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 as described herein, or a pharmaceutically acceptable salt thereof, and uses of or methods of using a compound as described herein, 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-L1INCORPORATION 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 under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 553,844, filed February 15, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] The present application relates to the fields of chemistry, biochemistry, molecular biology and medicine. The present disclosure relates to compounds that can be useful as inhibitors of PD-1, PD-L1 and / or the PD-1 / PD-L1 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-a, IFN-y) 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 as described herein, 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 disclosed herein, 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figures 1A and IB show the absolute configuration structure and ORTEP crystal structure of the chloride salt of Intermediate 2B-1.DETAILED DESCRIPTION

[0010] Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC can be caused by a variety of conditions, such as alcohol consumption, cirrhosis, and viral infections that cause hepatitis, such as hepatitis B virus, hepatitis C virus, and hepatitis D virus. The inflammation, fibrosis, and cirrhosis linked with these conditions can induce malignancies 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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 transmission of 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 (superinf ection). 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.

[0015] Programmed cell death 1, or programmed death 1 (PD-1) is a 268 amino acid long type I transmembrane protein found as a surface marker on T cells and other immune cells. As an immune checkpoint, PD-1 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.

[0016] 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 hasbeen 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 skill in 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

[0017] 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.

[0018] 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)).

[0019] 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 ornaphthalenesulfonic 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.

[0020] 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 or composition, the term "comprising" means that the compound or composition includes at least the recited features or components but may also include additional features or components.

[0021] 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.

[0022] 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 (Reconfiguration 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 doublebond(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.

[0023] 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).

[0024] 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.

[0025] 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

[0026] Examples of embodiments of the present application include the following:Embodiment 1

[0027] A compound selected from:pharmaceutically acceptable salt of any of the foregoing.Embodiment 2 the compound can be, a pharmaceutically acceptable salt thereof.Embodiment 3

[0029] In some embodiments, the compound can bepharmaceutically acceptable salt thereof.Embodiment 4

[0030] In some embodiments, the compound can be, or a pharmaceutically acceptable salt thereof.Embodiment 5 the compound can be, a pharmaceutically acceptable salt thereof.Embodiment 6

[0032] A pharmaceutical composition that can include an effective amount of a compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, and an excipient.Embodiment 7

[0033] 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 1-5, or a pharmaceutically acceptable salt thereof.Embodiment 8

[0034] 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 1-5, or a pharmaceutically acceptable salt thereof.Embodiment 9

[0035] The method of any one of Embodiments 7-8, that can further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.Embodiment 10

[0036] A compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis B.Embodiment 11

[0037] A compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC).Embodiment 12

[0038] The compound of any one of Embodiments 10-11, or a pharmaceutically acceptable salt thereof, wherein the use can further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.Embodiment 13

[0039] Use of a compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatitis B. Embodiment 14

[0040] Use of a compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC).Embodiment 15

[0041] The use of any one of Embodiments 13-14, wherein the medicament can be for use in combination with surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.Methods of Preparation

[0042] The compounds described herein, along with pharmaceutically acceptable salts thereof, can be prepared according to the Examples 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.Pharmaceutical Compositions

[0043] Some embodiments described herein relate to pharmaceutical compositions that comprise, consist essentially of, or consist of an effective amount of a compound described herein, 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.

[0044] The terms “function” and “functional” as used herein refer to a biological, enzymatic, or therapeutic function.

[0045] 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.

[0046] ‘Formulation”, “pharmaceutical composition”, and “composition” as used interchangeably herein are equivalent terms referring to a composition of matter for administration to a subject.

[0047] The term “pharmaceutically acceptable” means compatible with the treatment of a subject, and in particular, a human.

[0048] 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.

[0049] 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 invertebratessuch 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.

[0050] 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 art including, 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.

[0051] 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.

[0052] 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.

[0053] 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 acceptablesalt 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.

[0054] 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 form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0055] 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.

[0056] 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, upregulation 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, a-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.

[0057] 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

[0058] Some embodiments disclosed herein relate 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 ordisorder 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.

[0059] 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, described herein 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).

[0060] 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. Changesin dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.

[0061] 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.

[0062] 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.

[0063] 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 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 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.

[0064] 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 described herein, or a pharmaceutically acceptable salt thereof. 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 inducingapoptosis 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.

[0065] 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.

[0066] 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.

[0067] 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 oneloading dose is a higher dose of a compound, or a pharmaceutically acceptable salt thereof, described herein than the at least one maintenance dose.

[0068] A potential advantage of utilizing a compound as described herein, or a pharmaceutically acceptable salt thereof, may include effective inhibition of PD-1 / PD-L1 interactions and / or inhibition of the PD-1 / PD-L1 pathway.

[0069] Additional advantages of utilizing a compound as described herein, or a pharmaceutically acceptable salt thereof, may include low toxicity and reduced drug-drug interactions. Further advantages of utilizing a compound as described herein, or a pharmaceutically acceptable salt thereof, may include increased levels of plasma exposure at lower dosages compared to INCB086550 and higher oral bioavailability in comparison to INCB086550. Even further advantages of utilizing a compound as described herein, or a pharmaceutically acceptable salt thereof, may include prolonged half-lives and / or liver-tropic tissue distributions.

[0070] 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 may be 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.

[0071] 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.

[0072] 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 and vinorelbine, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0073] 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 can be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid or oligonucleotide (along with pharmaceutically acceptable salts of any of the foregoing). A non-limiting list of 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 and vemurafenib, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0074] 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 can be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog,nucleic acid or oligonucleotide (along with pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the immune checkpoint can be the PD-1 / PD-L1 checkpoint. Examples of PD-1 checkpoint inhibitors includes, but is not limited to, nivolumab, pembrolizumab, spartalizumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224 and AMP-514, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing). Additional examples of PD-L1 checkpoint inhibitor includes, but is not limited to, atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA- 170 and BMS-986189, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the immune checkpoint can be the CTLA-4 checkpoint. A non-limiting list of CTLA-4 checkpoint inhibitors includes, but is not limited to, ipilimumab and tremilimumab, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0075] 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 can be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid or oligonucleotide (along with pharmaceutically acceptable salts of any of the foregoing). Examples ofVEGF 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 and vandetanib, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0076] As used herein, the term “antiviral medication” refers to a pharmaceutical composition administered to treat a viral infection. In some embodiments, the viral infection can be caused by adenovirus, Ebola virus, coronavirus, Epstein-Barr virus (EBV), Friend virus, hantavirus, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), human metapneumovirus, human papillomavirus (HPV), influenza virus, Japanese encephalitis virus, Kaposi’s sarcoma-associated herpesvirus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus and / or varicella zoster virus.

[0077] In some embodiments, the antiviral medication can be a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid or oligonucleotide (along with pharmaceutically acceptable salts of any of the foregoing). In some embodiments, the antiviral medication can be an interferon, a capsid assembly modulator, a sequence specific oligonucleotide, an entry inhibitor or a small molecule immunomodulatory. A non-limiting list of antiviral medications include, 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-a, 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), WX001, VTP-300, CVI-HBV-002, AIC-649, HB- 110, JNJ-64300535, CARG-201, PRGN-2013, SA104, VRGN-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, and ALG-125755, or any combination thereof (including pharmaceutically acceptable salts of any of the foregoing).

[0078] 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

[0079] 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.

[0080] Hereinafter, the term “rt”, “r.t.” or “RT” means room temperature; “EtOAc” or “EA” means ethyl acetate; “MeCN” or “ACN” means acetonitrile; “Pd(dppf)C12.” means [l.l'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II); “TCFH” means N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate; “NMI” means N-methylimidazole; “PE” means petroleum ether; “AcOK” means potassium acetate; “LC” means liquid chromatography; “LCMS” means Liquid Chromatography / Mass spectrometry; “HPLC” means high-performance liquid chromatography; “TFA” means trifluoroacetic acid; "min" means minute(s); "h” and “hr” mean hour(s); “v / v” means volume per volume.

[0081] 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.

[0082] 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 IntermediatesExample Al Preparation Intermediate 1, ,Intermediate 1-1 Intermediate 1

[0083] A mixture of 3-chloro-l-methoxy-5,6-dihydrocyclopenta[c]pyridin-7-one (7.0 g, 35 mmol), PinzB2 (18 g, 71 mmol), AcOK (10.4 g, 106 mmol) and PdCi2(dtbpf) (1.15 g, 1.77 mmol) in dioxane (70 mL) was degassed and purged with N2 (3 times), and the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was triturated with the mixture of methyl- tertiary-butyl ether and ethyl acetate (MTBE:EA = 3: 1) at 15 °C for 16 h to give Intermediate 1-1 (15 g, crude) as a black oil, which was used for next step reaction without further purification.

[0084] A mixture of Intermediate 1-1 (15.00 g), l,3-dibromo-2-chloro-benzene (23.5 g, 87.0 mmol), K2CO3 (18.0 g, 130 mmol), Pd(dppf)Ch (3.18 g, 4.35 mmol) in dioxane (150 mL) was degassed and purged with N2 (3 times), and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give Intermediate 1 (5 g) as a brown solid. MS: ES m / z calculated for CisH BrCINCh [M+H]+352.0, found 352.0.Example A2Preparation Intermediate 2A, 2B and 2B-1Intermediate 2A Intermediate 2BIntermediate 2B Intermediate 2B-1

[0085] A mixture of Intermediate 1 (3 g, 8.52 mmol), Ethyl piperidine-4- carboxylate (6.54 mL, 42.54 mmol) and 4A Molecular Sieve (3 g) in EtOH (60 mL) was adjusted to pH 5~6 and stirred at 80 °C for 16 h. NaBHsCN (1.60 g, 25.50 mmol, 3 eq) was added, and the mixture stirred at 80 °C for 24 h. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give Intermediate 2 (1.7 g, 96% purity) as a yellow oil. MS: ES m / z calculated for C23H27BrClN2O3 [M+H]+493.1, found 493.1.

[0086] A mixture of Intermediate 2 (1.7 g, 3.44 mmol) was separated by SFC to give Intermediate 2A (790 mg, 99% purity) as a yellow oil and Intermediate 2B (750 mg, yield, 99% purity) as a yellow oil. With analytic SFC condition (Column: Chiral NS-3 100 x 4.6mm I.D., 3um; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1 min, then 5% of B for 1 min Flow rate: 2.8mL / min; Column temp.: 35 °C; ABPR: 1500 psi), Intermediate 2A’s retention time is 2.33 minutes, and Intermediate 2B’s retention time 2.57 minutes.

[0087] Intermediate 2B (6 mg) and HC1 (1 mol / L in water, 15 pL) were dissolved in methanol (400 pL)and kept in a 4 mL vial. The solution evaporates slowly at rt. Crystals of Intermediate 2B-1 were observed on the second day. The crystal of Intermediate 2B-l’s HC1 salt was a colorless plate with the following dimensions: 0.20 x 0.15 x 0.02 mm3. The symmetry of the crystal structure was assigned the orthorhombic space group P212121 with the following parameters: a = 7.5631(2) A, b = 7.7926(2) A, c = 35.4625(8) A, a = 90°, P = 90°, y = 90°, V = 2090.03(9) A3, Z = 4, De = 1.596 g / cm3, F(000) = 1024.0, p(CuKa) = 5.252 mm-1, and T = 149.99(10) K.

[0088] The absolute configuration structure and ORTEP structure is provided in Figures 1 A and IB, respectively.Example A3 Preparation Intermediate 3-1Intermediate 3-1

[0089] A mixture of 2-Methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (26.6 g, 173 mmol), 3-bromo-2-methylaniline (32.8 g, 176 mmol), N-methylimidazole (NMI, 28.3 g, 345 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 121 g, 431 mmol) in MeCN (500 mL) was stirred at 65 °C for 12 h. The mixture wasfiltered and concentrated under reduced pressure to give a crude residue. The crude product was triturated with EtOAc (2 x 50 mL) to get Intermediate 3-1 (52.2 g) as a yellow solid.1H NMR (400 MHz, DMSO-rfc) 8 = 11.82 (s, 1H), 8.25 (d, J =4.4 Hz, 1H), 8.23 (d, J =4.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.30 (s, 3H).

[0090] The intermediate shown in Table 1 was prepared by an analogous reaction protocol as was used for the preparation of Intermediate 3-1 using the appropriate starting materials.Table 1Example A4Preparation Intermediate 4-1Intermediate 3-1 Intermediate 4-1

[0091] A mixture of Intermediate 3-1 (49.09 g, 153 mmol), Pimfh (77.39 g, 304.75 mmol, 2 eq), Pd(dppf)Ch (5.57 g, 7.62 mmol, 0.05 eq) and AcOK (44.86 g, 457.13 mmol, 3 eq) in dioxane (500 mL) was degassed and purged with N2 (3 times), and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE: hexane=l : 1 (160 mL). The crude product was triturated with hexane (70 mL) to give Intermediated 4-1 (60.79 g, 97.25% yield, 90% purity) as a black brown solid.JH NMR (400 MHz, Chloroform-^) 8 = 11.62 (br s,lH), 8.40 - 8.24 (m, 2H), 8.04 (d, J= 4.1 Hz, 1H), 7.61 (d, J = 7.4 Hz,lH), 7.26 - 7.22 (m, 1H), 3.97 (s, 3H), 2.64 (s, 3H), 1.37 (s, 12H).

[0092] The intermediate shown in Table 2 was prepared by an analogous reaction protocol as was used for the preparation of Intermediate 4-1 using the appropriate starting materials.Table 2Example A5Preparation Intermediate 5-1Intermediate 4-1 Intermediate 5-1

[0093] A mixture of Intermediate 2B (330 mg, 668 pmol), Intermediate 4-1 (271 mg, 735 pmol), K2CO3 (277 mg, 2.00 mmol), Pd-118 (44 mg, 67 pmol) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 (3 times). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography and repurified with prep-HPLC to give Intermediate 5-1 (150 mg) as a light brown solid. MS: ES m / z calculated for C36H39QN5O5 [M+H]+656.3, found 65

[0094] The intermediate shown in Table 3 was prepared by an analogous reaction protocol as was used for the preparation of Intermediate 5-2 using the appropriate starting materials.Table 3Preparation of CompoundsExample 1 Compound A

[0095] A mixture of Intermediate 5-1 (150 mg, 228 pmol) and LiOH’I O (28.8 mg, 686 pmol) in THF (8 mL) and H2O (4 mL) was stirred at 45 °C for 3 h to give a yellow mixture. The mixture was adjusted to pH~5 by addition 1 M HC1, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC and repurified by flash silica gel chromatography to give Compound A (91 mg) as a light yellow solid.JH NMR (400 MHz, chloroform-^) 8 = 11.71 (d, J = 1.8 Hz, 1H), 8.36 - 8.31 (m, 2H), 8.06 (dd, J = 1.1, 4.2 Hz, 1H), 7.62 (ddd, J = 1.6, 3.6, 7.7 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.24 (d, J = 5.1 Hz, 1H), 7.05(t, J = 8.3 Hz, 1H), 4.76 (br d, J = 8.1 Hz, 1H), 4.03 (s, 3H), 3.95 (d, J = 2.5 Hz, 3H), 3.52 - 3.45 (m, 1H), 3.33 - 3.15 (m, 4H), 3.08 - 2.98 (m, 3H), 2.88 (br dd, J = 9.4, 17.1 Hz, 2H), 2.79 - 2.74 (m, 1H), 2.49 - 2.43 (m, 1H), 2.23 (d, J = 9.9 Hz, 4H), 1.26 (br s, 1H).

[0096] The compound shown in Table 4 was prepared by an analogous reaction protocol as was used for the preparation of Compound A using the appropriate starting materials.Table 4Example ALCMS (Liquid chromatography / Mass spectrometry)

[0097] 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). Plow 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 lightmass spectrometers, "CLND", ChemiLuminescent Nitrogen Detector, "ELSD" Evaporative Light Scanning Detector.Table 5: LCMS Method CodesFlow expressed in mL / min; column temperature (T) in °C; Run time in minutes.Table 6: LCMS ResultsRetention time (Rt,) in min; LC / MS: without indication the mass is corresponding to [M+H]+.Example B PDL1 / PD1 Binding Assay

[0098] Compounds to be tested were serially diluted in DMSO, and further diluted in assay buffer (25 mMHepes pH 7.4, 150 mMNaCl, 0.005% Tween 20, BSA 0.01%). Diluted compounds were added to the wells with final concentration of DMSO at 1%. PDLl-6xHis protein was added to the wells, mixed well with compound. The plates were incubated for 30 min at room temperature. PDl-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. TheIC50 values were determined by fitting the curves using a four-parameter equation in Graphpad Prism 8.Example C PD-1 / PD-L1 NF AT Reporter Assay

[0099] Cellular activity of the compounds was assessed using a co-culture reporter assay in which TCR-mediated NF AT 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.

[0100] 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 NF AT promoter were then immediately seeded on the monolayer of CHO cells. The co-culture was then incubated for 6 h 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.

[0101] Compounds described herein, as exemplified in the Examples, showed ECso or ICso 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 7, the compounds described herein are active for controlling expression of PD-L1.Table 7Example D In vitro ADME ProfileTable 8* m / r / d / c / h: mouse / rat / dog / cynomolgus monkey / humanaCYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4-M / T (M = midazolam and T = testosterone as a substrate)Table 9

[0102] Compound A demonstrated did not demonstrate any of the following: in vitro drug-drug interaction, cytochrome P450 time-dependent inhibition and reactive metabolites.Example E Toxicology AssaysTable 10*Significant response designated as greater than 50% max response up to 10 pM.Example FMouse PO PharmacokineticsTable 11

[0103] The pharmacokinetic properties of Compound A were compared to knownPD-1 / PD-L1 inhibitor, INCB086550, along with Compound 1, having the structure:compared to Compounds 1 and 2. Oral dosages of 50 mg / kg for Compound A had higher plasma exposure than 100 mg / kg of INCB086550.Example GTissue Distribution in MiceTable 12*Mean of ratios from 3 individual valuesTable 13*Mean of ratios from 3 individual values

[0104] Compound A exhibited a liver-tropic tissue distribution as seen in Tables 12 and 13.Example H Rat PharmacokineticsTable 14Table 15

[0105] Compound A had a faster clearance and a shorter half-life in rats compared to INCB086550. Compound A demonstrated higher oral bioavailability compared toINCB086550 in rat.Example I Monkey PharmacokineticsTable 16

[0106] Compound A demonstrated low clearance and low- volume of distribution in monkey.

[0107] 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 selected from the group consisting of:a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of Claim 1, wherein the compound is, p y p .Claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

5. The compound of Claim 1 or 4, wherein the compound isor a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, and an excipient.

7. 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 1-5, or a pharmaceutically acceptable salt thereof.

8. 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 1-5, or a pharmaceutically acceptable salt thereof.

9. The method of any one of Claims 7-8, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

10. A compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis B.

11. A compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (HCC).

12. The compound of any one of Claims 10-11, or a pharmaceutically acceptable salt thereof, wherein the use further comprises administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

13. Use of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatitis B.

14. Use of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating hepatocellular carcinoma (HCC).

15. The use of any one of Claims 13-14, wherein the medicament is for use in combination with surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

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