Indenes as pd-l1 inhibitors

Abstract

Provided herein are compounds represented by Formula (I) or Formula (II), or a pharmaceutically acceptable salt or prodrug or bioisomer thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , R 2a’ , R 2b’ , R 2c’ , R 3’ , R 4’ , R 5’ , R 6a’ , R 6b’ , Y, Y', and subscripts m and n are as defined herein:

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 872,541, filed July 10, 2019, pursuant to USC §119(e), the disclosure of which is incorporated herein by reference in its entirety.

[0003] Declaration of rights to inventions made under federal government-funded research and development

[0004] not applicable

[0005] References to the "Serial List," forms, and computer program appendices submitted to the CD-ROM.

[0006] not applicable Background of the Invention

[0008] Programmed cell death protein 1 (PD-1) is a member of the DC28 superfamily that transmits negative signals through interactions with two ligands, PD-L1 and PD-L2. PD-1 and its ligands are widely expressed and play broad immunomodulatory roles in T cell activation and tolerance. PD-1 and its ligands are involved in reducing infectious and tumor immunity and promoting chronic infection and tumor progression.

[0009] Regulation of the PD-1 pathway has therapeutic potential in human diseases (Hyun-Tak Jin et al., Contemporary Microbiology and Immunology (2011); 350:17-37). Blockade of the PD-1 pathway has become an attractive target in cancer therapy. Therapeutic antibodies that block the programmed cell death (PD-1) immune checkpoint pathway can prevent T cell downregulation and promote immune responses to fight cancer. Several PD-1 pathway inhibitors have shown potent activity in clinical trials at different stages (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214-223).

[0010] Agents capable of blocking the interaction of PD-L1 with PD-1 or CD80 are needed. Several antibodies have been developed and commercialized. Some patent applications of non-peptide small molecules have been published (WO 2015 / 160641, WO 2015 / 034820, WO 2017 / 066227 and WO 2018 / 009505 by Bristol-Myers Squibb; WO 2015 / 033299 and WO 2015 / 033301 by Aurigene; WO 2017 / 070089, US 2017 / 0145025, WO 2017 / 106634, US 2017 / 0174679, WO 2017 / 192961, WO 2017 / 222976, WO 2017 / 205464, WO 2017 / 112730, WO 2017 / 041899 and WO 2018 / 013789 by Incyte; WO 2018 / 006795 by Maxinovel; and WO 2018 / 005374 by ChemoCentryx). Nonetheless, there is still a need for alternative compounds, e.g. small molecules, as inhibitors of PD-L1, and which have advantages in terms of oral dosing, stability, bioavailability, therapeutic index and toxicity. SUMMARY

[0011] In one aspect, the present application provides a compound of Formula (I) or Formula (II):

[0012]

[0013] or a pharmaceutically acceptable salt or prodrug or a biological isomer thereof, wherein:

[0014] R 1 , R2a, R2b, R2c, R3, R4, R5, R6a, R6b, R2a', R2b', R2c', R3', R4', R5', R6a', R6b', Y, Y' and subscripts m and n are defined below.

[0015] In addition to the compounds provided by the present application, the present application also provides pharmaceutical compositions containing one or more of the compounds and methods relating to the preparation and use of such compounds. In some embodiments, the compounds are used in methods of treatment related to PD-1 / PD-L1 pathway diseases. BRIEF DESCRIPTION OF DRAWINGS

[0016] None DETAILED DESCRIPTION

[0017] ABBREVIATIONS AND DEFINITIONS

[0018] The terms "a" and "an" as used herein mean one or more aspects, including plural aspects. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes more than one such cell, reference to "an agent" includes reference to one or more agents known to one skilled in the art, and so on.

[0019] The terms "about" and "approximately" as used herein refer generally to an acceptable degree of error for the quantity measured considering the nature of the measurement or the precision of the instrument used to make the measurement. Typical, exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Additionally, particularly in biological systems, the terms "about" and "approximately" can mean values that are within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a given value. Unless otherwise stated, the numerical values given herein are approximate, meaning that the term "about" or "approximately" can be inferred if not expressly stated.

[0020] The term "alkyl," by itself or as part of another substituent, means, unless otherwise indicated, a straight-chain or branched-chain carbon-based group, as indicated by the number of carbon atoms specified (e.g., C 1-8 Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to unsaturated alkyl groups containing one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups containing one or more triple bonds. Examples of alkenyl groups include ethenyl, 2-propenyl, octenyl, 2-iso-pentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs.

[0021] The term "cycloalkyl" refers to a hydrocarbon ring or ring system having the number of ring atoms specified (e.g., C 3-6 cycloalkyl), and is fully saturated or has no more than one double bond between ring vertices. "Cycloalkyl" also refers to bicyclic or polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. The bicyclic or polycyclic rings can be fused, bridged, spiro, or a combination thereof.

[0022] The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing from 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. The heterocycloalkyl group can be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings can be fused, bridged, spiro, or a combination thereof. It will be understood that, by way of example, C 4-12Heterocyclyl refers to a group containing 4-12 ring members, at least one of which is a heteroatom. Non-limiting examples include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidine, tetrazolone, endectin, dioxane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-s-oxide, thiomorpholine-s-s-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiolane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, quinoline, and the like. The heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0023] The term "alkylene" by itself or as part of a substituent group refers to a divalent group derived from an alkane, e.g., -CH2CH2CH2CH2-. The alkylene group can be straight-chained or branched. For example, -CH2C(CH3)2CH2-, -CH2C(CH3)2-, or -CH(CH3)CH2CH2-. A typical alkyl (or alkylene) group contains 1-12 carbon atoms, with the present application preferably 8 or fewer carbon atoms. Similarly, alkenylene and alkynylene refer to unsaturated alkylene groups containing a double or triple bond, respectively.

[0024] The terms "alkoxy," "alkylamino," and "alkylthioxy" (or thioalkoxy) are used in their conventional sense and refer to an alkyl group attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. In addition, for dialkylamino groups, the alkyl moieties can be the same or different and can combine with the nitrogen atom to form a 3-7 membered ring. Correspondingly, an alkylamino group can be represented as -NHR a R b The groups represented by R

[0025] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of a substituent group refers to a fluorine, chlorine, bromine, or iodine atom. In addition, the term "haloalkane" includes mono-haloalkanes and poly-haloalkanes. For example, the term "C 1-4 haloalkane" includes trifluoroethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. As noted above, the term "hydroxyalkyl" or "alkyl-hydroxy" refers to an alkyl group in which at least one (and up to three) hydrogen atoms is replaced by a hydroxyl group. For alkyl groups, the hydroxyalkyl group can have any convenient number of carbon atoms, such as C 1-6 Typical hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxyl at either the 1 or 2 position), hydroxypropyl (hydroxyl at either the 1, 2, or 3 position), and 2,3-dihydroxypropyl.

[0026] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon group that can be a single ring or multiple rings (up to three rings) that are fused together or linked covalently.

[0027] The term "heteroaryl" refers to a 5-10 membered aromatic ring (or ring system) having 1-5 heteroatom ring vertices each selected from nitrogen, oxygen, or sulfur atom, wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atoms can be optionally quaternized. The heteroaryl group can be attached to the remainder of the molecule through a heteroatom. It is understood that "C 5-10 The term "heteroaryl" refers to a 5 to 10 membered ring system having at least one ring member which 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, quinolyl, isoquinolyl, quinolyl, isoquinolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, benzotriazinyl, purinyl, benzimidazolyl, benzotriazinyl, benzotriazolyl, benzoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyrimidinyl, thienopyrimidinyl, pyrazolyl, benzothiophenyl, indolyl, quinazolinyl, isoquinazolinyl, isothiazolyl, isothiazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thiophenyl, and the like. Substituents for the aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0028] When any of the above recited terms (e.g., "alkyl," "aryl," and "heteroaryl") are referred to as "substituted" without further description, the substituents for the indicated group will be as described below.

[0029] Substituents for the alkyl group (including those typically referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from -halogen, -OR', -NR'R", -SR', -SiR'R"R", -OC(O)R', -C(O)R', -CO2R', -CONR", -OC(O)NR'R', -NR'C(O)R', -NR'C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH', -S(O)R', -S(O)2NR", -S(O)2NR", -CN and -NO2, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in the alkyl group. R', R" and R'" each independently refer to hydrogen, unsubstituted C 1-8 unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 alkoxy or C 1-8 thioalkoxy or unsubstituted aryl-C 1-4alkyl. 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"-NR'R' represents 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" by itself or as part of a substituent group, means an alkyl group in which the two substituents on the carbon atom bonded directly to the group are replaced with substituents =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0030] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R", -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", -N3, perfluoro(C1-C4)alkyoxy, perfluoro(C1-C4)alkyl, 0 to 4 substituents on the aryl ring, wherein said substituents are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, -OR', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R", -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", -N3, perfluoro(C1-C4)alkyoxy, perfluoro(C1-C4)alkyl, wherein R', R", and R'" are independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 alkyl, unsubstituted aryloxy-C 1-4 alkyl. Other suitable substituents include each of the aryl substituents described above attached to a ring atom by an alkyl chain of 1-4 carbon atoms.

[0031] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -A-(CH2)r-B-, in which 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 of from 1 to 3. One of the single bonds of the new ring so formed can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -(CH2) s -X-(CH2) t- 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 C 1-6 alkyl.

[0032] The term "heteroatom" as used herein is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0033] The present application also relates to prodrugs and bioisosteric forms thereof. Suitable bioisosteric forms should include carboxylate surrogates (phosphonate, phosphinate, sulfonate, sulfinic acid, and acidic heterocyclic groups such as tetrazole). Suitable prodrugs should include conventional groups known to be hydrolyzed and / or oxidized under physiological conditions to provide the compounds of Formula I.

[0034] The terms "patient" and "subject" include primates (especially humans), domesticated companion animals (such as dogs, cats, horses, etc.), and livestock (such as cows, pigs, sheep, etc.).

[0035] As used herein, the terms "treatment" or "treatment regimen" include both disease-modifying and symptomatic treatments, either of which can be prophylactic (i.e., to prevent, delay or lessen the severity of symptoms before they occur) or therapeutic (i.e., to lessen the severity and / or duration of symptoms after they have occurred).

[0036] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds which are relatively non-toxic. The salts can be prepared from a variety of non-toxic acids or bases including inorganic acids and bases and the salts can be prepared from pharmaceutically acceptable acids and bases. Salts of an acidic group, such as a carboxylic acid, on the compound of the application can be prepared by contacting the neutral form of such a compound in either the solid or in a suitable inert solvent with a sufficient amount of the desired base to produce the salt. Examples of salts of pharmaceutically acceptable inorganic bases include the aluminum, ammonium, calcium, copper, ferric, fennic, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts of pharmaceutically acceptable organic bases include salts of specific amines such as 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, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tuamine, and the like. Salts of an acidic group, such as a carboxylic acid, on the compound of the application can be prepared by contacting the neutral form of such a compound in either the solid or in a suitable inert solvent with a sufficient amount of the desired acid to produce the salt. 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, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzylic, salicylic, sulfanilic, toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, s.m. et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the application contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0037] The neutral form of the compounds can be regenerated by contacting the salt with a base or 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 otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.

[0038] Some compounds disclosed herein may exist in both solvated and solvated forms, including hydrated forms. Generally, solvated and non-solvated forms are equivalent and included within the scope of this invention. Some compounds studied herein may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated by this invention and are included within the scope of this invention.

[0039] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regio isomers, and single isomers (e.g., separated enantiomers) are all included within the scope of the present invention. As described in the stereochemical description, it refers to a compound with one isomer and substantially no other isomer. “Substantially no” another isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, the number of one isomer is at least 99%.

[0040] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more atoms constituting these compounds. For example, these compounds can be radiolabeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variants, whether radioactive or not, are included within the scope of this invention. For example, deuterium (C) can be used in the preparation of compounds. 2 (H) Isotopes replace any number of hydrogen atoms. The compounds in this study may also contain one or more non-natural proportions of atomic isotopes constituting these compounds. A non-natural proportion of isotopes can be defined as a quantity ranging from those found in nature to those comprising 100% of the atoms in question. For example, these compounds may contain radioactive isotopes such as tritium (H). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium (2H) or carbon-13 (13C). Isotope variants can provide additional utility for the isotopes described elsewhere in this invention. For example, isotope variants in these compounds may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotope variants of the compounds studied in this study can alter their pharmacokinetic and pharmacodynamic characteristics, which may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotope variants of the compounds disclosed herein, whether or not radioactive, are included within the scope of this disclosure.

[0041] compound

[0042] In one aspect, the present application provides a compound of Formula (I) or Formula (II):

[0043]

[0044] or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0045] wherein:

[0046] Y and Y' are each independently selected from the group consisting of O, NH and N(C 1-4 alkyl);

[0047] R 1 is independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, -O-C 1-4 alkyl and -O-C 1-4 haloalkyl;

[0048] each R 2a , R 2b , R 2c , R 2a’ , R 2b’ and R 2c’ is independently selected from the group consisting of hydrogen, halogen, -CN, -R a ,-CO2R b ,-CONR b R c ,-OC(O)NR b R c ,-NR c C(O)R b ,-NR c C(O)2R a ,-NR b -C(O)NR b R c ,-NR b R c ,-OR b ,-X 1 -OR b ,-X 1 -NR b R c ,-X 1 -CO2R b ,-SF5, and -S(O)2NR b R c wherein each X 1 is C 1-4 alkylene, each R b and R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom, can combine with that nitrogen atom to form a five- or six-membered ring having 0-2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with oxygen; each R a is independently selected from the group consisting of: C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;

[0049] R 3 and R 3’ are each independently selected from the group consisting of: -NR d R e and 4-12 membered monocyclic, bicylic or spiro non-aromatic heterocyclic rings, optionally substituted with 1-6 R 3a substituents,

[0050] wherein R d is independently selected from the group consisting of: H, C 1-8 haloalkyl, and C 1-8 alkyl;

[0051] R e is selected from the group consisting of: H, -C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, X2-CO2Rg, X2-CONR g R h , -X 2 -CONHSO2R g , -X 2 -SO2NR g R h , -X 2 -SO3R g , -X 2 -B(OH)2, -X 2 -PO3H2, -X 2 -C(O)NHOH, -X 2 -NR g R h , -C(O)R g , C 3-10 cycloalkyl, -C 3-10 cycloalkyl-COOR g , -C 3-10 cycloalkyl-OR g , C 4-8 heterocyclyl, -C 4-8 heterocyclyl-COOR g , -C 4-8 heterocyclyl-OR g , -X 2 -C 4-8 heterocyclyl, -C(=O)O-X2 -C 4-8 heterocyclyl, -X 2 -C 3-10 cycloalkyl, C 5-10 heteroaryl, -X 2 -C 5-10 heteroaryl, -X 2 -C 6-10 aryl, -X 2 -(C=O)-C 6-10 aryl, -CO2-X 2 -O2C-C 1-8 alkyl, -X 2 -NH(C=O)-C 2-8 alkenylene, -X 2 -NH(C=O)-C 1-8 alkyl, -X 2 -NH(C=O)-C 2-8 alkynyl, -X 2 -(C=O)-NH-X 2 -COOR g and -X 2 -(C=O)-NH-X 2 -OR g , optionally substituted with CO2H, wherein R e of the alkyl or alkenyl portion is optionally substituted with 1 to 3 substituents independently selected from OH, COOH, SO2NH2, CONH2, C(O)NHOH, COO-C 1-8 alkyl or PO3H2; R e of the C 5-10 heteroaryl and C 6-10 aryl portion is optionally substituted with 1 to 3 substituents independently selected from OH, B(OH)2, COOH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 alkyl, C 1-4 alkyl, C 1-4 alkylene-OH, C 1-4 alkylene-SO2NH2, C 1-4 alkylene-CONH2, C 1-4 alkylene-C(O)NHOH, C 1-4 alkylene-PO3H2 or C 1-4 alkylene-COOH; R e of the C 4-8 heterocyclyl and C 3-10 cycloalkyl portion is optionally substituted with

[0052] 1 to 4 R w substituents;

[0053] or

[0054] R e It combines with the N-terminus linked to it to form a monoamino acid, dipeptide, or tripeptide containing both natural and non-natural amino acids, wherein the non-natural amino acid is selected from C. 2-4 Hydroxyalkyl, C 1-3 alkylguanidine or C 1-4 The α-carbon substituent of the alkyl-heteroaryl group, wherein the α-carbon of each natural and non-natural amino acid is optionally further replaced by a methyl group, and the terminal fragment of the monopeptide, dipeptide, or tripeptide is selected from: C(O)OH, C(O)OC. 1-6 Alkyl groups, C(O)NH2, and PO3H2;

[0055] Each R 3a Independently selected from: halogen, -CN, oxygen, -R f -CO2R g -CONR g R h -CONHC 1-6 alkyl-OH, -C(O)R g -OC(O)R g -OC(O)NR g R h -NR g C(O)R h -NR g C(O)2R h -CONHOH, -PO3H2, -NR g -X 2 -C(O)2R h -NR g C(O)NR g R h -NR g R h -OR g -S(O)2NR g R h -OX 2 -OR g -OX 2 -NR g R h -OX 2 -CO2R g -OX 2 -CONR g R h -X 2 -OR g -X 2 -NR g Rh , -X 2 -CO2R g , -X 2 -CONR g R h , -X 2 -CONHSO2R g and SF5, wherein X 2 is C 1-6 alkylene, optionally further substituted with OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 alkyl or CO2H, wherein each R g and R h is independently selected from the group consisting of: hydrogen, C 32 alkyl optionally substituted with 1-2 substituents selected from the group consisting of OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 alkyl and CO2H; 1-8 alkyl optionally substituted with 1-2 substituents selected from the group consisting of OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 alkyl or CO2H; 1-8 haloalkyl, or when R g and R h are attached to the same nitrogen atom, R g and R h may combine with the nitrogen atom to form a five or six membered ring having from 0 to 2 additional heteroatoms selected from N, O or S as ring members and optionally substituted with oxygen; each R f is independently selected from the group consisting of: -OH, C 1-8 alkyl, C 2-8 alkenyl and C 1-8 haloalkyl, each of which is optionally substituted with OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 alkyl or CO2H;

[0056] each R w substituent is independently selected from the group consisting of: C 1-4 alkyl, C 1-4 alkylene-OH, C 1-4 alkylene-COOH, C 1-4 alkylene-SO2NH2, C 1-4 alkylene-CONH2, C 1-4 alkylene-C(O)NHOH, C 1-4 alkylene-PO3H, OH, COO-C 1-8alkyl, COOH, SO2NH2, CONH2, C(O)NHOH, PO3H2, and oxygen;

[0057] each R 4 and R 4’ are independently selected from the group consisting of: O-C 1-8 alkyl, O-C 1-8 haloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -O-C 1-4 alkyl-C 4-7 heterocycloalkyl, -O-C 1-4 alkyl-C 6-10 aryl and -O-C 1-4 alkyl-C 5-10 heteroaryl, wherein each group is optionally substituted with 1-5 R 4a ;

[0058] each R 4a is independently selected from the group consisting of: halo, -CN, -R i , -CO2R j , -CONR j R k , -C(O)R j , -OC(O)NR j R k , -NR j C(O)R k , -NR j C(O)2R i , -NR j -C(O)NR j R k , -NR j R k and -OR j , wherein

[0059] each R i is independently selected from the group consisting of: C 1-8 alkyl, C 2-8 alkenyl and C 1-8 haloalkyl, optionally, when two R 4a substituents are on adjacent atoms, they can combine to form a fused five- or six-membered carbocyclic or heterocyclic ring, optionally substituted with oxygen;

[0060] each R j and R k is independently selected from the group consisting of: hydrogen, C 1-8 alkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0-2 additional heteroatoms selected from N, O or S as ring members, and optionally substituted with oxygen;

[0061] each n is independently 0, 1, 2, or 3;

[0062] each R 5 and R 5’ are independently selected from the group consisting of: halo, -CN, -R q , -CO2R r , -CONR r R s , -C(O)R r , -NR r R s , and -OR r , wherein each R r and R s is independently selected from the group consisting of: hydrogen, C 1-4 alkyl and C 1-4 haloalkyl, when taken together with the nitrogen atom to which they are attached form a five or six membered ring having 0-2 additional heteroatoms selected from N, O, or S, and optionally substituted with oxygen; each R q is independently selected from the group consisting of: C 1-8 alkyl C 1-8 haloalkyl;

[0063] each R 6a and R 6a’ is independently selected from the group consisting of: H, C 1-4 alkyl and C 1-4 haloalkyl;

[0064] each m is independently 0, 1, 2, 3, or 4;

[0065] each R 6b and R 6b’ is independently selected from the group consisting of: F, C1-4alkyl and C 1-4 haloalkyl;

[0066] In one set of embodiments, the compounds provided herein are represented by the general formula (I).

[0067] In one set of embodiments, the compounds provided herein are represented by the general formula (II).

[0068] In one set of embodiments, the compounds represented by general formula (I) or (II) are those wherein Y and Y' are each independently selected from O or NH.

[0069] In one set of embodiments, the compounds represented by general formula (I) or (II) are those wherein Y and Y' are each O.

[0070] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each subscript n is 0 or 1. In some embodiments, the compound of Formula (I) or (II) is a compound wherein each subscript m is 0 or 1. In some embodiments, the compound of Formula (I) or (II) is a compound wherein each subscript n is 0 or 1, and each subscript m is 0 or 1.

[0071] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each R 3 and R 3’ is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocycle, optionally substituted with 1-4 R 3a .

[0072] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each R 3 and R 3’ is independently -NR d R e .

[0073] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each R3and R3' is independently -NR d R e , R e is combined with the N to which it is attached is a natural or unnatural amino acid, wherein the unnatural amino acid has an alpha carbon substituent selected from C 2-4 hydroxyalkyl or C 1-3 alkyl-guanidino, wherein the alpha carbon of each natural or unnatural amino acid can be optionally further substituted with a methyl group, and the terminal moiety is selected from C(O)OH, C(O)O-C 1-6 alkyl or C(O)NH2.

[0074] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each R3and R3' is independently -NR d R e , and R e is combined with the N to which it is attached is a natural or unnatural amino acid, wherein the unnatural amino acid has a C 2-4 hydroxyalkyl alpha carbon, wherein the alpha carbon of each natural or unnatural amino acid is further substituted with a methyl group, and the terminal moiety is selected from C(O)OH, C(O)O-C 1-4 alkyl or C(O)NH2.

[0075] In some embodiments, the compound of Formula (I) or (II) is a compound wherein each R 2a , R 2、 R 2cR 2a’ R 2b’ and R 2c’ Selected independently from H, halogen, -CN, and -R a -CO2R b -CONR b R c -NR b R c or -OR b ; where each R b and R c Selected independently from hydrogen and C 1-8 Alkyl or C 1-8 Halogenated alkyl groups, or when bonded to the same nitrogen atom, can combine with that nitrogen atom to form a five- or six-membered ring having 0-2 additional heteroatoms selected from N, O, or S as ring members, optionally substituted with oxygen; each R a Independently selected from C 1-8 Alkyl, C 2-8 alkenyl or C 1-8 Halogenated alkyl groups.

[0076] In some embodiments, the compounds represented by general formula (I) or (II) are compounds in which each R 4 and R 4’ Independently selected from: OC 1-8 Alkyl, OC 1-8 Halogenated alkyl groups, -OC 1-4 Alkyl-C 6-10 Aryl and -OC 1-4 Alkyl-C 5-10 Heteroaryl groups, each group optionally surrounded by 1-5 R groups 4a replace.

[0077] In some embodiments, the compounds represented by general formula (I) or (II) are compounds in which each R 4 and R 4’ Independently selected from: OC 1-8 Alkyl, -OC 1-4 Alkyl-phenyl and -OC 1-4 alkyl-pyridyl groups, each group optionally surrounded by 1-3 R groups 4a replace.

[0078] In some embodiments, the compounds represented by general formula (I) or (II) are compounds in which each R 2a R 2b R 2c R 2a’ R 2b’ and R 2c’ Each is independently selected from H, halogen, -CN, -R a -CO2Rb , -CONR b R c , -NR b R c , or -OR b ; wherein each R b and R c is independently selected from hydrogen, C 1-8 alkyl or C 1-8 haloalkyl, or when attached to the same nitrogen atom can combine with the nitrogen atom to form a five or six membered ring having 0-2 additional heteroatoms selected from N, O or S as a ring member and optionally substituted with oxygen; each R a is independently selected from C 1-8 alkyl, C 2-8 alkenyl or C 1-8 haloalkyl; each R 3 is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocyclic ring, optionally substituted with 1-4 R 3a ; each R 4 is selected from O-C 1-8 alkyl, -O-C 1-4 alkyl-phenyl or -O-C 1-4 alkyl-pyridyl, each optionally substituted with 1-3 R 4a .

[0079] In some embodiments, each R 2a , R 2b , R 2c , R 2a’ R 2b’ and R 2c’ in the compound of Formula (I) or (II) is independently selected from: hydrogen, halogen, -CN, -R a , -CO2R b , -CONR b R c , -NR b R c , or -OR b ; wherein each R b and R c is independently selected from hydrogen, C 1-8 alkyl or C 1-8 haloalkyl, or when attached to the same nitrogen atom can combine with the nitrogen atom to form a five or six membered ring having 0-2 additional heteroatoms selected from N, O or S as a ring member and optionally substituted with oxygen; each R a is independently selected from C 1-8 alkyl, C 2-8 alkenyl or C 1-8 haloalkyl; each R 3 is -NR d R eand R e is a naturally or non-naturally occurring amino acid, wherein the non-naturally occurring amino acid has an alpha carbon substituted with a group selected from C 2-4 hydroxyalkyl or C 1-3 alkyl-guanidino, wherein the alpha carbon in each naturally or non-naturally occurring amino acid can be further substituted with a methyl group, and the terminal moiety is selected from C(O)OH, C(O)O-C 1-6 alkyl or C(O)NH2; each R 4 is selected from O-C 1-8 alkyl, -O-C 1-4 alkyl-phenyl or -O-C 1-4 alkyl-pyridinyl, each of which is optionally substituted with 1-3 R 4a groups.

[0080] In some embodiments, the compound of Formula (II) is one wherein R 1 is H, halogen, CN or C 1-4 alkyl.

[0081] In some embodiments, including any one of the above mentioned embodiments, further embodiments include compounds of Formula (I) or (II), wherein each R 3 and R 3’ is independently selected from the group consisting of:

[0082]

[0083] In some embodiments of each of Formula (I) and (II), and the above further selected embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from those compounds having ++ or +++ activity in Table 1.

[0084] In addition to the compounds provided above, pharmaceutically acceptable salts of these compounds are also provided. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of salts of ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine diamine, diethylaminoethanol, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, dopamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, amebutol, hydrochloric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of salts of ammonium, calcium, magnesium, potassium, sodium, hydrochloric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, acetic acid, propionic acid, isobutyric acid, propionic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is a sodium salt or a hydrochloric acid salt.

[0085] In addition to salt forms, the present application provides compounds which are in a prodrug form. Prodrugs of the compounds of the present application are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein. Additionally, prodrugs can be converted by chemical or biochemical methods into the compounds of the present application. For example, where a prodrug is in the form of a transdermal patch reservoir, the prodrug can be slowly converted into the compound of the present application as the patch is worn on the skin.

[0086] Esters can serve as prodrugs of the corresponding carboxylic acid. 1-10 Alkyl esters or C 1-10 Haloalkyl esters can serve as prodrugs of the corresponding carboxylic acid. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

[0087] Pharmaceutical compositions

[0088] In addition to the compounds provided herein, compositions of these compounds generally include a pharmaceutical carrier or diluent.

[0089] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0090] In another embodiment, a pharmaceutical composition is provided, the composition comprising a compound described herein, including a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0091] 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 antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, anti-hormonal agents, antifibrotic agents, radiotherapy, radiotherapeutic agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents is an antagonist of a chemokine and / or a chemokine receptor, 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 and / or chemokine receptor antagonists are known in the art and described in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 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, WO2006 / 076644, WO2008 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092.Chemokine and / or chemokine receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0092] Pharmaceutical compositions for administration of the compounds of the present application can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical compositions of the present application can contain a therapeutically effective amount of the active ingredient, in combination with a suitable amount of carrier so as to provide the form for the intended treatment.

[0093] The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, pastilles, gels, gums, chewing tablets, effervescent powders or tablets, and the like. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets can contain the active ingredient in admixture with one or more excipients which are nontoxic and pharmaceutically acceptable. These excipients can be inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, dextrose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn 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. Tablets can be uncoated or they can be coated by known techniques so as to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Tablets of the application can be coated by known techniques including

[0094] Oral formulations can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Moreover, a sustained release formulation, e.g., a solution or suspension, can be provided by utilizing, for example, a slow-release matrix for the formulation. Alternatively, a sustained release formulation can be provided by encapsulating the active ingredient in a slow-release formulation, for example, a wax.

[0095] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, sodium

[0096] 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. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0097] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition thereto of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0098] The pharmaceutical compositions of this application can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive or peanut oil, or a mineral oil, such as liquid paraffin or a mixture of any of these. Suitable emulsifying agents can be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean or lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate. These emulsions can also contain sweetening and flavoring agents.

[0099] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring or coloring agents. Oral fluids can be prepared with a binder and a vehicle. They can also contain certain active ingredients such as a cyclodextrin, a polyethylene glycol, and a hydroxypropylmethyl cellulose.

[0100] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known art using suitable dispersing or wetting agents and suspending agents described supra. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0101] The compounds of the present application can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered through ocular administration by way of solution or ointment. Further, transdermal delivery of the compounds can be accomplished by means of iontophoresis and the like. Topical applications include creams, ointments, gels, solutions or suspensions containing the compounds of the present application. Topical use as used herein also includes the use of mouth washes and mouth rinses.

[0102] The compounds of the present application can also be conjugated to a carrier, wherein the carrier is a polymer suitable for targeting a drug carrier. These polymers can include vinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyoxyethylene-polylysine substituted with palmitoyl residues. In addition, the compounds of the present application can be conjugated to a carrier, wherein the carrier is a biodegradable polymer that can aid in achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, copolymer of polylactic and polyglycolic acid, polysilalkyl lactone, polyhydroxybutyric acid, polyether ester, polyacetal, polydihydropyran, polycyanoacrylate, and cross-linked or amphipathic block hydrogels. The polymer and semi-permeable polymer matrices can form shaped articles such as valves, stents, tubing, prostheses, and the like. In one embodiment of the present application, the compounds of the present application are conjugated to a polymer or semi-permeable polymer matrix formed into a stent or stent graft device.

[0103] Methods of treating diseases and disorders

[0104] The compounds described herein can be used as immunomodulators. The compounds described herein can be used as agonists, antagonists, partial agonists, inverse agonists, and inhibitors of PD-1 and / or PD-L1 in various in vitro and in vivo settings. In some embodiments, the compounds of the present application can be used as inhibitors of the PD-1 / PD-L1 protein-protein interaction. In some embodiments, the compounds of the present application can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present application can be used as inhibitors of the CD80 / PD-L1 protein-protein interaction. In some embodiments, the compounds of the present application can be used to inhibit the interaction between PD-1 and PD-L1 and / or PD-1 and CD80 and / or PD-1 and PD-L2 in vitro or in vivo. In some embodiments, the compounds of the present application can be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of the present application can be inhibitors of the PD-1 / PD-L1 protein-protein interaction and inhibitors of VISTA and / or TIM-3. In some embodiments, the compounds can be inhibitors of CTLA-4 and / or BTLA and / or LAG-3 and / or KLRG-1 and / or 2B4 and / or CD160 and / or HVEM and / or CD48 and / or E-cadherin and / or MHC-II and / or Semaphorin-9 and / or CD86 and / or PD-L2 and / or VISTA and / or tim3 and / or CD80 in addition to being inhibitors of the PD-1 / PD-L1 protein-protein interaction.

[0105] The compounds of the application can be contacted with receptors with which they interact in aqueous solution and under other conditions suitable for binding of the ligand to the receptor. The receptors can be present in suspension (e.g., in isolated membrane or cell preparations), in cultured or isolated cells, or in tissues or organs.

[0106] It is preferred that the compounds be contacted with receptors in amounts sufficient to inhibit PD-1 / PD-L1 binding in vitro, e.g., as determined using an ELISA. The receptors can be present in solution or suspension, in a cultured or isolated cell preparation, or in a patient.

[0107] In some embodiments, the compounds of the application are beneficial in restoring and enhancing T cell activation. In some embodiments, the compounds of the application are beneficial in increasing the immune response in a patient. In some embodiments, the compounds of the application are beneficial in treating, preventing, or ameliorating the progression of a disease or condition in a variety of disease areas, such as cancer or infectious disease.

[0108] In some embodiments, the compounds of the application are useful in treating a patient having a disease that is responsive to modulation of PD-1 / PD-L1 protein interactions.

[0109] In some embodiments, a method of modulating a PD-1 signaling pathway-mediated immune response in a subject is provided, comprising administering to the subject a therapeutically effective amount of a compound of the application, including a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, a method of increasing, stimulating, modulating, and / or augmenting an immune response in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the application, including a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, a method of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the application, including a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, a method of treating a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present application, including a compound represented by Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a composition containing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the subject has a disease or disorder selected from the group consisting of infectious diseases, bacterial infectious diseases, viral infectious diseases, fungal infectious diseases, solid tumors, hematological malignancies, immune diseases, inflammatory diseases, and cancer. In some embodiments, the disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, anti-castration prostate cancer, chronic myelogenous leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, biliary tract tumor, basal cell carcinoma, thymic tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, neural tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous small cell carcinoma (NSCLC), colorectal cancer, ovarian cancer, stomach cancer, liver cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, head or neck cancer of squamous cell carcinoma of the head and neck, gastrointestinal tract, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, neuroendocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis cancer, central nervous system tumor, tumor angiogenesis, spinal column tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, hyperplasia, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0114] In some embodiments, the subject is further administered a therapeutically 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: an antibacterial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an anti-hormonal agent, an antifibrotic agent, a radiation agent, a radiotherapeutic agent, an antitumor agent, and an antiproliferative agent. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokine and / or chemoattractant receptors, 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 and / or chemoattractant receptor antagonists are known in the art and described, for example, in WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815, WO 2010 / 030815, WO 2010 / 075257, WO 2011 / 163640, WO 2010 / 054006, WO 2010 / 051561, WO 2011 / 035332, WO 2013 / 082490, WO 2013 / 082429, WO 2014 / 085490, WO 2014 / 100735, WO 2014 / 089495, WO 2015 / 084842, WO 2016 / 187393, WO 2017 / 127409, WO 2017 / 087607, WO 2017 / 087610, WO 2017 / 176620, WO 2018 / 222598, WO 2018 / 222601, WO 2013 / 130811, WO 2006 / 076644, WO 2008 / 008431, WO 2009 / 038847, WO 2008 / 008375, WO 2008 / 008374, WO 2008 / 010934, WO 2009 / 009740, WO 2005 / 112925, WO 2005 / 112916, WO 2005 / 113513, WO 2004 / 085384, WO 2004 / 046092.Chemokine and / or chemoattractant receptor antagonists 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.

[0115] In some embodiments, the compounds of the present application can also be used to inhibit infectious diseases. In some embodiments, the infectious diseases include, but are not limited to, HIV, influenza, herpes, flagellate, malaria, leishmaniasis, hepatitis A, B, and C viruses, herpes viruses (such as VZV, HSV-I, HAV-6, HSV-II, CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, soft virus, poliovirus, rabies virus, JC virus, arboviral encephalitis virus, chlamydia, rickettsia, mycobacterium, staphylococcus, streptococcus, pneumococcus, meningococcus and diplococcus, klebsiella, proteus, serratia, pseudomonas, escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulinum, anthrax, plague, leptospira, lyme disease bacteria, pathogenic fungal candida (c. albicans, c. krusei, c. glabrata, c. tropicalis, etc.), cryptococcus neoformans, aspergillus (a. fumigatus, a. niger, etc.), mucorales (mucor, aspergillus flavus, rhizopus, etc.), sporothrix schenckii, blastomyces dermatitidis, babesia microfi, plasmodium vivax, theileria parva, trypanosoma brucei, trypanosoma cruzi, babesia divergens, toxoplasma gondii, and / or brugia malayi.

[0116] In some embodiments, the compounds of the present application can be used to inhibit HIV infection, delay progression of AIDS, deplete the HIV reservoir, or reduce the severity of symptoms of HIV infection and AIDS.

[0117] The compounds of the present application can be used for the treatment of cancer and precancerous lesions in a subject.

[0118] Generally, the methods of treatment described herein comprise administering to a patient an effective amount of one or more of the compounds provided herein. Suitable patients include those suffering from or susceptible to a condition or disease identified herein. Typical patients for treatment described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated companion animals (e.g., dogs, cats, horses, etc.) or livestock (e.g., cows, pigs, sheep, etc.).

[0119] Generally, the methods of treatment provided herein comprise administering to a patient an effective amount of one or more of the compounds provided herein. In preferred embodiments, the compounds are preferably administered to a patient (e.g., a human) intravenously, orally, or topically. An effective amount can be an amount sufficient to modulate PD-1 / PD-L1 interaction and / or to reduce symptoms present in a patient. Preferably, the amount administered is sufficient to produce a sufficiently high plasma concentration of the compound (or an active metabolite thereof, if the pharmaceutical compound is a prodrug) to adequately modulate PD-1 / PD-L1 interaction. The treatment regimen can vary depending on the compound used and the particular condition being treated; for most indications, four or fewer times per day is preferred. In general, a dosage regimen of two times per day is more desirable, especially one time per day. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease being treated, and the judgment of the prescribing physician. In general, the use of the minimum effective dose promotes greater patient compliance and reduces the likelihood of adverse side effects. The effectiveness of the treatment can generally be monitored using medical or veterinary standards appropriate for the disease being treated or prevented.

[0120] Combination

[0121] Concomitant medications including the compounds of the present application and other drugs can be administered either as a combined preparation, where both components are included in a single formulation, or as separate formulations. Separate formulations include simultaneous administration and administration at different times. In the case of administration at different times, the compound of the present application can be administered first, or the other drug can be administered first. The methods of administration of the different drugs can be the same or different.

[0122] The dose of other drugs can be appropriately selected according to the dose used in clinical use. The compound of the present application and other drugs can be combined in a ratio appropriate to the age and body weight of the subject to be administered, the administration method, the administration time, the disorder to be treated, the symptoms, and combinations thereof. For example, the quality of the compound of the present application can be 1 unit, and the quality of another drug can be used between 0.01 and 100 units. Another drug can be two or more arbitrary drugs combined in an appropriate ratio.

[0123] The compound of the present application can be used in combination with one or more therapeutic agents, such as antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents. These therapeutic agents can be in the form of a compound, an antibody, a polypeptide, or a polynucleotide.

[0124] The compound described herein can be used in combination with one or more therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins such as Fab derivatives), antibody drug conjugates (ADCs), viruses, oncolytic viruses, gene modification or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, or any combination thereof.

[0125] The class of chemotherapeutic agents includes alkylating agents, nitrosourea agents, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormonal agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents, and other anticancer drugs.

[0126] The compound of the present application can be used simultaneously or in combination in a mixture with cancer treatment aids such as drugs for treating leukopenia (neutropenia), drugs for treating thrombocytopenia, drugs for stopping vomiting, and drugs for cancer pain intervention.

[0127] The compound of the present application can be used in combination with a kinase inhibitor.

[0128] In one embodiment, the compounds of the application can be used simultaneously or in combination with other immunomodulatory and / or potentiating agents. Immunomodulatory agents include various cytokines, vaccines, and adjuvants. These cytokines, vaccines, and adjuvants that stimulate an immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3, IL-12, Poly(I:C), and CPG. Potentiating agents include cyclophosphamide and analogs of cyclophosphamide, anti-tgf and imatinib (Gleevac), mitotic inhibitors such as paclitaxel, sunitinib (Sutent), or other anti-angiogenic drugs, aromatase inhibitors such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0129] In some embodiments, the compounds described herein can be used in combination with one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5, or one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In certain embodiments, the modulator is an antagonist.

[0130] In some embodiments, the compounds described herein can be used or combined with one or more chemokines and / or chemoattractant receptor antagonists described in, for example, WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815, WO 2010 / 030815, WO 2010 / 075257, WO 2011 / 163640, WO 2010 / 054006, WO 2010 / 051561, WO 2011 / 035332, WO 2013 / 082490, WO 2013 / 082429, WO 2014 / 085490, WO 2014 / 100735, WO 2014 / 089495, WO 2015 / 084842, WO 2016 / 187393, WO 2017 / 127409, WO 2017 / 087607, WO 2017 / 087610, WO 2017 / 176620, WO 2018 / 222598, WO 2018 / 222601, WO 2013 / 130811, WO 2006 / 076644, WO 2008 / 008431, WO 2009 / 038847, WO 2008 / 008375, WO 2008 / 008374, WO 2008 / 010934, WO 2009 / 009740, WO 2005 / 112925, WO 2005 / 112916, WO 2005 / 113513, WO 2004 / 085384, WO 2004 / 046092. Useful chemokines and / or chemoattractant receptor antagonists described herein also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0131] Dose

[0132] Dosage levels of about 0.1 mg to about 140 mg per kilogram of body weight per day can be used for the treatment or prevention of disorders involving PD-1 / PD-L1 interaction (about 0.5 mg to about 7 g per day for an adult human patient). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A unit dosage form will generally contain between about 1 milligram and 500 milligrams of an active ingredient. For oral, transdermal, intravenous or subcutaneous administration to an adult human, an amount sufficient to achieve levels between 5 ng (nanogram) / mL and 10 μg (microgram) / mL of serum, more preferably 20 ng / mL to 1 μg / mL, and most preferably 50 ng / mL to 200 ng / mL of serum is preferred. For direct injection into the synovial membrane (for the treatment of arthritis), an amount sufficient to achieve a local concentration of about 1 micromolar is preferred.

[0133] The frequency of dosage can also vary according to the compound used and the particular disease treated. However, for the majority of disease states, a dosage regime of 4 times per day, 3 times per day or less is preferred, with a dosage regime of once per day or twice per day being especially preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (for example, other drugs being administered to the patient), the severity of the particular disease being treated, and other factors known to those skilled in the art.

[0134] In another aspect of the application, the compounds of the application can be used in a variety of non-pharmaceutical in vitro and in vivo applications. The compounds of the application can also be used as positive controls in assays of PD-1 / PD-L1 interaction activity, i.e., as a standard for determining the ability of a candidate agent to bind to PD-1 and / or PD-L1, or as a radiotracer for positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0135] Kits containing a compound or pharmaceutically acceptable salt of the application, and instructions for use, are within the scope of the application. The kits can further comprise at least one additional reagent. The kits will typically contain a label indicating that the contents are used for the indicated purposes. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit. Examples

[0136] The following examples illustrate various methods of preparing the compounds described herein, including compounds of Formula (I) or (II). The following examples are provided to illustrate, not limit, the claimed invention.

[0137] The reagents and solvents used below were obtained from commercial sources, such as Aldrich Chemical Company (Milwaukee, Wisconsin, USA). Nuclear magnetic resonance spectra were recorded on a Varian Mercury 400 MHz nuclear magnetic resonance spectrometer. Significant peaks are provided relative to TMS and are listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and proton number. Mass spectral results are expressed in the form of mass over charge ratio. In the examples, the mass spectral results are single m / z values for the m+H (or m-H as noted) ion containing the most common atomic isotope. In all cases, the isotope pattern was consistent with the expected formula. Electrospray ionization (ESI) mass spectral analysis was performed on a Hewlett Packard MSD electrospray mass spectrometer using HP 1100 high performance liquid chromatography. Normally, the analyte was dissolved in 0.1 mg / mL methanol or CH3CN and 1 microliter of the solvent was injected into the mass spectrometer along with the delivery solvent, and the mass spectrometer scanned from 100 to 1000 Daltons. All compounds were analyzed in either the positive or negative ESI mode using acetonitrile / water and 1% formic acid as the delivery solvent.

[0138] The following abbreviations are used in the examples and throughout the specification: TLC represents thin layer chromatography

[0139] The compounds described below within the scope of the present invention can be synthesized using various reactions known to those skilled in the art. Those skilled in the art will also recognize that alternative methods can be employed to synthesize the target compounds of the present invention and that the methods described herein are not exhaustive but do provide widely applicable and practical routes to synthesize the compounds of interest.

[0140] Certain molecules described in this patent can exist in different enantiomeric and diastereomeric forms, and all such variations of the compounds are claimed unless a particular enantiomer is specified.

[0141] The experimental procedures for the synthesis of key compounds are described in detail herein and the molecules are described by physical data and the structures associated therewith.

[0142] Those skilled in the art will also recognize that acids and bases are frequently used in the standard work-up procedures of organic chemistry. In the experimental procedures described herein, salts are sometimes produced if the parent compound has the necessary inherent acidity or basicity.

[0143] Example 1: Synthesis of (2S,2'S)-2,2'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H- [4,4'-biindene]-1,1'-diyl)bis(oxy)bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1- phenylene)bis(methylene)bis(azanediyl)bis(3-hydroxypropanoic acid)

[0144]

[0145] A solution of (S)-5-((4-chloro-2-formyl-5-((4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)methyl)nicotinonitrile (350 mg, 0.66 mmol), 5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine- 3-carbonitrile (320 mg, 0.66 mmol) and 2M aqueous K2CO3(1.0 mL, 2.0 mmol) in dioxane (13 ml) was degassed with nitrogen for 30 min, followed by the addition of 1,1’- bis(diphenylphosphino)ferrocene]-dichloropalladium(ll) complex with dichloromethane (110 mg, 0.13 mmol). After a further 10 min degassing, the solution was heated to 90 °C and stirred at this temperature for 4 h. Water (20 mL) was then added to the reaction mixture and the mixture was extracted with 2:1 chloroform:isopropanol (20 mL x 3). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexanes prepared 50% ethyl acetate to 100% hexanes) to give 5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'- diyl)bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy)bis(methylene) dinitrile.

[0146] Step b: A solution of 5,5'-((((((lS, 1'S)-2,2',3,3'-tetrahydro-lH, 1'H- [4,4'-biindene]-l,r-diyl)bis(oxy))bis(4-chloro-6-formyl-3,l-phenylene))bis(oxy) bis(methylene)dimalononitrile (100 mg, 0.124 mmol) and L-serine (130 mg, 1.24 mmol) in DMF (4 mL) was stirred for 1 h, followed by the addition of sodium triacetoxyborohydride (0.72 g, 3.4 mmol) in small portions over 10 min. The reaction mixture was stirred at room temperature overnight. Most of the DMF was removed in vacuo and the crude was purified with reverse phase preparative HPLC (CH3CN-H2O + 0.1% NH4CO3H) to give ((2S, 2'S)-2,2'-((((((lS, 1'S)-2,2',3,3'-tetrahydro-lH, 1'H- [4,4'-biindene]-l,r-diyl)bis(oxy))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)- 4, 1 -phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid). MS: (ES) m / z C 52 H 46 Cl2N6O 10 [M+H]+calcd 985.3, found 985.7. 1H NMR (400 MHz, Methanol-d4) δ 9.02 - 8.99 (m, 2H), 8.91 (d J = 1.9 Hz, 2H), 8.46 (t, J = 1.9 Hz, 2H), 7.51 (s, 2H), 7.36 - 7.29 (m, 4H), 7.30 - 7.24 (m, 2H), 7.08 (s, 2H), 6.08 - 5.94 (m, 2H), 5.41 (s, 4H), 4.61 (s, 4H), 4.37 (d J = 13.1 Hz, 2H), 4.25 (d J = 13.0 Hz, 2H), 3.99 (dd, J = 11.9, 3.9 Hz, 2H), 3.84 (dd, J = 11.8, 7.1 Hz, 2H), 3.55 (dd, J = 7.0, 3.9 Hz, 2H), 3.09 - 2.93 (m, 2H), 2.83 - 2.69 (m, 2H), 2.60 - 2.44 (m, 2H), 2.18 - 2.04 (m, 2H).

[0147] Bioexample: Enzyme-Linked Immunosorbent Assay (ELISA)

[0148] A 96 well plate was coated with 1 μg / mL of human PD-L1 (obtained from R&D) in PBS overnight at 4°C. The wells were then blocked with 0.05% TWEEN-20 and 2% BSA (w / v) in PBS for 1 hour at 37°C. After washing the plate 3 times with PBS / 0.05% TWEEN-20, the compounds were diluted 1:5 in dilution medium and added to the ELISA medium. Human PD-1 and biotin 0.3 μg / mL (ACRO Biosystems) were added and incubated for 1 hour at 37°C, then the plate was washed 3 times with PBS / 0.05% TWEEN-20. A second blocking was performed with 2% BSA (w / v) / 0.05% TWEEN-20 in PBS for 10 minutes at 37°C, and the plate was washed 3 times with PBS / 0.05% TWEEN-20. Streptavidin-HRP was added for 1 hour at 37°C, then the plate was washed 3 times with PBS / 0.05% TWEEN-20. TMB substrate was added and the reaction was allowed to proceed for 20 min at 37°C. Stop solution (2N H2SO4 in water) was added. The absorbance was read at 450 nm with a microplate spectrophotometer. The results are shown in Table 1: IC50 values are as follows: from 100 to 10000 nM (+); less than 100 nm (++)

[0149] Table 1

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] The compounds of Table 1 were prepared using synthetic methods analogous to those described in Example 1.

[0160] Particular embodiments of the application are described in the detailed description of the application. Variations of embodiments of the application that are not described can be apparent to those of ordinary skill in the art and the scope of the present application is not intended to be limited to the particulars of the application described. Accordingly, a variety of alternatives and equivalents are possible. Accordingly, the application is intended to embrace all such alternatives and equivalents as permitted by the applicable law. In addition, any combination of the above described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise obvious to one of ordinary skill in the art.

[0161] All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Claims

1. A compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein Y is O, and Y' is selected from the group consisting of: O and NH; each n is 0; R 1 is C1alkyl; each R 2a and R 2a’ is independently selected from the group consisting of H, halogen, -R a and -OR b wherein each R b is C 1-2 1-6 alkyl and each R a is C 1-2 1-6 alkyl; each R 2b , R 2c , R 2b’ , and R 2c’ is H; R 3 and R 3’ are each independently selected from the group consisting of: -NR d R e ; wherein R d selected from: H and C 1-4 alkyl; R e selected from: H, C 1-4 alkyl, -X 2 -SO3R g ; wherein said alkyl moiety is optionally further substituted with 1 to 3 substituents selected from OH, COOH and COO-C1alkyl; X 2 is C 1-6 alkylene, each R is independently selected from hydrogen, C1-6alkyl optionally substituted with 1-2 NH2, C3-6cycloalkyl optionally substituted with 1-2 NH2, and phenyl optionally substituted with 1-2 NH2; g 1-8 alkyl;​ each R is independently selected from the group consisting of: -OH and C f is independently selected from the group consisting of: -OH and C 1-8 alkyl; each R 4 and R 4’ is O-C 1-8 alkyl, wherein each group is optionally substituted with 1-3 R 4a ; Each R 4a For -CN, each m is independently 0 or 1; and R 6a’ is hydrogen; the compound is selected from the group consisting of: R 6b’ is F.

2. The compound of claim 1, wherein each R 2a and R 2a’ is chloro.

3. The compound of claim 1, wherein Each R 3 and R 3’ Select independently from the following groups:

4. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, the compound is optically pure or enriched isomer.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein 6. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. further comprising one or more additional therapeutic agents.

7. The pharmaceutical composition as set forth in claim 6, characterized by the one or more additional therapeutic agents are selected from the group consisting of: an antibacterial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, an anticancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent, a radiotherapeutic agent, and an anti-proliferative agent.

8. The pharmaceutical composition as set forth in claim 7, characterized by 9. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 6-8, in the manufacture of a medicament for modulating a PD-1 signaling pathway-mediated immune response in a subject.

10. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 6-8, in the manufacture of a medicament for modulating an immune response in a subject in need thereof.

11. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 6-8, in the manufacture of a medicament for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof.

12. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 6-8, in the manufacture of a medicament for treating a subject having or susceptible to a PD-1 signaling pathway-mediated disease or disorder. the subject has cancer.

13. Use according to any one of claims 9 to 12, characterized in that, the subject has a disease or disorder selected from the group consisting of: an infectious disease, a solid tumor, a hematological malignancy, and an immune disease.

14. Use according to any one of claims 9 to 12, characterized in that, the subject has an inflammatory disease.

15. Use according to any one of claims 9 to 12, characterized in that, the disease or disorder is selected from the group consisting of: prostate cancer, sarcoma, thyroid cancer, a neural tumor, an ovarian tumor, colorectal cancer, gastric cancer, pancreatic cancer, lung cancer, a liver infection, papilloma, leiomyoma, rhabdomyoma, leukemia, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

16. Use as claimed in claim 12, characterised in that, ​ 17. Use as claimed in claim 12, characterised in that, The disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, lymphoma, anti-castration prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sepsis, biliary tract tumor, thymic tumor, parathyroid cancer, uterine cancer, adrenal cancer, colon cancer, Hodgkin's disease, multiple myeloma, myelodysplastic syndrome, mesothelioma, breast cancer, squamous non-small cell lung cancer, non-squamous non-small cell cancer, ovarian cancer, pancreatic ductal adenocarcinoma, head and neck cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, influenza, skin cancer, rectal cancer, anal cancer, vaginal cancer, vulvar cancer, small bowel cancer, neuroendocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, tumor angiogenesis, spinal column tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, hyperplasia, seminoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma.

18. Use according to any one of claims 9 to 12, characterized in that The medicament further comprises a therapeutically effective amount of one or more additional therapeutic agents.

19. The use according to claim 18, characterized in that, The one or more additional therapeutic agents are selected from the group consisting of antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulators, anticancer agents, antiangiogenic agents, immunotherapeutic agents, anti-hormonal agents, antifibrotic agents, radiotherapeutic agents, and antiproliferative agents.

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