Indan as a PD-L1 inhibitor

Abstract

providing a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or prodrug or bioisostere thereof; JPEG2022539830000022.jpg87153 In the formula, 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

[Technical Field]

[0001] This application claims the benefit under U.S. Patent Law of U.S. Provisional Application No. 62 / 872,541, filed July 10, 2019, which is incorporated herein by reference in its entirety. STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] Not applicable Reference to a "Sequence Listing," a Table, or a Computer Program Listing Appendices submitted on a Compact Disc

[0003] Not applicable [Background technology]

[0004] Programmed cell death protein-1 (PD-1) is a member of the CD28 superfamily that transmits negative signals through interaction with its two ligands, PD-L1 and PD-L2. PD-1 and its ligands are widely expressed and exert a broad range of immunoregulatory roles in T cell activation and tolerance. PD-1 and its ligands have been implicated in attenuating infection and tumor immunity, promoting chronic infection and tumor progression.

[0005] Modulation of the PD-1 pathway has therapeutic potential for various human diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011); 350:17-37). Blockade of the PD-1 pathway has become a focus of attention in cancer treatment. Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent T cell downregulation and promote immune responses against cancer. Several PD-1 pathway inhibitors have shown potent activity in various stages of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214-223).

[0006] Agents that block the interaction of PD-L1 with either PD-1 or CD80 are desirable. Several antibodies have been developed and commercialized. Several patent applications have been published disclosing non-peptide small molecules (Bristol-Myers Squibb applications WO2015 / 160641, WO2015 / 034820, WO2017 / 066227, and WO2018 / 009505; Aurigene applications WO2015 / 033299 and WO2015 / 033301; Incyte applications WO2017 / 070089, US2017 / 0145025, WO2017 / 106634). (See, for example, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899, and WO2018 / 013789; Maxinovel application WO2018 / 006795; and ChemoCentryx application WO2018 / 005374). However, there remains a need for novel compounds, such as small molecules as PD-L1 inhibitors, that can exhibit beneficial characteristics in terms of oral bioavailability, stability, bioavailability, therapeutic index, and toxicity. Summary of the Invention

[0007] In one aspect, the present disclosure provides a compound having formula (I) or formula (II), or a pharmaceutically acceptable salt, or a prodrug or bioisostere thereof: [ka] [ka] In the formula, R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , R 2a’ , R 2b’ , R2c’ , R 3’ , R 4’ , R 5’ , R 6a’ , R 6b’ , Y, Y', and subscripts m and n are as defined herein.

[0008] In addition to the compounds provided herein, the disclosure further provides pharmaceutical compositions comprising one or more of these compounds, as well as methods relating to the preparation and use of such compounds. In some embodiments, the compounds are used in therapeutic methods to treat diseases associated with the PD-1 / PD-L1 pathway. [Brief explanation of the drawings]

[0009] Not applicable DETAILED DESCRIPTION OF THE INVENTION

[0010] Abbreviations and Definitions As used herein, the terms "a," "an," or "the" include aspects having one element as well as aspects having multiple elements. 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 a plurality of such cells, reference to "the agent" includes one or more agents known to those skilled in the art, and so forth.

[0011] The terms "about" and "approximately" generally refer to an acceptable degree of error for the measured quantity, taking into account the nature or precision of the measurement. Typical examples of the degree of error are within 20%, preferably within 10%, and more preferably within 5% of a given numerical value or numerical range. Alternatively, particularly in biological systems, the terms "about" and "approximately" may refer to a numerical value within one order of magnitude, preferably within 5 times, and more preferably within 2 times of a given numerical value. Numerical values ​​described herein are approximate unless otherwise specified, and the terms "about" or "approximately" mean that they may be inferred unless expressly stated.

[0012] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 (The symbol "(-)" means 1 to 8 carbons.) 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 unsaturated alkyl groups having one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups 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 the higher homologs and isomers.

[0013] The term "cycloalkyl" refers to a group having the indicated number of ring atoms (e.g., C 3-6 "Cycloalkyl" refers to a hydrocarbon ring that is fully saturated or has only one double bond between the ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo"2.2.1"heptane, bicyclo"2.2.2"octane, etc. The bicyclic or polycyclic rings may be fused, bridged, spiro, or combinations thereof.

[0014] The terms "heterocycloalkyl" or "heterocyclyl" refer to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings may be fused, bridged, spiro-, or combinations thereof. For example, "C 4-12 The term "heterocyclyl" is understood to refer to groups having 4 to 12 ring members, at least one of which 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, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0015] The term "alkylene," by itself or as part of another substituent, refers to a divalent radical derived from an alkane, as exemplified by -CHCHCHCH-. Alkylene groups may be linear or branched. Examples of the latter are -CHC(CH)CH-, -CHC(CH)-, or -CH(CH)CHCH-. Typically, alkyl (or alkylene) groups have 1 to 12 carbon atoms, with those groups having 8 or fewer carbon atoms being preferred in this disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0016] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to these alkyl groups attached to the remainder 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 combine to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Thus, -NR a R b A group designated as: is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0017] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0018] 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 has been replaced with a hydroxy group. With respect to alkyl groups, hydroxyalkyl groups are those having a C 1-6 Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxy is in the 1- or 2-position), hydroxypropyl (wherein the hydroxy is in the 1-, 2-, or 3-position), and 2,3-dihydroxypropyl.

[0019] The term "aryl," unless otherwise specified, means a polyvalent unsaturated hydrocarbon group, typically aromatic, which may be a single ring or multiple rings (up to three rings) that are fused or covalently linked to each other.

[0020] The term "heteroaryl" refers to a 5- to 10-membered aromatic ring having 1 to 5 heteroatom ring vertices, each of which is selected from N, O, and S, with the nitrogen and sulfur atoms optionally oxidized and the nitrogen atom optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. 5-10 The term "heteroaryl" is understood to refer to a heteroaryl moiety having 5 to 10 ring members, at least one of which is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, and indolyl. Examples include lysinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0021] When any of the above terms (e.g., "alkyl," "aryl," and "heteroaryl") are described as "substituted" without further indication of the substituent, the substitution forms of the specified group are as provided below.

[0022] Substituents for alkyl groups (including groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) range in number from 0 to (2m'+1) and include: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R" R', R" and R"' may each independently be a variety of groups selected from hydrogen, unsubstituted C(O)R', -NR'C(NH)=NH, -NR'C(NH)=NH, -NH-C(NH)=NR', -S(O)R', -S(O)R', -S(O)NR'R", -NR'S(O)R", -CN, and -NO, where m' is the total number of carbon atoms in the group. R', R" and R"' may each independently be hydrogen, unsubstituted C(O)R', -NR'C(NH)=NH, -NH-C(NH)=NR', -S(O)R', -S(O)NR'R", -NR'S(O)R", -CN, and -NO. 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted aryl-C 1-4 refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant 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 both substituents on the carbons closest to the point of attachment of the group are replaced with the substituent =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0023] Similarly, substituents on the aryl and heteroaryl groups vary and generally include, in numbers ranging from zero to the total number of open valences on the aromatic ring system, -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'- and R', R", and R"' are selected from hydrogen, 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)alkoxy, and perfluoro(C1-C4)alkyl, wherein R', R", and R"' are 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 and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of 1 to 4 carbon atoms.

[0024] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a group of the formula: -TC(O)-(CH) q Each of the aryl or heteroaryl rings may optionally be substituted with a substituent of the formula -U-, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer of 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula: -A-(CH2) rA and B may be substituted with a substituent of the formula -B-, where 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 with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula: -(CH2) s -X-(CH2) t where s and t are independently integers of 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 hydrogen or an unsubstituted C 1-6 alkyl.

[0025] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0026] The present disclosure further relates to prodrugs and bioisosteres thereof. Suitable bioisosteres include, for example, carboxylic acid substitutes (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, and acidic heterocyclic groups such as tetrazole). Suitable prodrugs contain conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide compounds of Formula I.

[0027] The terms "patient" and "subject" include primates (especially humans), domesticated companion animals (such as dogs, cats, and horses), and farm animals (such as cows, pigs, and sheep).

[0028] As used herein, the term "treating" or "treatment" includes both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., preventing, delaying, or reducing the severity of symptoms before the onset of symptoms) or therapeutic (i.e., reducing the severity and / or duration of symptoms after the onset of symptoms).

[0029] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functionality, the neutral form of the compound can be contacted with a sufficient amount of the desired base, either neat or in a suitable inert solvent, to obtain a base addition salt. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines 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, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc., cyclic amines, naturally occurring amines, etc. When a compound of the present disclosure contains a relatively basic functionality, the neutral form of the compound can be contacted with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, to obtain an acid addition salt. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0030] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent forms of the compounds for the purposes of this disclosure.

[0031] Certain compounds of the present disclosure can exist in non-solvated form and solvated form, including hydrated form.In general, solvated form is equivalent to non-solvated form and is intended to be included in the scope of the present disclosure.Certain compounds of the present disclosure may exist in multiple crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use envisioned by the present disclosure and are intended to be included in the scope of the present disclosure.

[0032] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereoisomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical diagram is shown, it is meant to refer to a compound in which one of the isomers is present and substantially free of the other isomer. "Substantially free" of another isomer indicates that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or even 95 / 5 or greater. In some embodiments, one of the isomers is present in an amount of at least 99%.

[0033] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure. For example, a compound can be prepared by substituting any number of hydrogen atoms with deuterium ( 2 The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. Unnatural proportions of an isotope may be defined as a range from the amount found in nature to the amount consisting of 100% of the atom in question. For example, the compounds may be prepared so that they are substituted with tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes such as C) may be incorporated. Such isotopic variations can provide additional utility to the variations described elsewhere in this application. For example, isotopic variants of the disclosed compounds can find additional utility, for example, but not limited to, as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the disclosed compounds can have altered pharmacokinetic and pharmacodynamic properties that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of the disclosed compounds, whether radioactive or not, are intended to be included within the scope of this disclosure. compound

[0034] In one aspect, the disclosure provides a compound having formula (I) or formula (II), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: [ka] [ka] During the ceremony, Y and Y' are O, NH, and N(C 1-4 alkyl); R 1 H, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, and -OC 1-4 independently selected from the group consisting of haloalkyl; R 2a , R 2b , R 2c , R 2a’ , R 2b’ , and R 2c’ are H, halogen, -CN, and -R, respectively. 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 and each X is independently selected from the group consisting of 1 is C 1-4 alkylene; R b and R c Each of these is hydrogen, C 1-8 Alkyl, and C 1-8haloalkyl, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, and S, and optionally substituted with oxo; each R a is C 1-8 Alkyl, C 2-8 Alkenyl, and C 1-8 independently selected from the group consisting of haloalkyl; R 3 and R 3’ are -NR d R e and 4-12 membered monocyclic, bicyclic, or spirocyclic non-aromatic heterocycles, and optionally 1-6 R 3a is replaced by; R d is H, C 1-8 Haloalkyl, and C 1-8 selected from the group consisting of alkyl; R e -H, -C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 2 -CO2R g , -X 2 -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 , C4-8 Heterocyclyl, -C 4-8 Heterocyclyl-COOR g , -C 4-8 Heterocyclyl-OR g , -X 2 -C 4-8 Heterocyclyl, -C(=O)OX 2 -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 Alkenyl, -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 optionally substituted with COH 2 -(C=O)-NH-X 2 -OR g Selected from;R e The alkyl or alkylene portion of the alkyl group may optionally be OH, COOH, SO2NH2, CONH2, C(O)NHOH, COO-C 1-8 alkyl, and PO3H2; R e C 5-10 Heteroaryl moiety and C 6-10 The aryl moiety may optionally be OH, B(OH), COOH, NH, SONH, CONH, C(O)NHOH, POH, COO-C 1-8 Alkyl, C 1-4 Alkyl, C 1-4 Alkylene-OH, C 1-4Alkylene-SO2NH2, C 1-4 Alkylene CONH2, C 1-4 Alkylene-C(O)NHOH, C 1-4 Alkylene-PO3H2, and C 1-4 alkylene-COOH; R e C 4-8 Heterocyclyl moiety and C 3-10 The cycloalkyl moiety may optionally be one to four R w substituted with a substituent; or R combined with the N to which it is attached e is a monoamino acid, dipeptide, or tripeptide containing natural and unnatural amino acids, the unnatural amino acids being C 2-4 Hydroxyalkyl, C 1-3 Alkylguanidinyl, and C 1-4 alkylheteroaryl, wherein each alpha carbon of the natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal portion of the mono-, di-, or tripeptide is C(O)OH, C(O)OC 1-6 selected from the group consisting of alkyl, C(O)NH2, and PO3H2; Each R 3a is halogen, -CN, oxo, -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 , -NRg R h , -OR g , -S(O)NR 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 R h , -X 2 -CO2R g , -X 2 -CONR g R h , -X 2 -CONHSO2R g and SF5; 2 is C 1-6 Alkylene, and optionally OH, NH, SO, NH, CONH, C(O)NHOH, PO, COO-C 1-8 Further substituted with alkyl or COH, R g and R h Each of these is hydrogen, and in some cases OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 C substituted with 1 to 2 substituents selected from alkyl and COH 1-8 Alkyl, and sometimes OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 C substituted with 1 to 2 substituents selected from alkyl and COH 1-8 haloalkyl, or when attached to the same nitrogen atom, R g and R hcan be combined with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each R f are -OH, each of which can be OH, NH2, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 C optionally substituted with alkyl or COH 1-8 Alkyl, C 2-8 Alkenyl, and C 1-8 independently selected from the group consisting of haloalkyl; Each R w The substituent is 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-POH, OH, COO-C 1-8 independently selected from alkyl, COOH, SO2NH2, CONH2, C(O)NHOH, PO3H2, and oxo; R 4 and R 4’ Each of them may have 1 to 5 R 4a Replaced by OC 1-8 Alkyl, OC 1-8 Haloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -OC 1-4 Alkyl-C 4-7 Heterocycloalkyl, -OC 1-4 Alkyl-C 6-10 Aryl, and -OC 1-4 Alkyl-C 5-10 independently selected from the group consisting of heteroaryl; Each R 4a is halogen, -CN, -R i , -CO2R j , -CONR j R k , -C(O)Rj , -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 independently selected from the group consisting of: Each R i is C 1-8 Alkyl, C 2-8 Alkenyl, and C 1-8 haloalkyl; optionally, two R 4a When the substituents are on adjacent atoms, they combine to form a 5- or 6-membered fused carbocyclic or heterocyclic ring, optionally substituted with oxo; R j and R k are hydrogen and 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 5- or 6-membered ring having 0-2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each n is independently 0, 1, 2, or 3; R 5 and R 5’ are halogen, -CN, and -R, respectively. q , -CO2R r , -CONR r R s , -C(O)R r , -NR r R s , and -OR r are independently selected from the group consisting of R r and R s are hydrogen and C 1-4 Alkyl, and C 1-4haloalkyl, or when attached to the same nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each R q is C 1-8 Alkyl and C 1-8 independently selected from the group consisting of haloalkyl; R 6a and R 6a’ are H and C, respectively. 1-4 Alkyl, and C 1-4 independently selected from the group consisting of haloalkyl; each m is independently 0, 1, 2, 3, or 4; R 6b and R 6b’ are F and C, respectively. 1-4 Alkyl, and C 1-4 haloalkyl.

[0035] In one group of embodiments, the compounds provided herein are represented by formula (I):

[0036] In one group of embodiments, the compounds provided herein are represented by formula (II):

[0037] In one group of embodiments, the compounds of formula (I) or formula (II) are those in which Y and Y' are each independently selected from the group consisting of O and NH.

[0038] In one group of embodiments, the compounds of formula (I) or formula (II) are those in which Y and Y' are each O.

[0039] In some embodiments, the compound of Formula (I) or Formula (II) is a compound where each subscript n is 0 or 1. In some embodiments, the compound of Formula (I) or Formula (II) is a compound where each subscript m is 0 or 1. In some embodiments, the compound of Formula (I) or Formula (II) is a compound where each subscript n is 0 or 1 and each subscript m is 0 or 1.

[0040] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 3 and R 3’ Each of these may contain 1 to 4 R 3a and a 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocycle substituted with

[0041] In some embodiments, the compounds of Formula (I) or Formula (II) may each R 3 and R 3’ independently -NR d R e It is a compound in which

[0042] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 3 and R 3’ are each independently -NR d R e and R in combination with the N to which it is attached e is a compound that is a natural amino acid or an unnatural amino acid, wherein the unnatural amino acid is C 2-4 Hydroxyalkyl and C 1-3 alkylguanidinyl, wherein each alpha carbon of the natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal moiety is C(O)OH, C(O)OC 1-6 alkyl, and C(O)NH2.

[0043] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 3 and R 3’are each independently -NR d R e and R in combination with the N to which it is attached e is a natural amino acid or an unnatural amino acid, wherein the unnatural amino acid is C 2-4 The terminal moiety has a hydroxyalkyl α-carbon, and each α-carbon of a natural or unnatural amino acid is optionally further substituted with a methyl group, and is C(O)OH, C(O)OC 1-4 alkyl, and C(O)NH2.

[0044] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 2a , R 2b , R 2c , R 2a’ , R 2b’ and R 2c’ are H, halogen, -CN, and -R, respectively. a , -CO2R b , -CONR b R c , -NR b R c , and -OR b wherein R is a compound independently selected from the group consisting of b and R c are hydrogen and 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 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each R a is C 1-8 Alkyl, C 2-8 Alkenyl, and C 1-8 haloalkyl.

[0045] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 4 and R 4’ are respectively, OC 1-8 Alkyl, OC1-8 Haloalkyl, -OC 1-4 Alkyl-C 6-10 Aryl, and -OC 1-4 Alkyl-C 5-10 heteroaryl, each of which optionally comprises 1 to 5 R 4a It is a compound substituted with

[0046] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 4 and R 4’ are respectively, OC 1-8 Alkyl, -OC 1-4 Alkylphenyl, and -OC 1-4 alkylpyridyl, each of which optionally has 1 to 3 R 4a It is a compound substituted with

[0047] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 2a , R 2b , R 2c , R 2a’ , R 2b ', and R 2c’ are H, halogen, -CN, and -R, respectively. a , -CO2R b , -CONR b R c , -NR b R c , and -OR b wherein R is a compound independently selected from the group consisting of b and R c are hydrogen and 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 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each R a is C 1-8 Alkyl, C 2-8 Alkenyl, and C1-8 haloalkyl; each R 3 is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocyclic ring, and optionally 1-4 R 3a Each R is substituted with 4 is O.C. 1-8 Alkyl, -OC 1-4 Alkylphenyl, and -OC 1-4 alkylpyridyl, each of which optionally has 1 to 3 R 4a is replaced by .

[0048] In some embodiments, the compound of Formula (I) or Formula (II) may comprise R 2a , R 2b , R 2c , R 2a’ , R 2b’ and R 2c’ are H, halogen, -CN, and -R, respectively. a , -CO2R b , -CONR b R c , -NR b R c , and -OR b wherein R is a compound independently selected from the group consisting of b and R c are hydrogen and 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 5- or 6-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O, or S, and optionally substituted with oxo; each R a is C 1-8 Alkyl, C 2-8 Alkenyl, and C 1-8 haloalkyl; each R 3 Ha-NR d R e and R combined with the N to which it is attached e is a natural or unnatural amino acid, and unnatural amino acids are C 2-4Hydroxyalkyl and C 1-3 alkylguanidinyl, wherein each alpha carbon of the natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal moiety is C(O)OH, C(O)OC 1-6 alkyl, and C(O)NH; each R 4 is O.C. 1-8 Alkyl, -OC 1-4 Alkylphenyl, and -OC 1-4 alkylpyridyl, each of which optionally has 1 to 3 R 4a is replaced by .

[0049] In some embodiments, the compound of formula (II) is R 1 is H, halogen, CN, or C 1-4 It is a compound that is alkyl.

[0050] In selected embodiments, including any of the above embodiments, further embodiments include R 3 and R 3’ each comprises a compound of Formula (I) or Formula (II) independently selected from the group consisting of: [ka]

[0051] In some embodiments, for each of Formula (I) and Formula (II), and in further selected embodiments described above, the compound or pharmaceutically acceptable salt thereof is a compound or salt thereof selected from Table 1 having ++ activity or +++ activity.

[0052] In addition to the compounds described above, pharmaceutically acceptable salts of these compounds are also provided. In some embodiments, the pharmaceutically acceptable salts include ammonium, calcium, magnesium, potassium, sodium, zinc, 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, The acid salt is selected from the salts of morpholine, piperazine, piperidine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, alginic acid, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from ammonium, calcium, magnesium, potassium, sodium, hydrochloric acid, carbonate, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, alginic acid, glucuronic acid, and galacturonic acid salts. In some embodiments, the pharmaceutically acceptable salt is a sodium or hydrochloric acid salt.

[0053] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch carrier with a suitable enzyme or chemical reagent.

[0054] Esters may be used as prodrugs of the corresponding carboxylic acids. 1-10 Alkyl ester or C 1-10 Haloalkyl esters may be used as prodrugs of the corresponding carboxylic acids. Esters such as tert-butyl esters, methyl esters, ethyl esters, isopropyl esters, etc. may be used. Pharmaceutical Composition

[0055] In addition to the compounds provided herein, compositions of those compounds typically include a pharmaceutical carrier or diluent.

[0056] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0057] In another embodiment, there is provided a pharmaceutical composition comprising a compound of the present disclosure, including a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0058] 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, antihormonal agents, antifibrotic agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are chemokine and / or chemoattractant receptor antagonists, 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 are described, for example, 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 / 0 No. 82429, No. WO2014 / 085490, No. WO2014 / 100735, No. WO2014 / 089495, No. WO2015 / 084842, No. WO2016 / 187393, No. WO2017 / 127409, WO 2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 2226 No. 01, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, and WO2004 / 046092. Chemokine and / or chemoattractant 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.

[0059] The pharmaceutical composition for administering the compounds of the present disclosure can be conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy and drug delivery.All methods include the step of combining the active ingredient with a carrier that constitutes one or more accessory ingredients.In general, pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.The active compound is contained in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

[0060] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations as described in US2002 / 0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can 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 to provide a pharmaceutically elegant and palatable formulation. Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, 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 cornstarch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be enterically or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0061] Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, polyethylene glycols (PEGs) of various average diameters (e.g., PEG400, PEG4000), and a specific surfactant such as Cremophor or Solutol, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Additionally, emulsions may be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono- or diglycerides, PEG esters, etc.

[0062] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia. Dispersing or wetting agents may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids such as ethylene polyoxystearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0063] Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings such as those mentioned above may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid.

[0064] Dispersible powders and granules suitable for preparing aqueous suspension by adding water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified above.Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0065] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers may be naturally occurring gums such as gum acacia or gum tragacanth, soybeans, naturally occurring phosphatides such as lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.Emulsions may also contain sweeteners and flavorings.

[0066] Syrups and elixirs may be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain thickeners, preservatives, flavorings, and coloring agents. Oral solutions may be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0067] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparation may 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. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, have been used in the preparation of injectables.

[0068] The compounds of the present disclosure may also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol. These compounds may also be administered via ocular delivery using solutions or ointments. Transdermal delivery of the target compounds may also be achieved using iontophoretic patches, etc. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds of the present disclosure are used. As used herein, "topical administration" also includes the use of mouthwashes and gargles.

[0069] The compounds of the present disclosure may also be coupled to carriers that are polymers suitable as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present disclosure may be coupled to carriers that represent a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinkable or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubes, and prostheses. In one embodiment of the present disclosure, the compounds of the present disclosure are coupled to polymer or semipermeable polymer matrices that are formed into stents or stent-graft prostheses. Methods of Treating Diseases and Disorders

[0070] Compounds of the present disclosure may be used as immunomodulatory agents. Compounds of the present disclosure may be used as agonists, antagonists, partial agonists, inverse agonists, or inhibitors of PD-1 and / or PD-L1 in a variety of settings, both in vitro and in vivo. In some embodiments, compounds of the present disclosure may be used as inhibitors of protein-protein interactions between PD-1 / PD-L1 proteins. In some embodiments, compounds of the present disclosure may be used as inhibitors of PD-L1. In some embodiments, compounds of the present disclosure may be used as inhibitors of protein-protein interactions between CD80 / PD-L1 proteins. In some embodiments, compounds of the present disclosure may be used to inhibit the interactions between PD-1 and PD-L1 and / or between PD-1 and CD80 and / or between PD-1 and PD-L2 in vitro or in vivo. In some embodiments, compounds of the present disclosure may be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of the disclosure may be inhibitors of protein-protein interaction between PD-1 / PD-L1 proteins and inhibitors of VISTA and / or TIM-3. In some embodiments, in addition to being inhibitors of protein-protein interaction between PD-1 / PD-L1 proteins, the compounds of the disclosure may also 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 Galectin-9 and / or CD86 and / or PD-L2 and / or VISTA and / or TIM-3 and / or CD80.

[0071] The compounds of the present disclosure may be contacted with the receptors with which they interact in aqueous solution and under conditions suitable for binding of the ligand to the receptor. The receptor may be in suspension (e.g., in an isolated membrane or cell preparation), in cultured or isolated cells, or in a tissue or organ.

[0072] Preferably, the amount of a compound of the present disclosure that contacts the receptor should be sufficient to inhibit PD-1 / PD-L1 binding in vitro, as measured, for example, using ELISA. The receptor may be in solution or suspension, in a cultured or isolated cell preparation, or within a subject.

[0073] In some embodiments, the compounds of the present disclosure are useful for restoring and enhancing T cell activation. In some embodiments, the compounds of the present disclosure are useful for enhancing immune responses in a subject. In some embodiments, the compounds of the present disclosure are useful for treating, preventing, or delaying the progression of diseases or disorders in various therapeutic areas, such as cancer and infectious diseases.

[0074] In some embodiments, the compounds of the present disclosure can be used to treat a subject suffering from a condition that responds to modulation of the protein-protein interaction between the PD-1 / PD-L1 proteins.

[0075] In some embodiments, there is provided a method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, there is provided a method of enhancing, stimulating, modulating, and / or increasing an immune response in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, there is provided a method of inhibiting cancer cell growth, proliferation, or metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, there is provided a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure, including a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the subject is suffering from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, 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 CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, bile duct tumor, basal cell carcinoma, thymus neoplasm, thyroid cancer, parathyroid cancer, uterine cancer, and adrenal gland tumor. Cancer, liver infection, Merkel cell carcinoma, neural tumors, follicle center lymphoma, colorectal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia, multiple myeloma, ovarian tumors, myelodysplastic syndrome, cutaneous or intraocular melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous non-small cell lung cancer (NSCLC), colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma cancer), pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus disease, papillomavirus disease, 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, endocrine system cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis cancer, central nervous system neoplasms ( CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyosarcoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0080] 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 antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents. In some embodiments, the one or more additional therapeutic agents are chemokine and / or chemoattractant receptor antagonists, 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 are described in, for example, WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147815, WO2010 / 030815, W No. O2010 / 075257, No. WO2011 / 163640, No. WO2010 / 054006, No. WO2010 / 051561, No. WO2011 / 035332, No. WO2013 / 082490, No. WO2013 / 08 No. 2429, No. WO2014 / 085490, No. WO2014 / 100735, No. WO2014 / 089495, No. WO2015 / 084842, No. WO2016 / 187393, No. WO2017 / 127409, WO 2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 2226 No. 01, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, and WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists further 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.

[0081] In some embodiments, compounds of the present disclosure can be used to inhibit infectious diseases, including, but not limited to, HIV, influenza, herpes, giardiasis, malaria, leishmaniasis, and hepatitis viruses (types A, B, and C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, and measles. Pathogenic infections caused by viruses, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum contagiosum virus, polio virus, rabies virus, JC virus, and arboviral encephalitis virus, as well as chlamydia, rickettsia, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and congenital malaria, klebsiella, proteus, serratia, pseudomonas, Escherichia coli, legionella, diphtheria, salmonella, bacillus, Pathogenic infections caused by Salmonella typhimurium, Vibrio cholerae, Clostridium tetani, Clostridium botulinum, Bacillus anthracis, Yersinia pestis, Leptospira, and Bordetella burgdorferi, as well as Candida species (e.g., Candida albicans, Krusei, Glabrata, and Tropicalis), Cryptococcus neoformans, Aspergillus fumigatus and Aspergillus niger, Mucorales species (e.g., Mucor, Pseudomonas aeruginosa, and Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Coccidioides immitis , and Histoplasma capsulatum fungi, as well as pathogenic infections with the following parasites: Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Nippon Strongylus brasiliensis.

[0082] In some embodiments, the compounds of the present disclosure may be used to inhibit HIV infection, slow the progression of AIDS, deplete HIV viral reservoirs, or reduce the severity of HIV infection and AIDS symptoms.

[0083] The compounds of the present disclosure may be used to treat cancer and precancerous conditions in a subject.

[0084] The therapeutic methods provided herein generally involve administering an effective amount of one or more compounds provided herein to a subject.Suitable subjects include those suffering from or susceptible to the disorders or diseases identified herein (i.e., prophylactic treatment).Typical subjects for the treatments described herein include mammals, particularly primates, especially humans.Other suitable subjects include domesticated companion animals such as dogs, cats, and horses, or livestock such as cows, pigs, and sheep.

[0085] In general, the therapeutic methods provided herein involve administering to a subject an effective amount of one or more compounds provided herein. In a preferred embodiment, the compounds of the present disclosure are preferably administered intravenously, orally, or topically to a subject (e.g., a human). An effective amount may be an amount sufficient to modulate PD-1 / PD-L1 interaction and / or to reduce or alleviate symptoms exhibited by the subject. Preferably, the administered amount is an amount sufficient to result in a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to reliably modulate PD-1 / PD-L1 interaction. Treatment regimens may vary depending on the compound used and the particular condition being treated, with a dosing frequency of four times per day or less being preferred for the treatment of most disorders. Generally, a twice-daily dosing regimen is more preferred, with once-daily administration being particularly preferred. However, it is understood that the specific dose level and treatment regimen for any particular subject will depend on various factors, such as the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combinations (i.e., other drugs administered to the subject), and the severity of the specific disease being treated, as well as the judgment of the prescribing medical professional.In general, it is preferable to use the minimum dose that is sufficient to provide effective treatment.In general, the subject may be monitored for therapeutic effectiveness using medical or veterinary diagnostic criteria that are appropriate for the condition being treated or prevented. combination

[0086] A combination pharmaceutical containing a compound of the present disclosure and another drug may be administered as a combined preparation in which both components are contained in a single preparation, or as separate preparations. Administration using separate preparations includes simultaneous administration and administration at a certain time interval. When administering at a certain time interval, the compound of the present disclosure may be administered first, followed by administration of another drug, or the other drug may be administered first, followed by administration of the compound of the present disclosure. The administration method for each drug may be the same or different.

[0087] The dosage of the other drug can be appropriately selected based on the dosage used clinically. The mixing ratio of the compound of the present disclosure and the other drug can be appropriately selected depending on the age and weight of the subject to be administered, the administration method, the administration time, the disorder and symptoms to be treated, and combinations thereof. For example, the other drug may be used in an amount of 0.01 to 100 parts by mass per part by mass of the compound of the present disclosure. The other drug may be a combination of two or more drugs in an appropriate ratio.

[0088] The compounds described herein may be used or combined with one or more therapeutic agents, such as antibacterial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapeutic agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents. These therapeutic agents may be in the form of chemical compounds, antibodies, polypeptides, or polynucleotides.

[0089] The compounds described herein may be used or combined with one or more of therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives, etc.), antibody-drug conjugates (ADCs), viruses, oncolytic viruses, gene modifiers or editors such as CRISPRs (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T-cell immunotherapeutics, or any combination thereof.

[0090] Examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormones, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents, and other anticancer agents.

[0091] The compounds described herein may be used or combined in combination or in adjunct forms with cancer treatment adjuncts such as leukopenia (neutropenia) treatment agents, thrombocytopenia treatment agents, antiemetics, and cancer pain intervention agents.

[0092] The compounds described herein may be used or combined with kinase inhibitors.

[0093] In one embodiment, the compounds of the present disclosure may be used in combination or in a mixed form with other immunomodulators and / or enhancers. Examples of immunomodulators include various cytokines, vaccines, and immunostimulators. Examples of these cytokines, vaccines, and immunostimulators that stimulate an immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-α, β, or γ, IL-1, IL-2, IL-3, IL-12, poly(I:C), and CPG. Potentiating agents include cyclophosphamide and cyclophosphamide analogs, anti-TGF and mitotic inhibitors such as imatinib (Gleevac), paclitaxel, sunitinib (Sutent) or other antiangiogenic agents, aromatase inhibitors such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0094] In some embodiments, the compounds described herein may be used or combined with a modulator of one or more of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modulator is an antagonist.

[0095] In some embodiments, the compounds described herein may be prepared in a variety of ways, including, for example, by the methods disclosed 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 / 0 No. 75257, No. WO2011 / 163640, No. WO2010 / 054006, No. WO2010 / 051561, No. WO2011 / 035332, No. WO2013 / 082490, No. WO2013 / 08242 No. 9, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO 2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 1 No. 30811, No. WO2006 / 076644, No. WO2008 / 008431, No. WO2009 / 038847, No. WO2008 / 008375, No. WO2008 / 008374 , WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists useful in the present disclosure further 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. Dosage

[0096] Dosage levels of about 0.1 mg to about 140 mg per kg of body weight per day are useful for treating or preventing conditions involving PD-1 / PD-L1 interaction (about 0.5 mg to about 7 g per human subject per day). The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Dosage unit forms generally contain about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferable to administer an amount of compound sufficient to achieve a serum concentration of 5 ng / mL to 10 μg / mL serum, more preferably 20 ng / mL to 1 μg / mL serum, and most preferably 50 ng / mL to 200 ng / mL serum. For direct injection into the synovium (for the treatment of arthritis), it is necessary to administer enough compound to achieve a local concentration of about 1 μmol.

[0097] The frequency of administration can also be changed depending on the compound used and the specific disease being treated.However, for the treatment of most disorders, the administration schedule of 4 times a day, 3 times a day or less is preferred, and the administration schedule of 1 time a day or 2 times a day is particularly preferred.However, it is understood that the specific dose level for any specific subject depends on various factors, including the activity of the specific compound used, age, body weight, general health condition, sex, diet, administration time, administration route, excretion rate, drug combination (i.e. other drugs that are administered to the subject), the severity of the specific disease being treated, and other factors, including the judgment of the medical professional who prescribes.

[0098] In another aspect of the present disclosure, the compounds of the present disclosure can be used in a variety of in vitro and in vivo applications other than as pharmaceuticals. The compounds of the present disclosure may also be used as positive controls in measuring PD-1 / PD-L1 interaction activity, i.e., as standards for determining the ability of candidate agents to bind to PD-1 and / or PD-L1, or as radiotracers for positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0099] Also included within the scope of this disclosure is a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and instructions for use. The kit may further comprise at least one additional reagent. The kit typically includes a label indicating the intended use of the contents of the kit. The term "label" includes any written or recorded material provided on or with the kit, or otherwise associated with the kit. [Example]

[0100] The following examples illustrate various methods of preparing compounds of the present disclosure, including compounds of Formula (I) or Formula (II). The following examples are offered by way of illustration and not by way of limitation of the claimed disclosure.

[0101] Reagents and solvents used below are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1 H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are assigned relative to tetramethylsilane (TMS) and are tabulated in order of multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet) and proton number. Mass spectrometry results are reported as mass-to-charge ratios. In the examples, a single m / z value is reported for the M+H (or MH, as noted) ion containing the most common isotopic atom. The isotopic type corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC for sample delivery. Typically, the analyte was dissolved at 0.1 mg / mL in methanol or CH3CN, and 1 μL of this was infused into the mass spectrometer along with the delivery solvent, scanning over a range of 100–1000 Da. All compounds could be analyzed in either positive or negative ESI mode using acetonitrile / water containing 1% formic acid as the delivery solvent.

[0102] TLC stands for thin layer chromatography, and this abbreviation is used throughout the examples and description of this disclosure.

[0103] Compounds within the scope of the present 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 further recognize that alternative methods can be used to synthesize the target compounds of the present disclosure, and that the approaches described within the body of this document, while not exhaustive, provide widely applicable and practical routes to the compounds of interest.

[0104] Certain molecules claimed in this patent can exist in various enantiomeric and diastereomeric forms, and unless a particular enantiomer is specified, all such variations of these compounds are claimed.

[0105] Detailed descriptions of the experimental procedures used to synthesize compounds of interest in this document provide molecules that are described by the physical data that identifies them, as well as their associated structural diagrams.

[0106] Those skilled in the art further recognize that acids and bases are frequently used during standard isolation and purification procedures in organic chemistry. Salts of parent compounds may also be produced during the experimental procedures described in this patent if those salts possess necessary inherent acidity or basicity. Example 1: ((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) [ka]

[0107] Step a: 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 2 M aqueous KCO (1.0 mL, 2.0 mmol) in dioxane (13 mL) was degassed under nitrogen for 30 minutes, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (110 mg, 0.13 mmol). After degassing for an additional 10 minutes, the solution was heated to 90°C and stirred at this temperature for 4 hours. Water (20 mL) was then added to the reaction mixture, and the mixture was extracted with 2:1 chloroform:isopropanol (3 x 20 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (SiO, 50% EtOAc to 100% EtOAc in hexanes) afforded 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))dinicotinonitrile.

[0108] Step b: 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))dinicotinonitrile (100 mg, 0.124 mmol) and L-serine (130 mg, 1.24 mmol) were stirred in DMF (4 mL) for 1 h, after which sodium triacetoxyborohydride (0.72 g, 3.4 mmol) was added portionwise over 10 min. The reaction mixture was stirred at room temperature overnight. The majority of the DMF was removed in vacuo and the crude material was purified by reverse-phase preparative HPLC (CHCN-HO containing 0.1% NHCOH) to give ((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). 52 H 46 Cl2N6O 10 [M+H] + MS: (ES) m / z calculated 985.3, observed 985.7. 1H NMR (400 MHz, メタノール-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). Biotechnology Example: Enzyme-binding immunosorbent assay-ELISA

[0109] A 96-well plate was incubated with 1 μg / mL human PD-L1 (obtained from R&D) in PBS overnight at 4°C. The wells were then sealed with 2% (w / v) BSA in PBS containing 0.05% TWEEN-20 for 1 hour at 37°C. The plate was washed three times with 0.05% TWEEN-20 in PBS, and each compound was serially diluted (1:5) in dilution medium and added to the ELISA plate. Human PD-1 and 0.3 μg / mL biotin (ACRO Biosystems) were added and incubated for 1 hour at 37°C, followed by washing three times with 0.05% TWEEN-20 in PBS. The second sealing was performed with 2% (W / V) BSA in PBS containing 0.05% TWEEN-20 for 10 minutes at 37°C, and the plates were washed three times with PBS containing 0.05% TWEEN-20. Streptavidin-HRP was added for 1 hour at 37°C, and then the plates were washed three times with PBS containing 0.05% TWEEN-20. TMB substrate was added and reacted for 20 minutes at 37°C. A stop solution (2 N H2SO4 aqueous solution) was added. The absorbance was read at 450 nm using a microplate spectrophotometer. The results are shown in Table 1. IC 50 Values ​​are shown as 100–10,000 nM (+); <100 nM (++). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0110] The compounds in Table 1 were prepared using synthetic methods similar to those described in Example 1.

[0111] Specific embodiments of the present invention are described herein for carrying out the invention. It is anticipated that, upon reading the foregoing description, variations of the disclosed embodiments may become apparent to those skilled in the art, who may employ such variations as appropriate. Accordingly, the present invention may be practiced otherwise than as specifically described herein, and the present invention is intended to include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0112] All publications, patent applications, accession numbers, and other references cited herein are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 【Chemical 1】 【Chemistry 2】 During the ceremony, Y and Y′ are each independently selected from the group consisting of O and NH; R 1 is C 1-4 is alkyl; R 2a and R 2a’ are H, halogen, and -R a , -CO 2 R b , and -OR b and each R is independently selected from the group consisting of b is C 1-8 alkyl; and each R a is C 1-8 is alkyl; R 2b , R 2c , R 2b’ , and R 2c’ are each H; R 3 and R 3’ are respectively -NR d R e and 4-9 membered monocyclic or spirocyclic non-aromatic heterocycles, and optionally 1-2 R 3a is replaced by; R d is H and C 1-8 selected from the group consisting of alkyl; R e is H, -C 1-8 Alkyl, -X 2 -CONHSO 2 R g , -X 2 -SO 3 R g , C 3-10 Cycloalkyl, C 4-8 heterocyclyl, and -X 2 -C 4-8 heterocyclyl; R e The alkyl or alkylene portion of 2 , and COO-C 1-8 is further substituted with 1 to 3 substituents independently selected from alkyl; e C 4-8 Heterocyclyl moiety and C 3-10 The cycloalkyl moiety optionally contains 1 to 4 R w substituted with a substituent; Each R 3a is oxo, -R f , and —OC(O)R g are independently selected from the group consisting of: 2 is C 1-6 alkylene and optionally further substituted with OH; R g each of which is hydrogen, optionally NH 2 C substituted with 1 to 2 substituents selected from 1-8 independently selected from alkyl; Each R f is -OH and C 1-8 independently selected from the group consisting of alkyl; Each R w the substituents are independently selected from OH and oxo; R 4 and R 4’ each of which may optionally be 1 to 4 R 4a substituted with O—C 1-8 Alkyl, —O—C 1-4 Alkyl-C 6-10 Aryl, and —O—C 1-4 Alkyl-C 5-10 independently selected from the group consisting of heteroaryl; Each R 4a is —CN; each n is independently 0; R 6a and R 6a’ are each H; each m is independently 0 or 1; and R 6b and R 6b’ and R is H, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. 2. The compound of claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. 2. The compound of claim 1, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

4. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein Y and Y' are each O.

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein each subscript m is 1.

6. The R 3 and R 3’ are each independently a 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocycle, optionally with one or two R 3a 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, substituted with:

7. The R 3 and R 3’ are each independently -NR d R e 2. The compound of claim 1, wherein:

8. The R 3 and R 3’ are -NR d R e and R in combination with the N to which it is attached e is a natural amino acid or an unnatural amino acid, and the unnatural amino acid is C 2-4 Hydroxyalkyl and C 1-3 alkylguanidinyl, wherein each α-carbon of said natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal moiety is C(O)OH, C(O)O-C 1-6 Alkyl, and C(O)NH 2 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from the group consisting of:

9. The R 3 and R 3’ are -NR d R e and R in combination with the N to which it is attached e is a natural amino acid or an unnatural amino acid, and the unnatural amino acid is C 2-4 The hydroxyalkyl α-carbon of each of the natural or unnatural amino acids is further substituted with a methyl group, and the terminal moiety is C(O)OH, C(O)O—C 1-4 Alkyl, and C(O)NH 2 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from the group consisting of:

10. The R 2a and R 2a’ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein each is a halogen.

11. The R 1 4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: is C1-2 alkyl.

12. The R 4 and R 4’ are each independently O-C 1-8 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R is alkyl.

13. The R 4 and R 4’ are each independently —O—C 1-4 alkylpyridyl, which optionally contain 1 to 3 R 4a 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, substituted with:

14. The R 2a and R 2a’ are each independently selected from the group consisting of H and halogen; 3 is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocyclic ring, optionally containing 1-2 R 3a each R 4 and R 4’ is O-C 1-8 Alkyl, —O—C 1-4 alkylphenyl, and —O—C 1-4 alkylpyridyl, each of which is optionally selected from the group consisting of 1 to 3 R 4a 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, substituted with:

15. The R 2a and R 2a’ are each independently selected from the group consisting of H, and halogen; 4 and R 4’ is O-C 1-8 Alkyl, —O—C 1-4 alkylphenyl, and —O—C 1-4 alkylpyridyl, each of which optionally has one to two R 4a 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, substituted with:

16. The R 3 and R 3’ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: 【Chemistry 3】

17. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from the following compounds: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 【Chemistry 4-5】 【Chemistry 4-6】

18. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure isomer or an enriched isomer.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

20. 20. The pharmaceutical composition of claim 19, further comprising one or more additional therapeutic agents.

21. 21. The pharmaceutical composition of claim 20, wherein 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, antihormonal agents, antifibrotic agents, radiotherapeutic agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents.

22. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in modulating an immune response mediated by the PD-1 signaling pathway in a subject.

23. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for use in enhancing, stimulating, modulating and / or increasing an immune response in a subject in need thereof.

24. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof.

25. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway.

26. 26. The pharmaceutical composition of any one of claims 22 to 25, wherein the subject is suffering from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.

27. The disease or disorder may be 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 myeloid leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, bile duct tumor, basal cell carcinoma, thymic neoplasm , thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nerve tumors, follicle center lymphoma, colorectal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumors, myelodysplastic syndrome, cutaneous or intraocular melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous cell non-small cell lung cancer (SCLC), non-squamous cell carcinoma Non-small cell lung cancer (NSCLC), colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpesvirus infection, papillomavirus infection, 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, endocrine system cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis cancer 26. The pharmaceutical composition for use according to claim 25, wherein the therapeutic agent is selected from the group consisting of cancer, central nervous system neoplasm (CNS), tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyosarcoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

28. 28. The pharmaceutical composition for use according to any one of claims 22 to 27, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject together with a therapeutically effective amount of one or more additional therapeutic agents.

29. 29. The pharmaceutical composition for use of claim 28, wherein 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, antihormonal agents, antifibrotic agents, radiotherapeutic agents, radiotherapeutic agents, antitumor agents, and antiproliferative agents.

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