceptable” means compatible with the treatment of a subject, and in particular, a human.

[0220] The terms “agent” refers to an active agent that has biological activity and may be used in a therapy. Also, an “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 a derivative, analog, salt or a prodrug thereof. The agent can be present 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 pharmaceutical molecules or compounds, therapeutic molecules or compounds, matrix forming molecules or compounds, polymers, synthetic molecules and compounds, natural molecules and compounds, and any combination thereof.

[0221] The term “subject” as used herein has its ordinary meaning as understood in light of the specification and refers to an animal that is the object of treatment, inhibition, or amelioration, observation or experiment. “Animal” has its ordinary meaning as understood in light of the specification and includes cold- and warm-blooded vertebrates and / or invertebrates such as fish, shellfish, or reptiles and, in particular, mammals. “Mammal” has its ordinary meaning as understood in light of the specification, and includes but is not limited to mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as humans, monkeys, chimpanzees, or apes. In some embodiments, the subject is human.

[0222] Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the artincluding, but not limited to, enteral, oral, rectal, topical, sublingual, buccal, intraaural, epidural, epicutaneous, aerosol, parenteral delivery, including intramuscular, subcutaneous, intra-arterial, intravenous, intraportal, intra-articular, intradermal, peritoneal, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. Pharmaceutical compositions can also be administered to isolated cells from a patient or individual, such as T cells, Natural Killer cells, B cells, macrophages, lymphocytes, stem cells, bone marrow cells, or hematopoietic stem cells.

[0223] The pharmaceutical compound can also be administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, tissue, cancer, tumor or infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue specific antibody. The liposomes may be targeted to and taken up selectively by the organ, tissue, cancer, tumor, or infected area.

[0224] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.

[0225] As used herein, a “carrier” refers to a compound, particle, solid, semi-solid, liquid, or diluent that facilitates the passage, delivery and / or incorporation of a compound to cells, tissues and / or bodily organs. For example, without limitation, a lipid nanoparticle (LNP) is a type of carrier that can encapsulate a compound, or a pharmaceutically acceptable salt thereof, as described herein to thereby protect the compound, or a pharmaceutically acceptable salt thereof, as described herein from degradation during passage through the bloodstream and / or to facilitate delivery to a desired organ, such as to the liver.

[0226] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common formof diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0227] The term “excipient” has its ordinary meaning as understood in light of the specification, and refers to inert substances, compounds, or materials added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. Excipients with desirable properties include but are not limited to preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizing agents, 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, sodium taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea, or vitamins, or any combination thereof. The amount of the excipient may be found in a pharmaceutical composition at a percentage of 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% w / w or any percentage by weight in a range defined by any two of the aforementioned numbers.

[0228] The term “adjuvant” as used herein refers to a substance, compound, or material that stimulates the immune response and increase the efficacy of protective immunity and is administered in conjunction with an immunogenic antigen, epitope, or composition. Adjuvants serve to improve immune responses by enabling a continual release of antigen, up- regulation of cytokines and chemokines, cellular 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, oils, mineral oil, paraffin oil, oil-in-water emulsions, detergents, MF59®, squalene, AS03, Į-tocopherol, polysorbate 80, AS04, monophosphoryl lipid A, virosomes, nucleic acids, polyinosinic:polycytidylic acid, saponins, QS-21, proteins, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21,imidazoquinolines, CpG oligonucleotides, lipids, phospholipids, dioleoyl phosphatidylcholine (DOPC), trehalose dimycolate, peptidoglycans, bacterial extracts, lipopolysaccharides, or Freund’s Adjuvant, or any combination thereof.

[0229] The term “purity” of any given substance, compound, or material as used herein refers to the actual abundance of the substance, compound, or material relative to the expected abundance. For example, the substance, compound, or material may be at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% pure, including all decimals in between. Purity may be affected by unwanted impurities, including but not limited to side products, isomers, enantiomers, degradation products, solvent, carrier, vehicle, or contaminants, or any combination thereof. Purity can be measured technologies including but not limited to chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-visible spectrometry, infrared spectrometry, mass spectrometry, nuclear magnetic resonance, gravimetry, or titration, or any combination thereof. Methods of Use

[0230] Some embodiments disclosed herein related to selecting a subject or patient in need. In some embodiments, a patient is selected who is in need of treatment, inhibition, amelioration, prevention or slowing of diseases or conditions associated with PD-L1 dysregulation. In some embodiments, such diseases or conditions associated with PD-L1 dysregulation may include, for example, cancer, HCC, viral infections, or HBV. In some embodiments, a subject can be selected who has previously been treated for the disease or disorder described herein. In some embodiments, a subject can be selected who has previously been treated for being at risk for the disease or disorder described herein. In some embodiments, a subject can be selected who has developed a recurrence of the disease or disorder described herein. In some embodiments, a subject can be selected who has developed resistance to therapies for the disease or disorder described herein. In some embodiments, a subject can be selected who may have any combination of the aforementioned selection criteria.

[0231] Compounds, and pharmaceutically acceptable salts thereof, disclosed herein can be evaluated for efficacy and toxicity using known methods. A non-limiting list of potential advantages of a compound, or a pharmaceutically acceptable salt thereof, describedherein include improved stability, increased safety profile, increased efficacy, increased binding to the target, increased specificity for the target (for example, a cancer cell or virally infected cell).

[0232] The terms “treating,” “treatment,” “therapeutic,” or “therapy” as used herein has its ordinary meaning as understood in light of the specification, and do not necessarily mean total cure or abolition of the disease or condition. The term “treating” or “treatment” as used herein (and as well understood in the art) also means an approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. “Treating” and “treatment” as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may comprise a series of administrations. The compositions are administered to the subject in an amount and for a 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 profile of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.

[0233] Some embodiments described herein relate to a method of treating, inhibiting, ameliorating, preventing, or slowing the disease or disorder described herein. In some embodiments, the methods include administering to a subject identified as suffering from the disease or disorder described herein an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof,as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating, inhibiting ameliorating, preventing, or slowing the disease or disorder described herein. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating, inhibiting ameliorating, preventing, or slowing the disease or disorder described herein.

[0234] Some embodiments described herein relate to a method for inhibiting replication of a cancer cell or a virus that can include contacting the cell or virus or administering to a subject identified as suffering from a cancer or a viral infection with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting replication of a cancer cell or virus. Still other embodiments described herein relate to an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein for inhibiting replication of a cancer cell or virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus is hepatitis B.

[0235] Some embodiments described herein relate to a method for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus, that can include administering to a subject identified as suffering from a disease wherein inhibiting cell proliferation is desirable with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or apharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus. Still other embodiments described herein relate to an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the cell infected with a virus is infected with hepatitis B virus.

[0236] Some embodiments described herein relate to a method of inducing apoptosis of a cell (for example, a cancer cell or cell infected with a virus) that can include contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inducing apoptosis of a cell, such as a cancer cell or cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for inducing apoptosis of a cell, such as a cancer cell or cell infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the cell infected with a virus is infected with hepatitis B virus.

[0237] Some embodiments described herein relate to a method of decreasing the viability of a cell (for example, a cancer cell or cell infected with a virus) that can include contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for decreasing the viability of a cell, such as a cancer cell or cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for decreasing the viability of a cell, such as a cancer cell or cell infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the cell infected with a virus is infected with hepatitis B virus.

[0238] Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from test results. An effective therapeutic daily amount would be from about 0.005 mg / kg to 50 mg / kg, in particular, 0.01 mg / kg to 50 mg / kg body weight, more in particular from 0.01 mg / kg to 25 mg / kg body weight, preferably from about 0.01 mg / kg to about 15 mg / kg, more preferably from about 0.01 mg / kg to about 10 mg / kg, even more preferably from about 0.01 mg / kg to about 1 mg / kg, most preferably from about 0.05 mg / kg to about 1 mg / kg body weight.

[0239] In some embodiments, the effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein is dosed more than one time. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, described herein can be 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 period or combination thereof within the range defined by any two aforementioned times. In some embodiments, at least one loading dose and at least one maintenance dose is administered to the subject, where the at least one loading dose is a higher dose of a compound, or a pharmaceutically acceptable salt thereof, described herein than the at least one maintenance dose.

[0240] As used herein, the term “combination therapy” is intended to define therapies which comprise the use of a combination of two or more pharmaceutical compounds / agents or therapies. Thus, references to “combination therapy”, “combinations” and the use of compounds / agents “in combination” in this application may refer to compounds / agents that are administered as part of the same overall treatment regimen. As such, the dosage or timing of each of the two or more compounds / agents may differ: each maybe administered at the same time or at different times. Accordingly, the compounds / agents of the combination may be administered sequentially (e.g., before or after) or simultaneously, either in the same pharmaceutical formulation (i.e., together), or in different pharmaceutical formulations (i.e., separately). Each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration.

[0241] The term “inhibitor”, as used herein, refers to an enzyme inhibitor or receptor inhibitor which is a molecule that binds to an enzyme or receptor, and decreases and / or blocks its activity. The term may relate to a reversible or an irreversible inhibitor.

[0242] Cancer may be treated with surgery, radiation therapy, chemotherapy, targeted therapies, immunotherapy or hormonal therapies. Any of these mentioned therapies may be used in conjunction with another therapy as a combination therapy. Chemotherapeutic compounds include but are not limited to alemtuzumab, altretamine, azacitidine, bendamustine, bleomycin, bortezomib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denosumab, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gemcitabine, gemtuzumab, hydroxycarbamide, ibritumomab, idarubicin, ifosfamide, irinotecan, ixabepilone, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, ofatumumab, oxaliplatin, paclitaxel, pemetrexed, pentostatin, pertuzumab, procarbazine, raltitrexed, streptozotocin, tegafur, temozolomide, temsirolimus, teniposide, tioguanine, topotecan, tositumomab, valrubicin, vinblastine, vincristine, vindesine, vinflunine, or vinorelbine, or any combination thereof.

[0243] As used herein, the term “protein kinase inhibitor” refers to inhibitors of protein kinases, serine / threonine kinases, tyrosine kinases, or dual-specificity kinases for the treatment of cancer or other illness. In some embodiments, the protein kinase inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the protein kinase inhibitor includes but is not limited to acalabrutinib, adavosertib, afatinib, alectinib, axitinib, binimetinib, bosutinib, brigatinib, cediranib, ceritinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib,erdafitinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, lortatinib, masitinib, momelotinib, mubritinib, neratinib, nilotinib, nintedanib, olmutinib, osimertinib, pacritinib, panitumumab, pazopanib, pegaptanib, ponatinib, radotinib, regorafenib, rociletinib, ruxolitinib, selumetinib, semaxanib, sorafenib, sunitinib, SU6656, tivozanib, toceranib, trametinib, trastuzumab, vandetanib, or vemurafenib, or any combination thereof.

[0244] 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, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the immune checkpoint is the PD- 1 / PD-L1 checkpoint. In some embodiments, the PD-1 checkpoint includes but is not limited to nivolumab, pembrolizumab, spartalizumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224 or AMP-514, or any combination thereof. In some embodiments, the PD-L1 checkpoint inhibitor includes but is not limited to atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170, or BMS-986189, or any combination thereof. In some embodiments, the immune checkpoint is the CTLA-4 checkpoint. In some embodiments, the CTLA-4 checkpoint inhibitor includes but is not limited to ipilimumab or tremilimumab, or any combination thereof.

[0245] As used herein, the term “VEGF inhibitor” refers to inhibitors of vascular endothelial growth factor (VEGF) or a VEGF receptor (VEGFR). In some embodiments, the VEGF inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the VEGF inhibitor includes but is not limited to aflibercept, axitinib, bevacizumab, brivanib, cabozantinib, cediranib, lenvatinib, linifinib, nintedanib, pazopanib, ponatinib, ramucirumab, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, or vandetanib, or any combination thereof.

[0246] As used herein, the term “antiviral medication” refers to a pharmaceutical composition administered to treat a viral infection. In some embodiments, the viral infection is caused by adenovirus, Ebola virus, coronavirus, Epstein-Barr virus (EBV), Friend virus, hantavirus, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, humanimmunodeficiency virus (HIV), human metapneumovirus, human papillomavirus (HPV), influenza virus, Japanese encephalitis virus, Kaposi’s sarcoma-associated herpesvirus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus, varicella zoster virus.

[0247] In some embodiments, the antiviral medication is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the antiviral medication is an interferon, a capsid assembly modulator, a sequence specific oligonucleotide, an entry inhibitor, or a small molecule immunomodulatory. In some embodiments, the antiviral medication 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, faldaprevir, famciclovir, favipiravir, filibuvir, fomivirsen, foscarnet, galidesivir, ganciclovir, glecaprevir, GLS4, grazoprevir, idoxuridine, imiquimod, IFN-Į, interferon alfa 2b, JNJ-440, JNJ-6379 (JNJ-56136379), lamivudine, laninamivir, ledipasvir, mericitabine, methisazone, MK-608, moroxydine, narlaprevir, NITD008, NZ-4, odalasvir, ombitasvir, oseltamivir, paritaprevir, peginterferon 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, tenofovir alfenamide, triazavirin, trifluridine, tromantadine, umifenovir, uprifosbuvir, valaciclovir, valgancicovir, vaniprevir, vedroprevir, velpatasvir, vidarabine, 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.

[0248] The term “% w / w” or “% wt / wt” as used herein has its ordinary meaning as understood in light of the specification and refers to a percentage expressed in terms of the weight of the ingredient or agent over the total weight of the composition multiplied by 100. The term “% v / v” or “% vol / vol” as used herein has its ordinary meaning as understood in the light of the specification and refers to a percentage expressed in terms of the liquid volume of the compound, substance, ingredient, or agent over the total liquid volume of the composition multiplied by 100. EXAMPLES

[0249] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the present disclosure, as it is described herein above and in the claims.

[0250] Hereinafter, the term “rt”, “r.t.” or “RT” means room temperature; “Me” means methyl; “MeOH” means methanol; “Et” means ethyl; “EtOH” means ethanol; “NaH” means sodium hydride; “NaBH(AcO)3” or “NaBH(OAc)3” means sodium triacetoxyborohydride; “EtOAc” means ethyl acetate; "TEA” or "Et3N” means triethylamine; “DCM” means dichloromethane; “MeCN” or “ACN” means acetonitrile; “DMF” means - dimethyl formamide; “DMA” means dimethy1acetamide; “Pd(dppf)Cl2.” means [1.1'- Bis(diphenylphosphino)ferrocene]-dichloropalladium(II); “Pd-118” means 1,1’-Bis(di-ter- butylphosphino)ferrocene palladium dichloride; “THF” means tetrahydrofuran; “TCFH” means N,N,Nƍ,Nƍ-tetramethylchloroformamidinium hexafluorophosphate; “NMI” means N- methylimidazole; “m-CPBA” means meta-chloroperoxybenzoic acid; “ClCOOMe” means methyl carbonochloridate; “AcCl” means acetyl chloride; “i-PrOH” or “iPrOH” means 2- propanol; “LC” means liquid chromatography; “LCMS” means Liquid Chromatography / Mass spectrometry; “HPLC” means high-performance liquid chromatography; “prep-HPLC” means preparative high-performance liquid chromatography; “TFA” means trifluoroacetic acid; “RP” means reversed phase; "min" means minute(s); "h” means hour(s); “PE” means petroleumether; “v / v” means volume per volume; “Celite ®” 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” or “HOAc” 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” or “AcOK” means potassium acetate; “BOP” means benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; and “HATU” means hexafluorophosphate azabenzotriazole tetramethyl uronium.

[0251] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, estimated mol amounts (in some cases indicated by ~) are indicated in the reaction protocols described below, or alternatively theoretical mol amounts are indicated.

[0252] The meanings of the abbreviations in the nuclear magnetic resonance spectra are provided as follows: s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = doublet of doublets of doublets, Sept = septet, t = triplet, m = multiplet, br = broad, brs = broad singlet, q = quartet. Preparation of Intermediates Example A1 Intermediate1-1

[0253] 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 stirring the mixture at 100 °C for 2 h under N2atmosphere, the reaction was quenched with H2O (30 mL) and then extracted with EtOAc (3 x 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 1-1 (1.4 g) as a yellow solid. MS: ES m / z calculated for C12H9BrCl2N 315.9, found 316.0.

[0254] The intermediates shown in Table A-1 were prepared by an analogous reaction protocol as was used for the preparation of Intermediate 1-1 using the appropriate starting materials. Table A-1Example A2 Intermediate 2-1

[0255] A mixture of Intermediate 1-1 (52.5 g, 149 mmol), 2-Methyl-3-oxo-2,3- dihydropyridazine-4-carboxylic acid (23 g, 149 mmol), N,N,Nƍ,Nƍ- tetramethylchloroformamidinium hexafluorophosphate(TCFH (83.7 g, 299 mmol) and N- methylimidazole (NMI, 29.7 mL, 373 mmol) in MeCN (500 mL) was purged with N2 three times. The mixture was stirred at 60 °C for 16 h under N2 atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was triturated with EtOAc at 25 °C for 30 min. Intermediate 2-1 (48 g, 95% purity) was obtained as a white solid.1NMR (400 MHz, DMSO-d6) į 12.35 (s, 1H), 8.61 (dd, J = 1.4, 8.3 Hz, 1H), 8.32-8.20 (m, 2H), 7.87 (t, J = 4.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.44-7.37 (m, 2H), 7.16 (dd, J = 1.5, 7.6 Hz, 1H), 3.85 (s, 3H).

[0256] The intermediates shown in Table A-2 were prepared by an analogous reaction protocol as was used for the preparation of Intermediate 2-1 using the appropriate starting materials.Intermediate 2-1 Intermediate 3-1

[0257] A mixture of Intermediate 2-1 (48 g,101 mmol), Bis(pinacolato)diboron (76.7 g, 302 mmol), AcOK (29.6 g, 302 mmol), Pd(dppf)Cl2(5.89 g, 8.05 mmol) in dioxane (500 mL) was purged with N2(3x), and the mixture was stirred at 100 °C for 16 h under N2atmosphere. The mixture was concentrated under reduced pressure to remove the solvent. Theresidue was purified by column chromatography (SiO2, PE:EA = 100:1 to 3:2). Compound 3- 1 (60 g) was obtained as a white solid.1H NMR (400 MHz, CDCl3) į 12.21 (s, 1H), 8.61 (dd, J = 1.4, 8.3 Hz, 1H), 8.32 (d, J = 4.1 Hz, 1H), 8.05 (d, J = 4.1 Hz, 1H), 7.70 (dd, J = 2.9, 6.4 Hz, 1H), 7.38-7.30 (m, 3H), 7.07-7.02 (m, 1H), 3.97-3.95 (m, 3H), 1.39 (s, 12H).

[0258] The intermediates shown in Table A-3 were prepared by an analogous reaction protocol as was used for the preparation of Intermediate 3-1 using the appropriate starting materials. Table A-3Example A4 Intermediate 4-1

[0259] To a solution of tert-Butyl 7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)- carboxylate (2 g, 7.44 mmol) in DCM (20mL) was added m-CPBA (1.67 g, 9.67 mmol) at 20 °C. The mixture was stirred at 30 °C for 16 h. Extra m-CPBA (1.28 g, 7.44 mmol) was added into the mixture. The mixture was stirred at 30 °C for 3 h. The mixture was poured into sat. aq.NaHCO3(100 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. Intermediate 4-1 (1.7 g) was obtained as a white solid.1H NMR (400 MHz, CDCl3) į 8.21 (s, 1H), 7.26 (s, 1H), 4.54 (s, 2H), 3.66 (br t, J = 5.8 Hz, 2H), 2.77 (br t, J = 5.6 Hz, 2H), 1.49 (s, 9H). Example A5 Intermediate 5-1

[0260] A mixture of Intermediate 3-1 (2.91 g, 4.65 mmol), Intermediate 4-1 (800 mg, 2.81 mmol), 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (Pd-118, 183 mg, 281 μmol) and K2CO3(1.16 g, 8.43 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was stirred at 100 °C for 12 h under N2atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was first purified by flash silica gel chromatography and re-purified by prep-HPLC. Intermediate 5-1 (780 mg) was obtained as a black-brown solid. MS: ES m / z calculated for C31H30Cl2N5O5 [M+H]+622.2, found 622.9.1H NMR (400 MHz, CDCl3) į 12.23 (s, 1H), 8.64 (dd, J = 1.4, 8.3 Hz, 1H), 8.32 (d, J = 4.1 Hz, 1H), 8.22 (s, 1H), 8.09-8.02 (m, 1H), 7.54-7.43 (m, 2H), 7.42-7.36 (m, 2H), 7.18 (s, 2H), 4.60 (br s, 2H), 3.97 (s, 3H), 3.72 (br d, J = 6.9 Hz, 2H), 2.84 (br t, J = 5.4 Hz, 2H), 1.51 (s, 9H).

[0261] The intermediates shown in Table A-4 were prepared by an analogous reaction protocol as was used for the preparation of Intermediate 5-1 using the appropriate starting materials.Table A-4Example A6 Intermediate 6-1

[0262] To a solution of Intermediate 5-1 (500 mg, 803 μmol) in MeOH (40 mL) was added TEA (2.35 mL, 16.9 mmol) and methyl carbonochloridate (1.24 mL, 16.1 mmol) at 20 °C for 30 mins. Then extra TEA (2.35 mL, 16.9 mmol) and methyl carbonochloridate (1.24 mL, 16.1 mmol) was added into the mixture at 20 °C for 30 mins. The mixture was stirred at 70 °C for 13 h. The mixture was concentrated under reduced pressure. The residue was diluted with sat. aq. NaOH (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. Intermediate 6-1 (184 mg) was obtained as a yellow solid. MS: ES m / z calculated for C32H32Cl2N5O5 [M+H]+636.2, found 636.0.

[0263] The intermediates shown in Table A-5 were prepared by an analogous reaction protocol as was used for the preparation of Intermediate 6-1 using the appropriate starting materials. Table A-5Preparation of Compounds Example 1 Compound A-1

[0264] To a solution of Intermediate 6-1 (184 mg, 289 μmol) in DCM (8 mL) was added TFA (8 mL, 108 mmol). The mixture was stirred at 25 °C for 2 h. The mixture wasconcentrated under reduced pressure to give crude Compound A-1, which was used into the next step without further purification.

[0265] The compounds shown in Table B-1 were prepared by an analogous reaction protocol as was used for the preparation of Compound A-1 using the appropriate starting materials. Table B-1Example 2 Compound B-1

[0266] A solution of Compound A-1 (50 mg, 93.2 μmol) and methyl 4-(2- oxoethyl)bicyclo [2.2.1]-heptane-1-carboxylate (55 mg, 280 μmol) in MeOH (1 mL) wasstirred at 30 °C for 1 h. NaBH3CN (18 mg, 280 μmol) was added into the mixture. Then the mixture was stirred at 30 °C for 1.5 h. The mixture was filtered and concentrated under reduced pressure to give pink solid residue. The residue was purified by RP-HPLC and offered Compound B-1. MS: ES m / z calculated for C38H40Cl2N5O5 [M+H]+716.2, found 716.2.

[0267] The compounds shown in Table B-2 were prepared by an analogous reaction protocol as was used for the preparation of Compound B-1 using the appropriate starting materials. Table B-2Example 3 Compound C-1

[0268] To a solution of Compound, B-1 (65 mg, 90.7 μmol,) in H2O (1 mL) and THF (2 mL) was added LiOH.H2O (11.42 mg, 272 μmol). The mixture was stirred at 45 °Cfor 5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH~4. The residue was purified by prep-HPLC. Compound C-1 (6.43 mg) was obtained as a white solid. MS: ES m / z calculated for C37H38Cl2N5O5 [M+H]+702.2, found 702.6.1H NMR (400 MHz, CDCl3) į 12.24 (s, 1H), 8.64 (dd, J = 1.4, 8.3 Hz, 1H), 8.33 (d, J = 4.3 Hz, 1H), 8.06 (d, J = 4.3 Hz, 1H), 7.65 (dd, J = 1.6, 7.7 Hz, 1H), 7.41 (td, J = 7.8, 10.1 Hz, 2H), 7.29 (br d, J = 1.4 Hz, 1H), 7.12 (dd, J = 1.5, 7.6 Hz, 1H), 7.03-6.96 (m, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.70 (br s, 2H), 3.01-2.76 (m, 4H), 2.72-2.55 (m, 2H), 2.10-1.99 (m, 4H), 1.72-1.64 (m, 3H), 1.60 (s, 4H), 1.49-1.43 (m, 2H).

[0269] The compounds shown in Table B-3 were prepared by an analogous reaction protocol as was used for the preparation of Compound C-1 using the appropriate starting materials. Table B-3Example 4 Compound D-1

[0270] To a solution of Compound A-4 (70 mg, 128 μmol) and (S)-5- Bromomethyl-2-pyrrolidinone (23 mg, 128 μmol) in DMSO (1 mL) was added DIEA (223 μL, 1.28 mmol) and potassium iodide (213 mg, 1.28 mmol). The mixture was stirred at 40 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC and offered Compound D-1 (9.6 mg) as a white solid. MS: ES m / z calculated for C34H36ClN6O5 [M+H]+643.2, found 643.2.1H NMR (400 MHz, DMSO-d6) į 11.07 (s, 1H), 8.76 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.66-7.56 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.36-7.28 (m, 2H), 7.02-6.95 (m, 2H), 3.90 (s, 3H), 3.82-3.75 (m, 1H), 3.62 (s, 2H), 3.50 (s, 3H), 3.27 (s, 3H), 2.81-2.70 (m, 2H), 2.64 (br s, 2H), 2.49-2.41 (m, 2H), 2.21-2.07 (m, 6H), 1.77-1.66 (m, 1H).

[0271] The compounds shown in Table B-4 were prepared by an analogous reaction protocol as was used for the preparation of Compound D-1 using the appropriate starting materials. Table B-4Example 5 Compound E-1

[0272] A mixture of 3-Bromopropionic acid (9.63 μL, 93.2 μmol), Compound A- 1 (25 mg, 47 μmol), K2CO3(19.3 mg, 139 μmol) in DMF (0.5 mL) was stirred at 50 °C for 16 h. The mixture was filtered to give a residue. The residue was purified by prep-HPLC to give Compound E-1 (6.9 mg) as a white solid. ES m / z calculated for C30H28Cl2N5O5[M+H]+608.1, found 608.5.1H NMR (400 MHz, CDCl3) į 12.24 (s, 1H), 8.65 (dd, J = 1.4, 8.3 Hz, 1H), 8.33 (d, J = 4.3 Hz, 1H), 8.07 (d, J = 4.3 Hz, 1H), 7.65 (dd, J = 1.7, 7.7 Hz, 1H), 7.42 (td, J = 7.8, 13.2 Hz, 2H), 7.30 (dd, J = 1.7, 7.6 Hz, 1H), 7.12 (dd, J = 1.5, 7.6 Hz, 1H), 7.01 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.85 (s, 2H), 3.05 (br s, 2H), 2.97 (t, J = 6.2 Hz, 2H), 2.90-2.86 (m, 2H), 2.66 (t, J = 6.1 Hz, 2H). Example 6 Compound F-2

[0273] To a solution of Compound A-1 (25 mg, 47 μmol) in EtOH (1 mL) was added (S)-methyl oxirane-2-carboxylate (19 mg, 186 μmol). The mixture was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue withCompound F-1. The residue with Compound F-1 was used into the next step without further purification.

[0274] A solution of the residue with Compound F-1 (30 mg, 46 μmol) and LiOH.H2O (5.91 mg, 140 μmol) in H2O (1 mL) and THF (2 mL) was stirred at 45 °C for 3 h. The mixture was concentrated under reduced pressure to remove THF and H2O. The residue was adjusted to pH ~4. The residue was purified by prep-HPLC. Compound F-2 (8.42 mg) was obtained as a white solid. ES m / z calculated for C30H28Cl2N5O6[M+H]+ 624.1, found 624.5.1H NMR (400 MHz, CDCl3) į 12.24 (s, 1H), 8.65 (dd, J = 1.2, 8.3 Hz, 1H), 8.33 (d, J = 4.1 Hz, 1H), 8.08-8.03 (m, 1H), 7.63 (br d, J = 7.4 Hz, 1H), 7.41 (td, J = 7.8, 12.1 Hz, 2H), 7.30 (dd, J = 1.2, 7.4 Hz, 1H), 7.18-7.09 (m, 1H), 7.09-6.92 (m, 1H), 4.27 (br s, 3H), 4.02 (s, 3H), 3.96 (s, 3H), 3.57-3.12 (m, 6H), 2.99 (br s, 2H). Example 7 Compound G-1

[0275] To a solution of Compound D-3 (70 mg, 101.57 ^mol) in DCM (4 mL) was added TFA (2.15 g, 18.85 mmol, 1.40 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue containing compound G-1. The residue was purified by prep-HPLC. Compound G-1 (30 mg) was obtained as a white solid. ES m / z calculated for C31H34ClN6O4[M+H]+589.2, found 589.2. Example 8 Compound H-1

[0276] To a solution of Compound G-1 (30 mg, 51 μmol) and Ac2O (7 μL, 76 μmol) in DCM (1 mL) was added TEA (21μL, 153 μmol). The mixture was stirred at 25 °Cfor 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Compound H-1 (0.85 mg) was obtained as a white solid. ES m / z calculated for C33H36ClN6O5 [M+H]+631.2, found 631.2.

[0277] To a solution of Compound C-4 (20 mg, 28 μmol) in DMF (1.0 mL) was added NH4Cl (15 mg, 280 μmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 12 mg, 28 μmol) and TEA (16 μL, 112 μmol). The mixture was stirred at 25 °C for 12 h. The mixture was filtered and purified by prep-HPLC. Compound I- 1 (4.03 mg) was obtained as a white solid. ES m / z calculated for C39H44ClN6O5 [M+H]+711.3, found 711.3;1H NMR (400 MHz, DMSO-d6) į = 11.09 - 11.05 (m, 1H), 8.80 - 8.70 (m, 1H), 8.32 - 8.20 (m, 1H), 8.14 - 8.13 (m, 1H), 7.63 - 7.56 (m, 1H), 7.54 - 7.47 (m, 1H), 7.36 - 7.28 (m, 2H), 7.04 - 7.00 (m, 1H), 7.00 - 6.94 (m, 2H), 6.76 - 6.70 (m, 1H), 3.92 - 3.87 (m, 3H), 3.62 - 3.53 (m, 2H), 3.50 (s, 3H), 3.27 (s, 3H), 2.75 - 2.61 (m, 4H), 2.11 - 2.05 (m, 3H), 1.81 - 1.70 (m, 4H), 1.56 - 1.45 (m, 4H), 1.40 (s, 4H).

[0278] To a solution of Compound C-4 (20 mg, 28 μmol) and methanamine hydrochloride (3.79 mg, 56 μmol) in DMF (1.0 mL) was added DIEA (15 μL 11 mg, 84 μmol) and hexafluoro-phosphate azabenzotriazole tetramethyl uronium (HATU (21 mg, 56 μmol)). The mixture was stirred at 25 °C for 2 h. The mixture was purified by prep-HPLC. Compound J-1 (1.6 mg) was obtained as a white solid. ES m / z calculated for C40H46ClN6O5 [M+H]+725.3, found 725.3.Example 11 Compound M-1

[0279] To a solution of Compound A-4 (140 mg, 256 μmol) and tert-butyl 4-(2- oxoethyl)piperidine-1-carboxylate (117 mg, 513 μmol) in DCM (1 mL) and i-PrOH (1 mL) was added HOAc (59 μL, 1.03 mmol) and borane-2-methylpyridine complex (110 mg, 1.03 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give Compound K-1 (80 mg) as a white solid. ES m / z calculated for C41H49ClN6O6 [M+Na]+779.3, found 779.5.

[0280] To a solution of Compound K-1 (75 mg, 99 μmol) in DCM (2 mL) was added TFA (7.4 μL, 99 μmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The crude Compound L-1 was used in the next step without purification. ES m / z calculated for C36H42ClN6O4[M+H]+657.3, found 657.4.

[0281] To a solution of crude Compound L-1 (40 mg) in DCM (2 mL) was added TEA (25 μL, 183 μmol) and acetyl chloride (6.5 μL, 91 μmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Compound M-1 (8.60 mg) as a white solid. ES m / z calculated for C38H44ClN6O5[M+H]+699.3, found 699.3.1H NMR (400 MHz, DMSO-d6) į = 11.07 (s, 1H), 8.76 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.50 (t, J = 7.6 Hz,1H), 7.35 - 7.29 (m, 2H), 7.02 - 6.96 (m, 2H), 4.32 (d, J = 13.2 Hz, 1H), 3.89 (s, 3H), 3.76 (d, J = 13.6 Hz, 1H), 3.55 (s, 2H), 3.50 (s, 3H), 3.28 (s, 3H), 2.96 (t, J = 11.6 Hz, 1H), 2.68 (d, J = 5.2 Hz, 2H), 2.63 (d, J = 4.8 Hz, 2H), 2.49 - 2.44 (m, 3H), 2.09 (s, 3H), 1.96 (s, 3H), 1.69 (br t, J = 14.8 Hz, 2H), 1.55 (s, 1H), 1.50 - 1.43 (m, 2H), 1.09 (d, J = 3.6 Hz, 1H), 0.94 (dd, J = 3.6, 11.6 Hz, 1H). Example 12 Compound N-1

[0282] To a solution of Compound L-1 (20 mg) and N-methylcarbamoyl chloride (2.85 mg, 30.43 μmol) in DCM (1 mL) was added TEA (13 μL, 91 μmol). The mixture was stirred at 25 °C for 16 h. The mixture was quenched by H2O (5 ml), and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Compound N-1 (4.8 mg) as a white solid. ES m / z calculated for C38H45ClN7O5[M+H]+714.3, found 714.3. Example A LCMS (Liquid chromatography / Mass spectrometry)

[0283] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]-(deprotonated molecule). In case the compound was 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 value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "RT" room temperature, "BEH" bridged ethylsiloxane / silica hybrid, "DAD" Diode Array Detector, "HSS" High Strength silica., "Q-Tof Quadrupole Time-off light mass spectrometers, "CLND", ChemiLuminescent Nitrogen Detector, "ELSD" Evaporative Light Scanning Detector. Table C: LCMS Method CodesFlow expressed in mL / min; column temperature (T) in °C; Run time in minutes. Table D: LCMS ResultsRetention time (Rt,) in min; LC / MS: without indication the mass is corresponding to [M+H]+. Example B PDL1 / PD1 Binding Assay

[0284] Compounds to be tested were serially diluted in DMSO, and further diluted in assay buffer (25 mM Hepes pH 7.4, 150 mM NaCl, 0.005% Tween 20, BSA 0.01%). Dilutedcompounds were added to the wells with final concentration of DMSO at 1%. PDL1-6xHis protein was added to the wells, mixed well with compound. The plates were incubated for 30 min at room temperature. PD1-Fc-Avi-Biotin protein was added to the wells. Final concentration of PDL1 and PD1 protein is 0.3 nM and 2.5 nM, respectively. After a binding time of 30 min at room temperature, Anti-6xHis Acceptor beads (final concentration 20 ug / ml) were added to the wells, and the incubation continued for 1 h. Streptavidin Donor beads (final concentration 20 ug / mL) were added at reduced light. The plates were sealed with foil and incubated in the dark for additional 1 h or overnight before reading on an Envision reader. The IC50values were determined by fitting the curves using a four-parameter equation in Graphpad Prism 8. Example C PD-1 / PD-L1 NFAT Reporter Assay

[0285] Cellular activity of the compounds was assessed using a co-culture reporter assay in which TCR-mediated NFAT activity of Jurkat T cells is constitutively inhibited by the engagement of PD-1 by PD-L1 expressing CHO cells. Blocking the PD-1 / PD-L1 interaction will release the inhibitory signal and results in TCR signaling and NFAT-mediated luciferase activity.

[0286] CHO cells expressing surface-bound anti-CD3 antibodies and PD-L1 were first seeded overnight and treated with the compounds. Jurkat cells overexpressing PD-1 and a luciferase construct under NFAT promoter were then immediately seeded on the monolayer of CHO cells. The co-culture was then incubated for 6 hrs at 37 °C. Luciferase activity was assessed by adding the ONE-Glo reagent and measuring luminescence with a plate reader. EC50 values were determined from the fit of the dose-response curves.

[0287] Compounds described herein, as exemplified in the Examples, showed EC50 or IC50 values in the following ranges: A: IC50 or EC50 ^10 nM; B: 10 nM < IC50 or EC50 ^100 nM; C: 100 nM < IC50 or EC50 ^1000 nM; D: 1000 nM < IC50 or EC50 ^10000 nM; E: IC50 or EC50 > 10000 nM; n.d. = not determined; n.r. = EC50 not reached in the range of tested concentrations starting from 1 nM to 5000 nM. As shown by the data in Table E, the compounds described herein are active for controlling expression of PD-L1.Table E

[0288] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:; X1is selected from the group consisting of CH and N (nitrogen); X2is selected from the group consisting of C(R5) and N; Y1and Y2are each independently selected from the group consisting of N (nitrogen) and CH; R1ais selected from the group consisting of –C1-4 alkyl, –C1-4 haloalkyl, –CH2(C3-6 monocyclic cycloalkyl), –CH2(4-6 membered monocyclic heterocyclyl) and –CH2(5-6 membered monocyclic heteroaryl); R1band R1care each independently selected from the group consisting of hydrogen, halogen –C1-2alkyl, –C1-2haloalkyl, -OH, -OC1-2alkyl and –OC1-2haloalkyl; R1dand R1eare each independently selected from the group consisting of hydrogen, –C1-2alkyl and –C1-2haloalkyl; R1fand R1gare each independently selected from hydrogen, –C1-2alkyl and –C1-2haloalkyl; R2a, R2b, R2c, R2e, R2gand R2hare each independently selected from the group consisting of hydrogen and halogen;R2dand R2fare each independently selected from the group consisting of halogen, cyano, –CH3, –CH2CH3, –OCH3 and –SCH3; R3aand R3bare each independently selected from the group consisting of hydrogen, –C1-4 alkyl and –C2-4 haloalkyl; R4ais selected from the group consisting of hydrogen, –C1-4 alkyl and –C2-4 haloalkyl; R4bis selected from the group consisting of hydrogen, halogen, –OH, –CN, –C1-4alkyl and –C2-4haloalkyl; R5is selected from the group consisting of hydrogen and halogen; Rx1is selected from the group consisting of hydrogen, –C1-4alkyl and –Ry1, wherein the –C1-4 alkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, hydroxy, amino, –C1-4alkoxy, –C1-4 haloalkyl, , ,Ry1is selected from the group consisting of: , ,,1can be optionally substituted with one or two substituents independently selected from halogen, cyano, amino, hydroxy, –C alkoxy, –C haloalkyl, –CZ11-41-41-4haloalkoxy, –C(=O)OR , ,m1, m2 and m3 are each independently 1 or 2; n1 is 0, 1 or 2; RZ1, RZ2and RZ3are each independently selected from the group consisting of hydrogen, –C1-4alkyl and –C1-4haloalkyl; Rx2is selected from the group consisting of hydrogen, halogen, –C1-4alkyl, –C1-4haloalkyl, –C(=O)RW3,and –S(=O)N(RW1)RW2; and RW1, RW2and RW3are each independently selected from the group consisting of hydrogen, –C1-4 alkyl and –C1-4 haloalkyl.

2. The compound of Claim 1, wherein X1is CH.

3. The compound of Claim 1, wherein X1is N.

4. The compound of any one of Claims 1-3, wherein X2is C(R5).

5. The compound of Claim 4, wherein R5is H.

6. The compound of Claim 4, wherein R5is halogen.

7. The compound of any one of Claims 1-3, wherein X2is N.

8. The compound of any one of Claims 1-7, wherein R1ais –C1-4alkyl.

9. The compound of any one of Claims 1-7, wherein R1ais –C1-4 haloalkyl.

10. The compound of any one of Claims 1-7, wherein R1ais –CH2(monocyclic C3- 6 cycloalkyl).

11. The compound of any one of Claims 1-7, wherein R1ais –CH2(4-6 membered monocyclic heterocyclyl).

12. The compound of any one of Claims 1-7, wherein R1ais –CH2(5-6 membered monocyclic heteroaryl).

13. The compound of any one of Claims 1-12, wherein Rx1is hydrogen.

14. The compound of any one of Claims 1-12, wherein Rx1is –C1-4 alkyl.

15. The compound of Claim 14, wherein Rx1is –C1-4 alkyl substituted by amino.

16. The compound of Claim 14, wherein Rx1is –C1-4alkyl substituted by –OH.

17. The compound of Claim 14, wherein Rx1is –C1-4alkyl substituted by –C(=O)ORZ1.

18. The compound of Claim 17, wherein RZ1is hydrogen.

19. The compound of Claim 14, wherein Rx1is –C1-4 alkyl substituted by –N(RZ1)C(=O)RZ3or –N(RZ1)C(=O)ORZ3.

20. The compound of Claim 19, wherein RZ1is H; and RZ3is –C1-4 alkyl.

21. The compound of Claim 20, wherein RZ3is –CH3.

22. The compound of Claim 20, wherein RZ3is t-butyl.

23. The compound of Claim 14, wherein Rx1is –C1-4alkyl substituted by –N(RZ1)C(=O)N(RZ1)RZ3.

24. The compound of Claim 23, wherein RZ1is H; and RZ3is –C1-4alkyl.

25. The compound of Claim 24, wherein RZ3is –CH3.

26. The compound of any one of Claims 1-12, wherein Rx1is –Ry1.

27. The compound of Claim 26, wherein –Ry1is selected from the group consisting ,28. The compound of Claim 27, wherein n1 is 0.

29. The compound of Claim 27, wherein n1 is 1.

30. The compound of Claim 27, wherein n1is 2.

31. The compound of any one of Claims 27-30, wherein RZ1is H.

32. The compound of any one of Claims 27-30, wherein RZ1is –C1-4 alkyl.

33. The compound of Claim 32, wherein RZ1is –CH3.

34. The compound of any one of Claims 27-30, wherein RZ1is –C1-4 haloalkyl.

35. The compound of Claim 26, wherein –Ry1is selected from the group consisting a36. The compound of Claim 35, wherein m1 is 1.

37. The compound of Claim 35, wherein m1 is 2.

38. The compound of any one of Claims 35-37, wherein m2 and m3 are each 1.

39. The compound of any one of Claims 35-38, wherein RZ1is H.

40. The compound of any one of Claims 35-38, wherein RZ1is –C1-4alkyl.

41. The compound of Claim 40, wherein RZ1is –CH3.

42. The compound of any one of Claims 35-38, wherein RZ1is –C1-4haloalkyl.

43. The compound of Claim 26, wherein –Ry1is selected from the group consisting o.

44. The compound of Claim 43, wherein m1is 1.

45. The compound of Claim 43, wherein m1 is 2.

46. The compound of any one of Claims 43-45, wherein m2 and m3 are each 1.

47. The compound of any one of Claims 43-46, wherein RZ1is H.

48. The compound of any one of Claims 43-46, wherein RZ1is –C1-4 alkyl.

49. The compound of Claim 48, wherein RZ1is –CH3.

50. The compound of any one of Claims 43-46, wherein RZ1is –C1-4 haloalkyl.

51. The compound of Claim 26, wherein.

52. The compound of Claim 51, wherein m1 is 1.

53. The compound of Claim 51, wherein m1 is 2.

54. The compound of any one of Claims 51-53, wherein m2 and m3 are each 1.

55. The compound of any one of Claims 51-54, wherein RZ1is H.

56. The compound of any one of Claims 51-54, wherein RZ1is –C1-4alkyl.

57. The compound of Claim 56, wherein RZ1is –CH3.

58. The compound of any one of Claims 51-54, wherein RZ1is –C1-4haloalkyl.

59. The compound of Claim 26, wherein –Ry1is selected from the group consisting o.

60. The compound of Claim 59, wherein n1 is 0.

61. The compound of Claim 59, wherein n1 is 1.

62. The compound of Claim 59, wherein n1is 2.

63. The compound of any one of Claims 59-62, wherein m1and m2are each 1.

64. The compound of any one of Claims 59-62, wherein m1is 1 and m2is 2.

65. The compound of any one of Claims 59-62, wherein m1and m2are each 2.

66. The compound of any one of Claims 59-65, wherein Rx2is hydrogen.

67. The compound of any one of Claims 59-65, wherein Rx2is –C1-4 alkyl.

68. The compound of Claim 67, wherein Rx2is –CH3.

69. The compound of any one of Claims 59-65, wherein Rx2is –C(=O)RW3.

70. The compound of any one of Claims 59-65, wherein Rx2is –C(=O)ORW3.

71. The compound of Claim 69 or Claim 70, wherein RW3is hydrogen.

72. The compound of Claim 69 or Claim 70, wherein RW3is –C1-4alkyl.

73. The compound of Claim 72, wherein RW3is –CH3.

74. The compound of Claim 69 or 70, wherein RW3is –C1-4 haloalkyl.

75. The compound of any one of Claims 59-65, wherein Rx2is –C(=O)N(RW1)RW2.

76. The compound of Claim 75, wherein RW1is H and RW2is –C1-4 alkyl.

77. The compound of Claim 76, wherein RW2is –CH3.

78. The compound of any one of Claims 1-77, wherein R1band R1care each hydrogen.

79. The compound of any one of Claims 1-12, wherein Rx1can be selected from , , ,,,80. The compound of any one of Claims 1-79, wherein R1dand R1eare each hydrogen.

81. The compound of any one of Claims 1-80, wherein R1fand R1gare each hydrogen.

82. The compound of any one of Claims 1-81, wherein.

83. The compound of Claim 82, wherein Y1is nitrogen.

84. The compound of Claim 82, wherein Y1is CH.

85. The compound of any one of Claims 82-84, wherein R3ais hydrogen.

86. The compound of any one of Claims 82-84, wherein R3ais –C1-4alkyl.

87. The compound of Claim 86, wherein R3ais –CH3.

88. The compound of any one of Claims 82-84, wherein R3ais –C2-4 haloalkyl.

89. The compound of any one of Claims 82-88, wherein R3bis hydrogen. 9 The compound of any one of Claims 82-88, wherein R3bis –C1-4 alkyl. 9 . The compound of Claim 90, wherein R3bis –CH3. 9 The compound of any one of Claims 82-88, wherein R3bis –C2-4haloalkyl.

93. The compound of any one of Claims 1-81, wherein.

94. The compound of Claim 93, wherein Y2is nitrogen.

95. The compound of Claim 93, wherein Y2is CH.

96. The compound of any one of Claims 93-95, wherein R4ais hydrogen.

97. The compound of any one of Claims 93-95, wherein R4ais –C1-4 alkyl.

98. The compound of Claim 97 wherein R4ais –CH3.

99. The compound of any one of Claims 93-95, wherein R4ais –C2-4 haloalkyl.

100. The compound of any one of Claims 93-99, wherein R4bis hydrogen.

101. The compound of any one of Claims 93-99, wherein R4bis halogen.

102. The compound of any one of Claims 93-99, wherein R4bis –OH.

103. The compound of any one of Claims 93-99, wherein R4bis –CN.

104. The compound of any one of Claims 93-99, wherein R4bis –C1-4alkyl.

105. The compound of Claim 104, wherein R4bis –CH3.

106. The compound of any one of Claims 93-99, wherein R4bis –C2-4 haloalkyl.

107. The compound of any one of Claims 1-106, wherein R2a, R2b, R2c, R2e, R2gand R2hare each hydrogen.

108. The compound of any one of Claims 1-106, wherein R2a, R2c, R2e, R2gand R2hare each hydrogen; and R2bis halogen.

109. The compound of any one of Claims 1-106, wherein R2b, R2c, R2e, R2gand R2hare each hydrogen; and R2ais halogen.

110. The compound of any one of Claims 1-106, wherein R2a, R2b, R2e, R2gand R2hare each hydrogen; and R2cis halogen.

111. The compound of any one of Claims 1-106, wherein R2a, R2b, R2c, R2gand R2hare each hydrogen; and R2eis halogen.

112. The compound of any one of Claims 1-111, wherein R2dis halogen.

113. The compound of any one of Claims 1-111, wherein R2dis cyano.

114. The compound of any one of Claims 1-111, wherein R2dis –CH3.

115. The compound of any one of Claims 1-111, wherein R2dis –CH2CH3.

116. The compound of any one of Claims 1-111, wherein R2dis –OCH3.

117. The compound of any one of Claims 1-111, wherein R2dis –SCH3.

118. The compound of any one of Claims 1-117, wherein R2fis halogen.

119. The compound of any one of Claims 1-117, wherein R2fis cyano.

120. The compound of any one of Claims 1-117, wherein R2fis –CH3.

121. The compound of any one of Claims 1-117, wherein R2fis –CH2CH3.

122. The compound of any one of Claims 1-117, wherein R2fis –OCH3.

123. The compound of any one of Claims 1-117, wherein R2fis –SCH3.

124. The compound of any one of Claims 108-112 or 118, wherein the halogen is chloro or fluoro.

125. The compound of Claim 1, wherein a compound of Formula (I) is selected from the group consisting of: , ,,,,,,acceptable salt of any of the foregoing.

126. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof, and excipient.

127. A method for treating hepatitis B in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof.

128. A method for treating hepatocellular carcinoma (HCC) in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof.

129. The method of any one of Claims 127-128, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

130. A compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis B.

131. A compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC).

132. The compound of any one of Claims 130-131, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

133. Use of a compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatitis B.

134. Use of a compound of any one of Claims 1-125, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC).

135. The use of any one of Claims 133-134, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

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