HETEROARYL-BIPHENYL-AMIDE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER

Abstract

Methods for treating certain cancers are provided herein comprising administering to the subject in need an effective amount of a compound of Formula (I) (SEE FORMULA) (I) including the stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, Ra and Rb are as defined herein.

Description

CANCER TREATMENT METHODS USING HETEROARYLBIPHENYLAMIDE DERIVATIVES CROSS REFERENCES TO RELATED APPLICATIONS This application claims the benefit of priority pursuant to 35 USC § 119(e) of U.S. Provisional Patent Application No. 263 / 042,807, filed on December 23, 2020, the disclosure of which is incorporated herein by reference in its entirety. DECLARATION ON THE RIGHTS OF INVENTIONS MADE WITHIN THE FRAMEWORK OF RESEARCH AND DEVELOPMENT SPONSORED BY THE FEDERAL GOVERNMENT NOT APPLICABLE REFERENCE TO A LISTING OF SEQUENCES, A TABLE, OR AN APPENDIX OF A COMPUTER PROGRAM PRESENTED ON A COMPACT DISC NOT APPLICABLE BACKGROUND TO THE DISCLOSURE Programmed cell death protein-1 (PD-1) is a member of the CD28 superfamily that emits negative signals when interacting with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and exert a broad range of immunoregulatory functions in T cell activation and tolerance. PD-1 and its ligands are involved in the attenuation of infectious and tumor immunity, and facilitate chronic infection and tumor progression. Modulation of the PD-1 pathway has therapeutic potential in various human diseases (Hyun-TakJin et al., Curr Top Microbio! Immunol. (2011)350:17-37). Blocking the PD-1 pathway has become an attractive target in cancer therapy. Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent the downregulation of T cells and promote immune responses against cancer. Several PD-1 pathway inhibitors have shown robust activity in various phases of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214-223). Agents that block the interaction of PD-L1 with PD-1 or CD80 are desired. Some antibodies have been developed and marketed. Several patent applications have been published disclosing small non-peptide molecules (WO 2015 / 160641, WO 2015 / 034820 and WO 2017 / 066227 and W02018 / 009505 from BMS; WO 2015 / 033299 and WO 2015 / 033301 from Aurigene; WO 2017 / 070089, US 2017 / 0145025, WO 2017 / 106634, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899 and ML / WO2018 / 013789 from Incyte, WO2018 / 006795 from Maxinovel, and WO2018 / 005374 requested by us, ChemoCentryx). However, there remains a need for alternative compounds such as small molecules like PD-L1 inhibitors, which may have advantageous characteristics in terms of oral administration, greater tumor penetration, stability, bioavailability, therapeutic index, and toxicity. BRIEF SUMMARY OF THE DISCLOSURE In some respects, this document provides methods for treating cancer that involve administering to a subject in need an effective amount of a compound of Formula (I): Ra(|) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and Rbson are as described herein. In some embodiments, the cancer is selected from the group consisting of colon cancer, kidney cancer, colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, Merkel cell carcinoma, liver cancer, breast cancer, and head or neck cancer. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A-1B plots the PD1 / PD-L1 binding ELISA data (top panel) and the PD-1 / PD-L1 blocking cell-based assay data (bottom panel) for compounds 2.001 (FIG. 1A) and 2.002 (FIG. 1B). FIG. 2A-2C shows how compound 2.001 promotes an allogeneic human T cell immune response in an ex vivo mixed lymphocyte reaction (MLR) assay; T cell responses from three different donors are shown: Donor n.21 (A), Donor n.s2 (FIG. 2B), and Donor n.23 (FIG. 2C). FIG. 3A-3C shows how compound 2.002 promotes an allogeneic human T cell immune response in an ex vivo mixed lymphocyte reaction (MLR) assay; T cell responses from three different donors are shown: Donor n.s1 (A), Donor n.s2 (FIG. 3B), and Donor n.23 (FIG. 3C). Figures 4A–4B illustrate PBMC-mediated tumor cell elimination from compound 2002 (Figure 4A, leftmost columns), compound 2001 (Figure 4A, middle columns), and a control compound (Figure 4A, rightmost columns). MA / Additional control experiments used an anti-PD-L1 antibody (Durvalumab) (FIG. 4B, leftmost columns), and antibody isotype (FIG. 4B, rightmost columns). FIG. 5 shows that compounds 2.001 and 2.002 induce PD-L1 dimerization, whereas the anti-PD-L1 antibody and the tested controls do not. Figure 6 shows the surface levels of PD-L1 at 4 °C (lower panel) and 37 °C (upper panel) under various test conditions. This figure demonstrates that compounds 2.001 and 2.002 reduce the surface levels of PD-L1 specifically at 37 °C, suggesting internalization of PD-L1. Figure 7. MC38-hPD-L1 tumor model for evaluating human PD-L1 inhibitors in vivo. The manipulated MC38-hPD-L1 cells are suitable for evaluating the effects of specific human PD-L1 inhibitors in vivo. hPD-L1 and mPD-L1 bind to mPD-1 with similar affinity; current hPD-L1 inhibitors block the interaction of hPD-L1 with either hPD-1 or mPD-1 with similar potency (data not shown). MC38-hPD-L1 cells induce tumor growth in mice. Figures 8A–8C illustrate the dose-dependent suppression of tumor growth mediated by compound 2002 in an MC38-hPD-L1 tumor model. (Figure 8A) Plots of tumor volume versus days after tumor implantation; (Figure 8B) Plots of mean tumor weight after 35 days; (Figure 8C) Plots of peak plasma concentrations of the compound after 3 days of dosing. Figures 9A–9C represent tumor size at the indicated number of days for treatment with vehicle (filled circles) and API (anti-PD-L1 antibody or the indicated compound, filled squares). The APIs tested were compound 2001 (Figure 9A), compound 2003 (Figure 9B), and anti-PD-L1 antibody (Figure 9C). The upper panel plots the mean tumor size for each treatment group, while the lower panel plots the tumor size of each mouse in the treatment group. FIG. 10A-10B represents the minimum plasma concentration of compound 2001 (FIG. 10A) and compound 2003 (FIG. 10B) 12 hours post-dose, after 6 days of dosing, in the mouse model described in Biological Example 2. Figure 11 shows the human PD-L1 staining of cells when treated with the anti-PD-L1 antibody (Durvalumab), the isotype antibody, Compound 2001, and the vehicle. The PD-L1 detection antibody used in this assay is blocked by the binding of Compound 2001 to PD-L1. This figure demonstrates that MC38-hPD-L1 tumors treated with Compound 2001 have almost complete occupancy of Compound 2001. Figure 12 shows how different treatment conditions alter the number of immune cells infiltrating the tumor in the MC38-HPD-L1 tumor model. The bottom panel shows the number of CD8+ T cells measured; the middle panel shows the number of CD4+ T cells measured; and the top panel shows the number of CD8+ and CD4+ T cells measured. DETAILED DESCRIPTION OF THE DISCLOSURE I. General This disclosure provides methods for treating specific cancers using compounds of Formula (I). The claimed compounds possess robust antitumor properties, with a high affinity for PD-L1. When administered, these compounds effectively disrupt PD-1 / PD-L1 signaling and, in some embodiments, induce PD-L1 dimerization and internalization into cancer cells. The development of small-molecule PD-1 / PD-L1 modulators has been hampered by the need to balance several factors, including PD-1 / PD-L1 affinity, hydrophobicity / hydrophilicity of the compounds, biological clearance rate, and antitarget activity (e.g., CYP and hERG inhibition). In fact, to date, no PD-1 / PD-L1 inhibitors are approved for oral administration. Unlike intravenous drug formulations, the bioavailability of an orally administered compound requires, among other things, gastric absorption and resistance to significant degradation via the portal circulation to the liver (so-called first-pass metabolism). In some embodiments, the methods described herein provide PD-1 / PD-L1 modulators that are unexpectedly suitable for oral administration in the treatment of certain cancers. The compounds in the described methods do not require extremely high concentrations in the blood; instead, these compounds can exert their antitumor effects at levels in the ng / mL range. II. Abbreviations and definitions The terms a, an, the, and the used herein include not only one-membered aspects but also more-membered aspects. For example, the singular forms a, an, the, and the include plural referents unless the context clearly indicates otherwise. Thus, for instance, a reference to a cell includes a plurality of such cells, and a reference to the agent includes a reference to one or more agents known to those skilled in the art, and so on. The terms "around" and "approximately" will generally mean an acceptable degree of error for the measured quantity, given the nature or precision of the measurements. Typical and exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "around" and "approximately" may mean values ​​that are within an order of magnitude, preferably within 5 times, and more preferably within 2 times, of a given value. Numerical quantities stated herein are approximate unless otherwise indicated, meaning that the term "around" or "approximately" may be inferred when not explicitly stated. The term alkyl, by itself or as part of another substituent, means, unless otherwise specified, a straight-chain or branched hydrocarbon group with the designated number of carbon atoms (i.e., C1-e means from one to eight carbons). Some examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term alkenyl refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term alkynyl refers to an unsaturated alkyl group having one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.The term cycloalkyl refers to hydrocarbon rings that have the specified number of ring atoms (e.g., C3-6 cycloalkyl) and are fully saturated or have no more than one double bond between ring vertices. Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. Bicyclic or polycyclic rings may be fused, bridged, spiro, or a combination thereof. The term heterocycloalkyl or heterocyclyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system.Bicyclic or polycyclic rings may be fused, bridged, spiro, or a combination thereof. The designation C4-12 heterocycle is understood to refer to a group having 4 to 12 ring members, where at least one of the ring members is a heteroatom. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrana, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. A heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon or a heteroatom. The term alkylene, either by itself or as part of another substituent, means a divalent group derived from an alkane, exemplified by -CH₂CH₂CH₂CH₂-. An alkylene group can be linear or branched. Examples of branched groups are -CH₂C(CH₃)₂CH₂-, -CH₂C(CH₃)₂-, or -CH(CH₃)CH₂CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, with groups having 8 or fewer carbon atoms being preferred in this disclosure. Similarly, alkenylene and alkynylene refer to the unsaturated forms of alkylene that have double or triple bonds, respectively. The terms alkoxy, alkylamino, and alkylthio (or thioalkoxy) are used in their conventional sense and refer to alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, in the case of dialkylamino groups, the alkyl portions may be the same or different and may also combine to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Consequently, a group represented as -NRaRb is intended to include piperidinyl, pyrrolidine, morpholinyl, azetidine, and the like. The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise specified, an atom of fluorine, chlorine, bromine, or iodine. Furthermore, terms such as haloalkyl include monohaloalkyl and polyhaloalkyl. For example, the term C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term hydroxyalkyl or alkyl-OH refers to an alkyl group, as defined above, in which at least one (and up to three) of the hydrogen atoms is replaced by a hydroxyl group. As for the alkyl group, hydroxyalkyl groups can have any suitable number of carbon atoms, such as C1-6. Exemplary hydroxyalkyl groups include, but are not limited to, methyl hydroxyl, hydroxyethyl (where the hydroxyl is in the 1- or 2- position), hydroxypropyl (where the hydroxyl is in the 1-, 2-, or 3- position), and 2,3-dihydroxypropyl. The term aryl means, unless otherwise stated, a polyunsaturated hydrocarbon group, typically aromatic, which may be a single ring or multiple rings (up to three rings) fused together or covalently bonded. The term heteroaryl refers to aryl groups (or rings) containing from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom or atoms are optionally quaternized. A heteroaryl group may be attached to the rest of the molecule through a heteroatom. The recitation for C5-10 heteroaryl is understood to refer to a heteroaryl moiety having 5 to 10 ring members, where at least one of the ring members is a heteroatom.Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, and triazolyl. tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. The substituents for each of the aryl and heteroaryl ring systems mentioned above are selected from the group of acceptable substituents described below. The term carbocyclic ring refers to cyclic structures with only carbon atoms as ring vertices. Carbocyclic rings can be saturated or unsaturated and may be aromatic. Generally, carbocyclic rings have 3 to 10 ring members. Carbocyclic rings with multiple ring structures (e.g., bicyclic) can include a cycloalkyl ring fused to an aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings include cyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. The term heterocyclic ring refers to both heterocycloalkyl and heteroaryl rings. Thus, heterocyclic rings can be saturated or unsaturated and may be aromatic. Heterocyclic rings generally have 4 to 10 ring members and include piperidinyl, tetrazinyl, pyrazolyl, and indolyl. When any of the above terms (e.g., alkyl, aryl, and heteroaryl) are referred to as substituted without further notation on the substituents, the substituted forms of the indicated group shall be those indicated below. The substituents of alkyl groups (including the groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) can be a variety of groups selected from: -halogen, -OR', -NR'R, -SR', -SIR'RR', -OC(O)R', -C(O)R', -CO2R', -CONR'R, OC(O)NR'R, -NRC(O)R', -NR'-C(O)NRR', -NRC(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R, -NR'S(O)2R, -CN, and -NO2 in a number between zero and (2 m'+1), where m' is the total number of carbon atoms in such a group. R', R and R' each independently refer to hydrogen, unsubstituted C1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted Ci-8 alkyl, C1-8 alkoxy or Ci-s thioalkoxy groups, or unsubstituted Ci-4 aryl alkyl groups. When R' and R are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.For example, -NR'R is understood to include 1-pyrrolidinyl and 4-morpholinyl. The term acyl, used alone or as part of another group, refers to an alkyl group in which two substituents on the carbon nearest to the group's attachment point are replaced by the substituent =0 (e.g., C(O)CH3, -C(O)CH2CH2OR', and the like). Similarly, the substituents of the aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR', -OC(O)R', -NR'R, -SR', -R', -CN, -NO2, CO2R', -CONR'R, -C(O)R', -OC(O)NR'R, -NRC(O)R', -NRC(O)2R', -NR'-C(O)NRR', -NHC(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R, -NR'S(O)2R, -N3, perfluoro(Ci-C4)alkoxy and perfluoro(Ci-C4)alkyl, in a number between zero and the total number of open valences in the ring system aromatics; and where R', R and R' are independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl, unsubstituted C1-4 alkyl, and unsubstituted C1-4 aryloxy alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by a 1-4 carbon atom alkylene tie. Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -TC(O)-(CH2)qU-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -A-(CH2)rB-, wherein A and B are independently -CH2-, O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced by a substituent of the formula -(CH2)sX-(CH2)t-, where syt are independent integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-.The substituent R' in -NR'- and S(O)2NR'- is selected from hydrogen or unsubstituted C1-6 alkyl. As used herein, the term heteroatom includes oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). This disclosure also covers prodrugs and their bioisoters. Suitable bioisosteres, for example, will include carboxylate substitutes (phosphonic acids, phosphinic acids, sultanic acids, sulfinic acids, and acidic heterocyclic groups such as tetrazoles). Suitable prodrugs will include conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide a Formula I compound. The terms patient and subject include primates (especially humans), domesticated companion animals (such as dogs, cats, horses and the like) and livestock (such as cows, pigs, sheep and the like). As used herein, the term treat or treatment encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and / or duration of symptoms). The term pharmaceutically acceptable salts is intended to include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents present in the compounds described herein. When the compounds in this disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient quantity of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganese, potassium, sodium, zinc, and similar compounds.Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, natural amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, netylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds in this disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient quantity of the desired acid, either pure or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydridic or phosphoric acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutylic, malonic, benzoic, succinic, subehic, fumaric, mandelic, italic. ML / benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and similar compounds. Also included are amino acid salts such as arginate and similar compounds, and salts of organic acids such as glucuronic or galactunonic acids and similar compounds (see, for example, Berge, SM, et al., Pharmaceutical Salts'1, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds specific to this disclosure contain both basic and acidic functionalities that allow the compounds to be converted into basic or acidic addition salts. Neutral forms of the compounds can be regenerated by contacting the salt with a base or an acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for the purposes of this disclosure. Certain compounds in this disclosure may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of this disclosure. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within its scope. Some compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; it is intended that racemates, diastereomers, geometric isomers, regioisomers, and single isomers (e.g., separate enantiomers) be included within the scope of the present invention. When a stereochemical representation is shown, it refers to the compound in which one of the isomers is present and substantially free of the other isomer. "Substantially free of the other isomer" indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or higher. In some embodiments, one of the isomers will be present in an amount of at least 99%. The compounds in this disclosure may also contain non-natural proportions of atomic isotopes in one or more of the atoms that make up those compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). It is intended that all isotopic variations of the compounds in this disclosure, whether radioactive or not, are included within the scope of this disclosure. For example, the compounds may be prepared in which any number of hydrogen atoms are replaced by an isotope of deuterium (²H). The compounds in this disclosure may also contain non-natural proportions of atomic isotopes in one or more of the atoms that make up those compounds. Non-natural proportions of an isotope may be defined as ranging from the amount found in nature up to an amount that consists of 100% of the atom in question.For example, compounds may incorporate radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). Such isotopic variations may provide additional uses beyond those described elsewhere in this application. For example, isotopic variants of the compounds in this disclosure may find additional applications, including, but not limited to, use as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds in this disclosure may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to improved safety, tolerability, or efficacy during treatment. It is intended that all isotopic variations of the compounds in this disclosure, whether radioactive or not, are included within the scope of this disclosure. III. Achievements of Dissemination TREATMENT METHODS In some respects, this document provides methods for treating cancer that involve administering to a subject in need an effective amount of a compound of Formula (I): Ra(|) or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each selected independently from the group consisting of F, CI, CH3 and CF3; R3 is selected from the group consisting of F, CI, CH3, CF3, -O-CH3 and O-CFs; R4 is selected from the group consisting of -Y and -X1-Y wherein each X1 is a C1-4 alkylene and Y is selected from the group consisting of C3-6 cycloalkyl, C4-6 heterocycloalkyl with ring vertices of 1 to 3 heteroatoms independently selected from the group consisting of N, O and S and 5- to 6-membered heteroaryl with ring vertices of 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, each of which is unsubstituted or substituted with one or two substituents independently selected from the group consisting of oxo, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 hydroxyalkoxy; and Ray Rb is independently selected from the group consisting of H, C1-3 alkyl and haloalkyl C1-4. In some embodiments, R1 is selected from the group consisting of CI and CH3. In some embodiments, R1 is CI. In some embodiments, R1 is CH3. In some embodiments, R2 is selected from the group consisting of CI and CH3. In some embodiments, R2 is CI. In some embodiments, R2 is CH3. In some embodiments, R3 is selected from the group consisting of -O-CH3 and -OCF3. In some embodiments, R3 is -O-CH3. In some embodiments, R3 is -O-CF3. In some embodiments, Rase selects from the group consisting of H, CH3, and CF3. In some embodiments, R3 is CH3. In some embodiments, Rbse is selected from the group consisting of H, CH3 and CF3. In some embodiments, Rbes CH3. In some embodiments, the Formula I compound has the Formula (la): oz 1(la) or a pharmaceutically acceptable salt thereof. In some embodiments, -NH(R4) is selected from the group consisting of: ñ r° N' 'iN j |_l ·,H IhOHOH In some embodiments, -NH(R4) is selected from the group consisting of: In some implementations, -NHR4 is selected from the group consisting of: In some embodiments, the compound of Formula (I) is an optically pure or enriched isomer. In some embodiments, the compound of Formula (I) is selected from a compound in Table 1. As described herein, the disclosed methods for treating certain types of cancer do not require an extremely high concentration of a compound of Formula (I) in the blood. Instead, these compounds are potent enough to provide a therapeutic benefit at lower blood plasma concentrations. Accordingly, in some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 1,000 ng / mL. In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 750 ng / mL. In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 500 ng / mL.In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 400 ng / mL. In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 300 ng / mL. In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 200 ng / mL. In some embodiments, an effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of no more than 100 ng / mL. In some embodiments, the effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of approximately 2 ng / mL to 1,000 ng / mL. In some embodiments, the effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of approximately 5 ng / mL to 500 ng / mL. In some embodiments, the effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of approximately 10 ng / mL to 400 ng / mL. In some embodiments, the effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of approximately 20 ng / mL to 300 ng / mL. In some embodiments, the effective amount of a compound of Formula (I) maintains a minimum blood plasma concentration of approximately 40 ng / mL to 200 ng / mL. Several types of cancer can be treated with the methods described in this document. In some embodiments, the cancer is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymic neoplasm, thyroid gland cancer, parathyroid gland cancer, uterine cancer, adrenal gland cancer, liver infection, carcinoma Merkel cell carcinoma, nerve tumor, follicular center lymphoma,colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, liver cancer, breast cancer, non-small cell squamous lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, head or neck cancer, gastrointestinal tract cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancerFallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small bowel cancer, endocrine system cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureteral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasm, angiogenic tumor, spinal cord tumor, brainstem glioma, pituitary adenoma, squamous cell carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma osteoma, chondroma, lipoma, and fibroma. In some realizations,Each of the cancers listed are PD-L1 positive cancers. In some embodiments, the cancer is colon cancer, kidney cancer, colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, Merkel cell carcinoma, liver cancer, breast cancer, and head or neck cancer. In some embodiments, each of the listed cancers is PD-L1 positive. In some embodiments, the disease or disorder is colon cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is breast cancer. In some embodiments, each of the cancers listed is a PD-L1-positive cancer. In some embodiments, the subject is also administered an effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, radiotherapy, a radiotherapeutic agent, an antineoplastic agent, and an antiproliferative agent. In some embodiments, the one or more additional therapeutic agent is a chemokine receptor antagonist and / or chemoattractant, including but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR.Chemokine receptor antagonists and / or chemoattractants are known in the art and are described, for example, in documents W02007 / 002667, W02007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, W02007 / 115232, W02007 / 115231, WO2008 / 147815, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO 2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, W02006 / 076644, W02008 / 008431, W02009 / 038847, W02008 / 008375, W02008 / 008374, W02008 / 010934, W02009 / 009740, W02005 / 112925, W02005 / 112916, W02005 / 113513, W02004 / 085384, W02004 / 046092.Chemokine and / or chemoattractant receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX357, CCXXXX626 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 y / o CCX3843. The treatment methods provided herein generally include administering an effective amount of one or more of the compounds provided herein to a patient. Suitable patients include those who have or are susceptible to developing (i.e., prophylactic treatment) a disorder or disease identified herein. Typical patients for the treatment described herein include mammals, particularly primates, especially humans. Other suitable patients include domesticated companion animals, such as dogs, cats, horses, and the like, or livestock, such as cattle, pigs, sheep, and the like. ROUTES OF ADMINISTRATION AND DOSAGE The routes of administration contemplated in this disclosure include those known in the art for administering an active agent for the treatment of cancer. These include, but are not limited to, oral administration, intratumoral injection, intravenous administration, and subcutaneous injection. In some embodiments, the effective amount of a compound of Formula (I) is administered orally. In some embodiments, the effective amount of a compound of Formula (I) is administered by intratumoral injection. In some embodiments, the effective amount of a compound of Formula (I) is administered intravenously. In some embodiments, the effective amount of a compound of Formula (I) is administered by subcutaneous injection. In general, the treatment methods provided herein comprise the administration to a patient of an effective amount of a compound from Formula (I) or of one or more compounds provided herein. The effective amount may be sufficient to modulate the PD-1 / PD-L1 interaction, slow tumor growth, inhibit tumor growth, and / or reduce tumor size in the subject. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to adequately modulate the PD-1 / PD-L1 interaction. Treatment regimens may vary depending on the compound used and the specific condition being treated; for the treatment of most disorders, a dosing frequency of 4 times daily or less is preferred.In general, a twice-daily dosing regimen is preferred, with once-daily dosing being particularly preferred. It is understood, however, that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, timing of administration, route of administration, excretion rate, drug combination (i.e., other drugs being administered to the patient), and the severity of the particular disease being treated, as well as the prescribing physician's judgment. In general, the use of the lowest effective dose is preferred. The therapeutic efficacy of patients can usually be monitored using appropriate medical or veterinary criteria for the condition being treated or prevented. Dosage levels on the order of approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day are useful in the treatment or prevention of conditions involving PD-1 / PD-L1 interaction (approximately 0.5 mg to approximately 7 g per human patient per day). The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific route of administration. Unit dosage forms will generally contain between approximately 1 mg and approximately 500 mg of an active ingredient.For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred that a sufficient amount of the compound be administered to achieve a plasma concentration of 5 ng (nanograms) / mL-1 pg (micrograms) / mL of plasma, more preferably a sufficient amount of the compound be administered to achieve a plasma concentration of 20 ng-0.5 pg / ml of plasma, more preferably a sufficient amount of the compound be administered to achieve a plasma concentration of 30 ng / ml-200 ng / ml of plasma. The dosing frequency may also vary depending on the compound used, the route of administration, and the specific disease being treated. However, for the treatment of most disorders, a four-times-daily dosing regimen is preferred, with once-daily or twice-daily dosing being particularly preferable. It is understood, however, that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, timing of administration, route of administration and excretion rate, drug combinations (i.e., other medications being administered to the patient), the severity of the particular disease being treated, and other factors, including the prescribing physician's judgment. PHARMACEUTICAL COMPOSITIONS Formula (I), when administered to a subject, is usually presented in a pharmaceutical composition. The term composition, as used herein, is intended to encompass a product comprising the specified components in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified components in the specified amounts. Pharmaceutically acceptable means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and not harmful to the recipient. The pharmaceutical compositions for administering the compounds in this disclosure may be conveniently presented as unit-dose formulations for oral administration and may be prepared by any of the well-known methods in pharmacy and drug administration. All methods include the step of combining the active ingredient with a carrier, which constitutes one or more auxiliary components. In general, pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active compound is included in a sufficient quantity to produce the desired effect on the disease process or condition. Pharmaceutical compositions containing the active ingredient may be presented in a form suitable for oral use, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifications as described in U.S. Patent Application 20020012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gum, chewable tablets, effervescent powder, and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives in order to provide pharmaceutically appealing and palatable preparations.The tablets contain the active ingredient in a mixture with pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as maize starch or alginic acid; binding agents such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or enterically or otherwise coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period.For example, a retardant material such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated using the techniques described in U.S. Patents Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic controlled-release therapeutic tablets. Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, polyethylene glycol (PEG) of various medium sizes (for example, PEG400, PEG4000), and certain surfactants such as Cremophor or Solutol; or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin, or olive oil. Furthermore, emulsions may be prepared with a water-immiscible component, such as oils, and stabilized with surfactants such as mono- or diglycerides, PEG esters, and the like. Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; the dispersing or wetting agents may be a natural phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylenexycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavorings and one or more sweeteners, such as sucrose or saccharin. Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, as described above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid. Powders and dispersing granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavorings, and colorings, may also be present. The pharmaceutical compositions disclosed may also be presented as oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may include gums of natural origin, for example, acacia gum or tragacanth gum, phosphatides of natural origin, for example, soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. These formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants. The compounds in this disclosure may also be coupled to a carrier that is a polymer suitable for targeted drug delivery. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polysine substituted with palmitoyl residues. In addition, the compounds in this disclosure may be coupled to a carrier that is a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, polylactic-polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels. The polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses, and the like.In one embodiment of the disclosure, the disclosure compound is coupled to a semipermeable polymer or polymer matrix that forms as a stent or stent graft device. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, radiotherapy, a radiotherapeutic agent, an antineoplastic agent, and an antiproliferative agent. In some embodiments, the one or more additional therapeutic agent is a chemokine receptor antagonist and / or chemoattractant, including but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR.Chemokine receptor antagonists and / or chemoattractants are known in the art and are described, for example, in documents W02007 / 002667, W02007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, W02007 / 115232, W02007 / 115231, W02008 / 147815, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO 2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, W02006 / 076644, W02008 / 008431, W02009 / 038847, W02008 / 008375, W02008 / 008374, W02008 / 010934, W02009 / 009740, W02005 / 112925, W02005 / 112916, W02005 / 113513, W02004 / 085384, W02004 / 046092.Chemokine receptor antagonists and / or chemoattractants also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and / or CCX3384. EXAMPLES The following examples illustrate various methods of manufacturing compounds of this disclosure, including the compounds of Formulas (I) or (a). The following examples are provided to illustrate, but not to limit, the claimed disclosure. The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). The 1HNMR spectra were recorded on a Vahan Mercury 400 MHz NMR spectrometer. Significant peaks are provided relative to the TMS and are tabulated in the order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are presented as the mass-to-charge ratio. In the examples, a single m / z value is reported for the M+H ion (or, as noted, MH) containing the most common atomic isotopes. The isotopic patterns correspond to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was performed on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery.Typically, the analyte was dissolved in methanol or CH3CN at 0.1 mg / mL and 1 microliter of the delivery solvent was infused into the mass spectrometer, which scanned from 100 to 1000 Daltons. All compounds could be analyzed in either ESI positive or negative mode, using acetonitrile / water with 1% formic acid as the delivery solvent. The following abbreviations are used in the Examples and throughout the disclosure description: TLC stands for thin layer chromatography. The compounds within the scope of this disclosure can be synthesized as described below, using a variety of reactions known to those skilled in the art. Those skilled in the art will also recognize that alternative methods may be employed to synthesize the target compounds of this disclosure, and that the approaches described herein are not exhaustive but provide practical and widely applicable routes to the compounds of interest. Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variants of these compounds are claimed unless a particular enantiomer is specified. The detailed description of the experimental procedures used to synthesize the key compounds in this text leads to molecules that are described by the physical data that identify them, as well as by the structural representations associated with them. Those skilled in the art will also recognize that acids and bases are frequently used during standard organic chemistry preparation procedures. Salts of the original compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described in this patent. Example 1: A / -(2'-chloro-3'-(5-((((3fí,4fí)-3-hydroxytetrahydro-2 / 7-pyran-4-yl)amino)methyl)-6methoxy¡pyr¡din- 2-¡l)-2-methyl¡l-[1,rbiphen¡l]-3-¡l)-1,3-dimethyl-2,4-dioxo-1,2,3,4tetrahydropyrimidine-5-carboxamide Step a: To a mixture of 1,3-dimethyl-A / -(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (3.6 g, 9.0 mmol), 1,3-dibromo-2-chlorobenzene (6.9 g, 25.5 mmol) and K2CO3 (3.8 g, 27.5 mmol) in p-dioxane (40 mL) and DI H2O (6 mL) was added Pd(dppf)Cl2 complex with dichloromethane (912 mg, 1.12 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 90 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and dried over MgSCU. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (5 to 100% EtOAc in hexanes followed by 0 to 5% MeOH in EtOAc) to give A / -(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4ML / dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z calculated for C2oHisBrCIN3O3[M + H]+462.0, found 462.0. Step b: A mixture of A / -(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.4 g, 3.03 mmol), pinacol diborane (1.0 g, 3.94 mmol), and KOAc (1.2 g, 10.2 mmol) in p-dioxane (18 mL) was mixed with Pd(dppf)Cl2 complex with dichloromethane (350 mg, 0.43 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 90 °C for 3 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (10 to 60% EtOAc in hexanes) to give / V-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxaborolan-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z calculated for C26H3oBCIN305 [M + H]+510.2, found 510.1. Step c: A mixture of A / -(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaboran2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrmide-5-carboxamide (400 mg, 0.78 mmol), 6-chloro-2-methoxynicotinaldehyde (200 mg, 1.17 mmol) and K2CO3 (350 mg, 2.53 mmol) in p-dioxane (10 mL) and DI H2O (2 mL) Pd(dppf)CI2 complex with dichloromethane (70 mg, 0.086 mmol) was added. The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 95 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (10–65% EtOAc in hexanes) to give A / -(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyridin-5-carboxamide. MS: (ES) m / z calculated for C27H24CIN4O5[M + H]+519.1, found 519.1. Step d: To a stirred solution of A / -(2'-chloro-3'-(5-formyl-6-methoxypyridine-2-yl)-2-methyl[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyridine-5-carboxamide (40 mg, 0.077 mmol) and (3 / 2,4 / 2)-4-aminotetrahydro-2 / - / -pyran-3-ol hydrochloride (24 mg, 0.154 mmol) in dichloroethane (2 mL) and ethanol (1 mL), triethylamine (2 drops) was added, followed by acetic acid (2 drops). The reaction mixture was stirred at 70°C for 1 hour. The mixture was then cooled to 0 °C and NaCNBH3 (10 mg, 0.154 mmol) was slowly added. The mixture was stirred at 0 °C for 10 minutes. The mixture was passed through a syringe filter and then purified by preparative HPLC (0 to 40% to 100% acetonitrile / H2O) to give A / -(2'-chloro-3'-(5-((((3 / :?,4 / :?)-3-hydroxytetrahydro-2 / - / -p¡ran-4-¡l)amino)methyl)-6-methoxyp¡prid¡n-2-¡l)-2-methyl-[1,1 '-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrop¡nmid¡n-5-carboxamide.1H NMR (400 MHz, CD3OD) δ 11.18 (S, 1H), 8.63 (s, 1H), 8.13-8.06 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 7.6, 1.7 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.39-7.25 (m, 3H), 7.00 (d, J = 7.7 Hz, 1H), 4.35 (d, J= 13.3. MLB. Ηζ, 1 Η), 4.24 (d, J= 13.2 Ηζ, 1 Η), 4.11 -3.93 (m, 6Η), 3.61 -3.36 (m, 10Η), 2.13 (s, 4H), 1.87 (d, J = 12.4 Ηζ, 1H). MS: (ES) m / z calculated for C32H34CIN5O6 [M + H]+620.2, set at 620.2. Example 2: (S)- / V-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin2-i l)-2-methyl-[1,1 '-bife nyl]-3-i I )-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahidropyrimidin-5carboxamida OMe Me The title compound was prepared from A / -(2′-chloro-3′-(5-formyl-6-methoxy¡p¡ridin-2yl)-2-methy l-[1,1′-biphen¡l]-3-i I)-1,3-dimethyl-2,4-d¡oxo-1,2,3,4-tetrahydrom¡r¡md¡n-5-carboxamide and (S)-5-aminomethylpyrroliden-2-one chlorhydrate following the same procedure as in Example 1. The crude product was purified by reverse-phase HPLC. (C18 column, acetonitrile / H2O with 0.1% TFA as eluent) to give the desired product (S)- / V-(2'-chloro-3'(6-methoxy-5-((((5-oxopyrrolide¡n-2-¡l)methyl)amino)methyl)p¡ridin-2-yl)-2-m et¡l-[1,1'-biphenyl]-3-yl)-1,3dimethyl-2,4-dioxo-1,2,3,4-tetrahldrop¡r¡m¡din-5-carboxam¡da.1H NMR (400 MHz, CD3OD)ó 8.63 (d, J= 1.1 Ηζ, 1H), 8.12 (dd, J=7.9, 1.3 Ηζ, 1H), 7.88 (d, J=7.Q Hz, 1H), 7.61 (d, J=7.7, Hz, 1Hz, 1H). 7.6 Hz, 1 H), 7.41 - 7.25 (m, 3H), 7.00 (d, J = 7.5 Hz, 1H), 4.34 (d, J = 2.0 Hz, 2H), 4.13 - 4.00 (m, 4H), J= 1.0 Hz, 3H), 3.34 - 3.22 (m, 2H), 2.49 - 2.32 (m, 3H), 2.13 (s, 3H), 1.92 (q, J = 7.5 Hz, 1H).MS: (ES) m / z calculated for C32H33CIN6O5 [M + H]+617.2, found 617.2. Example 3: (S)-W-(2,2'-dichloro-3'-(6-methox¡-5-((((5-oxopyrrol¡d¡n-2i I)methyl)am¡no)methi I)pyride i η-2-yl)-[1,1 '-bif en yl]-3-i I)-1,3-dimethyl-2,4-dioxo-1,2,3,4tetrah¡drop¡r¡m¡n-5-carboxamide OMe As The composition of the title was prepared starting from / \ / -(2,2'-d¡chloro-3'-(5-formyl-6-methox¡pyridin2-¡l)-[1,1 '-biphenyl]-3-yl)-1,3-dimethyl-2,4-d¡oxo-1,2,3,4-tetrahidrop¡r¡m¡dina-5-carboxam¡da y chlorhidrato de(S)-5-(aminomethyl)p¡rrol¡d¡n-2-ona by a process similar to that of Example 1. The raw product is purified by preparatory HPLC (C18 column, MeCN / H2O with 0.1% TFA as eluent) to give fS)- / V-(2,2'-dichloro-3'-(6-methox¡-5-((((5-oxop¡rrol¡d¡n-2yl)met¡ l)am¡ no)methyl)p¡r¡din-2-yl)-[1,1 '-biphenyl]-3-yl)-1,3-dimet¡l-2,4-dioxo-1,2,3,4tetrahidropyrimidin-5-carboxamida.1H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.54 (d, J= 8.3 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.65 (dd, J= 7.8, 1.8 Hz, 1H), 7.51 (dd, J= 7.7, 7.7 Hz, 1H), 7.45-7.35 (m, 3H), 7.10 (d, J= 7.6 Hz, 1H),4.34 (s, 2H), 4.14-4.01 (m, 4H), 3.56 (d, J = 1.6 Hz, 3H), 3.39 (d, J = 1.8 Hz, 3H), 3.30 - 3.20 (m, 3H), 2.40 (dd, J = 11.8, 11.1 Hz, 2H), 2.03 (d, J = 1.7 Hz, 1H), 1.92 (d, J = 6.9 Hz, 1H).MS: (ES) m / z calculated for C31H31CI2N6O5 [M + H]+637.2, found 637.2. Biological Example 1: Enzyme-linked immunosorbent assay - ELISA 96-well plates were coated with 1 pg / mL of human PD-L1 (obtained from l+D) in PBS overnight at 4 °C. The wells were then blocked with 2% BSA in PBS (w / v) containing 0.05% TWEEN-20 for 1 hour at 37 °C. The plates were washed three times with PBS / 0.05% TWEEN-20, and the compounds were serially diluted (1:5) in dilution medium and added to the ELISA plates. Human PD-1 and 0.3 pg / mL biotin (ACRO Biosystems) were added, and the plates were incubated for 1 hour at 37 °C, followed by three washes with PBS / 0.05% TWEEN-20. A second blocking was performed with 2% BSA in 0.05% PBS (w / v) / TWEEN-20 for 10 min at 37 °C, and the plates were washed three times with 0.05% PBS / TWEEN-20. Streptavidin-HRP was added for 1 hour at 37 °C, and the plates were then washed three times with 0.05% PBS / TWEEN-20. TMB substrate was added and reacted for 20 min at 37 °C. A stop solution (2 N aqueous H₂SO₄) was added.Absorbance was measured at 450 nm using a microplate spectrophotometer. The results are shown in Table 1. The IC50 values ​​are indicated below: 1000 to 10,000 nM (+); 10 to 1000 nM (++); less than 10 nM (+++). ML / Biological Example 2: Antitumor effect of compounds 2001, 2002 and 2003 This example demonstrates the antitumor biological effects of compounds 2001, 2002, and 2003 disclosed herein. ELISA'. This assay was performed substantially as described in Biological Example 1. Cell lines and cell culture: CHO cells, which constitutively express the TCR agonist and PD-L1, were cultured in Ham solution supplemented with 10% FBS and used for the cell assay. The T-cell-like cell line (Jurkat) modified to constitutively express PD-1 and carry a TCR-inducible NFAT response element-driven luciferase reporter gene (effector cells, ECs) (Jurkat PD-1) was cultured in RPMI supplemented with 10% FBS and 1X penicillin-streptomycin and used for the cell assay. The human melanoma cell line A375 and the human breast cancer cell line MDA-MB-231 were obtained from ATTC and cultured in DMEM supplemented with 10% FBS and 1X penicillin-streptomycin. Human PBMCs were isolated internally and cultured in RPMI supplemented with 10% FBS and 1X penicillin-streptomycin. PD-1 / PD-L1 blocking cell assay: 6 x 10⁴ Cho PD-L1 cells were seeded in 96-well plates overnight at 37°C. After washing the cells with 1X PBS, 40 µL of compound diluted with RPMI 1% FBS (initial concentration of 5 µM followed by a 1:5 dilution) was added to each well along with 40 µL of TJurkat PD-1 (1 x 10⁶ cells / ml) and incubated for 6 hours at 37°C. After cooling the cells to room temperature, 80 µL of Bio-Glo reagent (Promega, Madison, Wl) was added to the medium, and relative light units (RLU) were measured on a FlexStation 3 plate reader at a rate of 500 ms / well. In ML / the two cells were co-cultured together, the PD-1 / PD-L1 interaction inhibited TCR signaling and NFAT-ER mediated luminescence. Adding anti-PD-1 or anti-PDL1 antibodies / compounds that block the PD-1 / PD-L1 interaction releases the inhibition signal and leads to TCR activation and NFAT-ER mediated luminescence. PBMC Isolation: Peripheral blood mononuclear cells (PBMCs) were isolated from the buffy coat layer of LRS chambers (leukoreduction systems) from healthy donors by density gradient centrifugation using StemCell SepMate™50 tubes (STEMCELL Technologies, Vancouver, CA) containing Ficoll-Paque Plus (Sigma Aldrich Inc., St. Louis, MO). Generation of monocyte-derived dendritic cells: CD14+ monocytes were isolated from PBMCs by magnetic separation using human CD14+ MicroBeads (MACS Miltenyi Biotech, Bergisch Gladbach, Germany) and an autoMACS® Pro Separator. The isolated monocytes were plateped at a concentration of 1 x 10⁶ cells / ml and differentiated into dendritic cells by adding GM-CSF (100 ng / ml) and IL-4 (50 ng / ml) for 6 days. Fresh media supplemented with cytokines were added on day 0 and day 2. Mature dendritic cells were induced on day 6 by the addition of IL-6 (2000 Ul / ml), IL-1B (400 Ul / ml) (Peprotech, Inc. Rocky Hill, NJ), TNFalfa (2000 Ul / ml) and PGE2 (2 ug / ml) (Sigma Aldrich, Inc.) and cultured for 24 hours. Preparation of human effector cells: CD4+ T cells were isolated from PBMCs by magnetic separation using human CD4+ MicroBeads (MACS Miltenyi Biotech) and an autoMACS® Pro Separator. Mixed lymphocyte reaction (MLR): Unmatched donor DCs and CD4+ T cells were cultured together in a 1:10 ratio for 5 days in 96-well flat-bottom plates (Thermo Scientific). Assay compounds were added as directed to an initial concentration of 1 μM with 1:4 dilutions using DMSO. PD-L1 antibody (AZ Med14736 analogue) and isotype control (human IgG1, Kappa isotype control) (CrownBio, Beijing) were used as positive and negative controls, respectively. Supernatants were harvested after 5 days of incubation, and human IFN-γ detection was performed by ELISA using the Human IFN-γ DuoSet ELISA (R&D Systems, Minneapolis) according to the manufacturer's instructions. In vitro immunotherapy potency assay: A375-eGFP-Puro (ATCC) cells were cultured in complete medium (DMEM + 10% FBS + 1X P / S) containing 1 µg / ml puromycin. Human peripheral blood mononuclear cells (hPBMCs) were isolated from the buffy coat layer of LRS chambers (leukoreduction systems) from healthy donors by density gradient centrifugation using StemCell SepMate™-50 tubes (STEMCELL Technologies, Vancouver, CA) containing Ficoll-Paque Plus (Sigma Aldrich Inc., St. Louis, MO). Freshly isolated hPBMCs were stimulated with 100 ng / ml of Staphylococcal enterotoxin B (SEB) (EMD Millipore, Cat 324798) for three days. The cells were washed twice and resuspended in normal growth media. 3 x 10⁴ A375eGFP-Puro cells were seeded into TC black-treated, 96-well clear-bottom plates to a final volume of 100 µL (Corning). Assay compounds or human anti-PD-L1 antibody (AZ Med14736 analogue, CrownBio, Beijing) were added to the wells at different concentrations. SEB-stimulated hPBMCs were added to the wells at an E:T (effector cell:target cell) ratio of 2:1. The pooled cells were incubated for 96–120 hours at 37°C in 5% CO2. The medium was carefully aspirated, and 100 μL of 1X PBS was added to each well.The fluorescence of A375-eGFP cells was detected using the FlexStation 3 plate reader. The PD-L1 protein dimerization assay was evaluated in vitro by chemiluminescent detection using the PathHunter® Dimerization Assay (DiscoverX, Fremont, CA). The assay was performed according to the vendor's protocol. 2 x 10⁴ U2OS cells were seeded into TC-treated, white-background 96-well plates (Costar, San Jose, CA) to a final volume of 100 µL. ChemoCentryx compounds or human anti-PD-L1 antibody (ANALOGUE AZ Med14736, CrownBio, Beijing) were added to the experimental cells at different concentrations and incubated for 16 hours at 37°C in 5% CO₂. 110 µL of PathHunter Flash detection reagent (DiscoverX) was added to each well and incubated for 1 hour at room temperature in the dark. The chemiluminescent signal was measured on a FlexStation 3 plate reader (Molecular Devices, San Jose, CA) at a rate of 100 ms / well. Internalization assay: MC38-hPD-L1 cells (GenOway SA, France) and RKO cells (ATCC) grown at 37°C in 5% CC₂ were separated, resuspended in cold FACS buffer (1X PBS with 10% FBS and 0.1% azide), and added to 96-well assay plates (V-bottom) (Axygen, Union City, CA) at a concentration of 10 x 10⁴ cells / well. ChemoCentryx compounds or human anti-PD-L1 antibody (AZ Med analogue 4736) were added to the wells at different concentrations and incubated for 2 hours at 37°C or 4°C. Cells were washed twice with ice-cold FACS buffer and stained with recombinant rabbit anti-human PD-L1 monoclonal antibody ([28-8] (PE) (ab209962), Abcam) or recombinant rabbit isotype IgG monoclonal control ([EPR25A] (PE) (ab209478), Abcam) for 30 minutes on ice. Cells were washed twice with FACS buffer before FACS analysis. Data were analyzed using FlowJo software. ML / Generation and culture of MC38-hPD-L1 cells: Since the compounds are known to cross-react only with human PD-L1, a syngeneic tumor model using murine MC-38 colon tumor cells expressing human PD-L1 (MC38-hPD-L1 tumor model) was used. MC38-hPD-L1 cells were generated by GenOway. First, endogenous mouse PD-L1 was removed from MC38 cells using CRISPR technology, and then human PD-L1 was stably transfected into these mouse PD-L1-deactivating MC38 cells. The MC38-hPD-L1 cells were cultured under standard MC38 cell conditions (DMEM with 10% fetal bovine serum and penicillin / streptomycin) with G418 to maintain transgene expression. Two days before inoculation of these cells into mice, the cells were trisinized and seeded without antibiotics. In vivo studies: Eight-week-old female C57BL / 6 mice were subcutaneously injected with 5 x 10⁵ MC38-hPD-L1 cells in the right flank. Nine days post-tumor inoculation, mice were randomly assigned to treatment groups based on tumor size. Only mice that developed measurable tumors were included in the studies. Anti-PD-L1 (Durvalumab) or isotype control was administered twice weekly at 100 µg per mouse per dose for 2 weeks. Compound 2001 and compound 2002 suspended in 1% HPMC were administered orally daily at the stated doses, dosage volume 100 µL per mouse. The vehicle, 1% HPMC, was administered in the same volume and frequency to control animals. Tumor volume was measured three times per week using a digital caliper and calculated as (width² length / 2). Mice were sacrificed when tumor volumes reached 2,000 mm³ according to IACUC guidelines. The width (W) and length (L) of the tumor were measured with calipers 3 times per week and the tumor volume was calculated using the formula V= (W (2) x L) / 2. When the tumors reached 2000 mm3 the mice were sacrificed and the tumor was removed for further analysis. Cellular phenotyping of tumor infiltrates: Excised tumors were finely chopped with a blade and passed through a 200µm sieve. The cells were then filtered through a 70µm sieve. The cells were washed and resuspended in FACS buffer (1X PBS with 10% FBS and 0.1% azide). Antibodies for flow cytometry were obtained from BioLegend (San Diego, CA). The flow cytometer panel included CD45 on FITC, PD-L1 on PE, CD8 on APC, and CD4 on APCCy7. Flow cytometry data were acquired using a FACSCanto II flow cytometer (BD Biosciences, San Jose, CA) and analyzed with FlowJO v10.2 (FlowJo, Ashland, OR). RESULTS: In an enzyme-linked immunosorbent assay (ELISA), both compounds 2001 and 2002 potently inhibited the direct interaction of PD-L1 with PD-1. The mean IC50 of 2001 and 2002 from multiple assays was 0.3 nM and 0.4 nM, respectively (Fig. 1). In a cell-based assay evaluating PD-1-mediated downstream signaling, these compounds enhanced the expression of luciferase driven by the NFAT promoter, which is suppressed by the PD-L1 / PD-1 interaction. The mean EC50 of compounds 2001 and 2002 in this assay was 52 nM and 46 nM, respectively. In the mixed lymphocyte reaction (MLR) assay (FIG. 2 and FIG. 3), compound 2001 and compound 2002 increased IFN-gamma release from human T cells in a dose-dependent manner. T cell responsiveness from different donors varied, but both compounds showed an EC50 below 100 nM with different T cells. In the presence of prestimulated primary human PBMCs, compounds 2001 and 2002 promote the destruction of the GFP-labeled human cancer cell line A375 (FIG. 4A). Durvalumab, the FDA-approved anti-PD-L1 antibody, was used as a positive control and comparator in this study (FIG. 4B). In the pathhunter assay (dimerization assay), the dimerization of two PD-L1 molecules would join the two enzyme subunits and form a functional enzyme, which generates the bioluminescent signal. Both compound 2001 and 2002 strongly induced the dimerization signal, while a control compound and the anti-PD-L1 antibody did not induce this signal (FIG. 5). Surface PD-L1 in a tumor cell line was measured by flow cytometry. The binding of the detection antibody to PD-L1 was unaffected by small-molecule inhibitors, as illustrated by the minimal changes in PD-L1 staining with compound treatment at 4°C. At 37°C, the temperature that allows receptor internalization, compounds 2001 and 2002 profoundly reduced surface PD-L1 levels on the cell surface (Fig. 6). The anti-PD-L1 antibody had no effect on surface PD-L1 levels. These findings suggest that compounds 2001 and 2002 promote PD-L1 internalization. A mouse tumor cell line, MC38, in which mouse PD-L1 was replaced by a human PD-L1 transgene, was used to induce tumor growth in mice (FIG. 7). We confirmed that human and mouse PD-L1 bind to mouse PD-1 with similar affinity, and our PD-L1 inhibitors block the interaction of human PD-L1 with mouse PD-1 with similar potency (data not shown). In this model, compound 2002, administered orally, suppressed tumor growth in a dose-dependent manner (FIG. 8A-8C). Eight of the ten mice treated with 30 mg / kg (bid.) of compound 2002 achieved complete tumor eradication (FIG. 8A). Final tumor weights were consistent with tumor size measurements, and eradicated tumors were not included in the tumor weight graph (FIG. 8B). Plasma concentrations of the compound also proved to be dose-dependent (FIG. 8C). Compound 2001 and compound 2003, each administered orally at 30 mg / kg (bid), also resulted in tumor suppression similar to that of the anti-PD-L1 antibody (Durvalumab) (Compare, FIG. 9A, FIG. 9B, and FIG. 9C). FIG. 9A depicts tumor growth when compound 2001 was administered to mice, FIG. 9B depicts tumor growth when compound 2003 was administered to mice, and FIG. 9C depicts tumor growth when anti-PD-L1 antibody (Durvalumab) was administered to mice. The top panel of each figure shows the mean tumor sizes of 10 mice in each group, and the bottom graphs show tumor progressions in individual animals. 6 animals from the anti-PD-L1 treated group, 4 from the compound 2.001 treated group, and 4 from the compound 2.001 treated group achieved complete regression. In the model mentioned above, the plasma concentration of compound 2001 and compound 2003 (each dosed at 30 mg / kg, orally, twice daily) was measured in each mouse after 6 days of dosing. The minimum plasma concentration is shown in FIG. 10. To examine the extent to which Compound 2001 occupies PD-L1 in tumor cells, we used another PD-L1 detection antibody to stain cells isolated from these tumors. This detection antibody does not bind to PD-L1 once Compound 2001 or the anti-PD-L1 treatment (Durvalumab) is bound. Cells from tumors treated with Compound 2001 completely lack PD-L1 staining by this detection antibody, demonstrating almost complete PD-L1 occupancy by Compound 2001 (FIG. 11). Each of the treatment conditions was analyzed in the mouse model referred to above for tumor-infiltrating immune cells. Both CD8+ and CD4+ T cells increased with treatment with compound 2001, similar to tumors treated with anti-PD-L1 (FIG. 12). This document describes particular embodiments of this invention, including the best manner known to the inventors for carrying out the invention. Upon reading the foregoing description, variations of the disclosed embodiments may be apparent to persons skilled in the art, and it is expected that such persons skilled in the art may employ such variations as appropriate. Accordingly, the invention is intended to be practiced in a manner other than as specifically described herein, and the invention is to include all modifications and material equivalents referred to in the appended claims hereto to the extent permitted by applicable law.Furthermore, any combination of the elements described above in all possible variations thereof is included in the invention, unless otherwise stated herein, or the context clearly indicates otherwise. All publications, patent applications, accession numbers, and other references cited in this descriptive memorandum are incorporated by reference in this document as if it were specifically and individually stated that each individual publication or patent application is incorporated by reference.

Claims

1. A method for treating a cancer selected from the group consisting of colon cancer, kidney cancer, colorectal cancer, gastric cancer, bladder cancer, melanoma, non-small cell lung cancer, Merkel cell carcinoma, liver cancer, breast cancer, and head or neck cancer comprising administering to a subject in need an effective amount of a compound of Formula (I): Ra(|) or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently selected from the group consisting of F, Cl, CH3, and CF3; R3 is selected from the group consisting of F, Cl, CH3, CF3, -O-CH3, and -O-CF3;R4 is selected from the group consisting of -Y and -X1-Y wherein each X1 is a C1-4 alkylene and Y is selected from the group consisting of C3-6 cycloalkyl, C4-6 heterocycloalkyl with ring vertices of 1 to 3 heteroatoms selected independently from the group consisting of N, O and S and 5- to 6-membered heteroaryl with ring vertices of 1 to 3 heteroatoms selected independently from the group consisting of N, O and S, each of which is unsubstituted or substituted with one or two substituents selected independently from the group consisting of oxo, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 hydroxyalkoxy; and Ra and Rb are selected independently from the group formed by H, C1-3 alkyl and C1-4 haloalkyl.; 2. The method according to claim 1, wherein the effective amount of a compound of Formula (I) is administered orally.

3. The method according to claim 1 or claim 2, wherein R1 is selected from the group consisting of Cl and CH3.

4. The method according to claim 1 or claim 2, wherein R1 is Cl.

5. The method according to claim 1 or claim 2, wherein R1 is CH3.

6. The method according to any one of claims 1 to 5, wherein R2 is selected from the group consisting of Cl and CH3.

7. The method according to any one of claims 1-5, wherein R2 is Cl. MA / 8. The method according to any one of claims 1 to 5, wherein R2 is CH3.

9. The method according to any one of claims 1 to 8, wherein R3 is selected from the group consisting of -O-CH3 and -O-CF3.

10. The method according to any of claims 1 to 8, wherein R3 is -OCH3.

11. The method according to any one of claims 1-8, wherein R3 is O-CF3.

12. The method according to any one of claims 1 to 11, wherein Ra is selected from the group consisting of H, CH3 and CF3.

13. The method according to any one of claims 1 to 11, wherein Ra is CH3.

14. The method according to any one of claims 1 to 13, wherein Rb is selected from the group consisting of H, CH3 and CF3.

15. The method according to any of claims 1 to 13, wherein Rb is CH3.

16. The method according to any of claims 1 to 5, wherein the compound of Formula I has Formula (la): oz 1 (la) or a pharmaceutically acceptable salt thereof.

17. The method according to any one of claims 1 to 16, wherein -NH(R4) is selected from the group consisting of: NNH -O O.. ÓH OH OH 18. The method according to any one of claims 1 to 16, wherein -NH(R4) is selected from the group consisting of: NH OH 19. The method according to any of claims 1 to 16 is selected from the group consisting of: to 16, wherein -NHR4 is NH NH N OH. ΓN 20.

21. H -N 3— O N' H CH: ,-N —o The method according to any of claims 1 to 16, wherein -NHR4 is HO The method according to any of claims 1 to 20, wherein the compound of Formula (I) is an optically pure or enriched isomer.

22. The method according to claim 1, wherein the compound of Formula (I) is selected from a compound in Table 1.

23. The method according to any of claims 1 to 22, wherein the effective amount of Formula (I) maintains a minimum blood plasma concentration of approximately 2 ng / mL to approximately 1,000 ng / mL.

24. The method according to any of claims 1 to 22, wherein the effective amount of Formula (I) maintains a minimum blood plasma concentration of approximately 5 ng / mL to approximately 500 ng / mL.

25. The method according to any of claims 1 to 22, wherein the effective amount of Formula (I) maintains a minimum blood plasma concentration of approximately 20 ng / mL to approximately 300 ng / mL 26. The method according to any of claims 1 to 22, wherein the effective amount of Formula (I) maintains a minimum blood plasma concentration of approximately 30 ng / mL to approximately 200 ng / mL.

27. The method according to any of claims 1 to 26, wherein the disease or disorder is colon cancer.

28. The method according to any one of claims 1 to 26, wherein the disease or disorder is colorectal cancer.

29. The method according to any one of claims 1 to 26, wherein the disease or disorder is breast cancer.

30. The method according to any one of claims 1 to 26, wherein the disease or disorder is liver cancer.

31. The method according to any one of claims 1 to 26, wherein the disease or disorder is melanoma.

32. The method according to any of claims 1 to 31, further comprising administering to the subject an effective amount of one or more additional therapeutic agents.

33. The method according to claim 32, wherein the one or more additional therapeutic agents are selected from the group consisting of a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, radiotherapy, a radiotherapeutic agent, an antineoplastic agent, and an antiproliferative agent.