Heterocyclic compounds as immunomodulators of PD-L1 interactions

Abstract

PD-L1 inhibitors of various compound formulas are disclosed generically and specifically. Methods for preparing such PD-L1 inhibitor compounds are disclosed generically and specifically. Methods of using such PD-L1 inhibitor compounds, alone or in combination with additional agents, and compositions of such PD-L1 inhibitor compounds for the treatment of cancer and other diseases are disclosed.

Description

[Technical Field]

[0001] This application relates generally to compounds, and in particular to compounds that modulate the biological activity of PD-L1 protein. [Background technology]

[0002] Programmed death-ligand 1 (PD-L1) is a protein that plays a key role in suppressing the adaptive arm of the immune system. Normally, the adaptive immune system responds to antigens associated with immune system activation by exogenous or endogenous danger signals. This is followed by the proliferation of clonal expansion of antigen-specific CD8+ T cells and / or CD4+ helper cells. Binding of PD-L1 to the inhibitory checkpoint molecule PD-1 on T cells delivers an inhibitory signal that reduces the proliferation of antigen-specific T cells in lymph nodes and simultaneously reduces the apoptosis of regulatory T cells (anti-inflammatory, suppressor T cells).

[0003] Molecules that can modulate PD-L1 activity may therefore have broad application in the treatment of various disease states. Summary of the Invention

[0004] One aspect of the present application relates to compounds having the general structure shown in Formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof: [ka] During the ceremony, A and B are each independently selected from halogen, cyano, -N3, alkyl and substituted alkyl, amine, alkylamine, and alkoxy; Z1-CR 1 = or -N=, Z2-CR 2 = and Z3-CR 3 = or -N=, Z4-CR 4= or -N=, Z5-CR 5 = and Z6-CR 6 = or -N=, R 1 and R 4 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 2 and R 5 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 3 and R 6 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; Y1 and Y2 are independently -C(R 7 )(R 8 )-, -CR 9 =, -NR 10 -, -O-, or -S-; X1 and X2 each independently represent -C(R 11 )(R 12 )-, -N=, -NR 13 -, -S- or -O-; R 7 , R 8 , R 9 , R 11 , and R 12 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 10 and R 13 are each independently -H, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkenyl, alkynyl, aryl, alkylamine, or alkoxy; L1 and L2 are alkyl, substituted alkyl, or heteroatom chains containing m atoms between ring 3 and W1, and between ring 6 and W2, respectively, where m=0, 1, 2, 3, 4, 5, or 6, and when m is 0, W1 or W2 is directly bonded to the corresponding nitrogen in ring 3 or ring 6, respectively; W1 and W2 are each independently hydrogen, a 5-membered heterocycle or a substituted 5-membered heterocycle, a 6-membered heterocycle or a substituted 6-membered heterocycle, a carboxylalkyl group or a substituted carboxylalkyl group, a cyanoalkyl group or a substituted cyanoalkyl group, an aminoalkyl group or a substituted aminoalkyl group, a hydroxyalkyl group or a substituted hydroxyalkyl group, an amino acid, an amino acid ester, an amino acid amide, a non-natural amino acid, a non-natural amino acid ester, or a non-natural amino acid amide.

[0005] Another aspect of the present application relates to a method for treating a disease or condition associated with the interaction between PD-L1 and PD-1 in a subject, the method comprising the step of administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof.

[0006] Another aspect of the present application relates to a process for preparing the compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0007] Reference will now be made in detail to certain aspects and exemplary embodiments of the present application, examples of which are illustrated in the accompanying structures and figures. While aspects of the present application will be described in conjunction with exemplary embodiments, including methods, materials, and examples, such description is not intended to be limiting, and the scope of the present application is intended to encompass all equivalents, alternatives, and modifications that are commonly known or incorporated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Those skilled in the art will recognize many techniques and materials similar or equivalent to those described herein, which can be used in the practice of aspects and embodiments of the present application. The described aspects and embodiments of the present application are not limited to the methods and materials described. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0008] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant in relation to the other endpoint, as well as independently of the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It is also understood that when a value is disclosed, "less than or equal to" "greater than or equal to" the value, and possible ranges between the values ​​are also disclosed, as appropriately understood by one of ordinary skill in the art. For example, if the value "10" is disclosed, "less than or equal to 10" and "greater than or equal to 10" are also disclosed.

[0009] At various places in the present specification, particular features of compounds are disclosed in groups or ranges, and such disclosure is specifically intended to include every individual subcombination of the members of such groups and ranges.

[0010] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present application. Cis and trans geometric isomers of the compounds of the present application are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0011] Resolution of racemic mixtures of compounds can be achieved by any of a number of methods known in the art. One method involves fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, and lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereomerically pure forms (e.g., S- and R-forms, or diastereomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, t-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0012] Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0013] In compounds with two or more chiral centers, unless otherwise indicated, each chiral center in the compound can independently be either (R) or (S).

[0014] The compounds of the present application also include tautomeric forms. Tautomeric forms result from the interchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position on the heterocyclic ring system (e.g., 1H- and 3 / f-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, H- and 2H-isoindole, and 1H- and 2 / / -pyrazole). Tautomeric forms can exist in equilibrium or can be sterically locked into one form by appropriate substitution.

[0015] The compounds of the present application may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present application may be replaced or substituted with a naturally or non-naturally occurring isotope of the atom. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms.

[0016] I. Definition As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. This term is also meant to refer to compounds of the present application regardless of how they are prepared, including by synthesis, by biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0017] All compounds and pharmaceutically acceptable salts thereof can be found together with or isolated from other substances, such as water and solvents (e.g., hydrates and solvates). When in the solid state, the compounds described herein and their salts can exist in various forms, for example, in the form of solvates, including hydrates. The compounds can be in any solid state form, such as polymorphs or solvates, and therefore, unless otherwise specified, references herein to compounds and salts thereof should be understood to encompass any solid state form of the compound.

[0018] In some embodiments, the compounds of the present application or salts thereof are substantially isolated. By "substantially isolated," it is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the present application.

[0019] Substantial separation can include compositions that contain at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound of the present application or a salt thereof.

[0020] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0021] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature such as a reaction temperature, i.e., the temperature of the room in which a reaction is carried out, for example, a temperature of about 20°C to about 30°C.

[0022] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present application include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0023] The terms "individual" or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0024] The phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, physician or other clinician.

[0025] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., preventing further progression of the pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder; and (2) ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), e.g., reducing the severity of the disease, in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

[0026] The term "solvate" refers to the compound formed by the interaction of a solvent with EPI, its metabolites, or salts. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0027] As used herein, the terms "substituted" or "optionally substituted" mean that one or more hydrogen atoms of the group to which the terms "substituted" or "optionally substituted" refer has been replaced with a lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxyester, carboxyl, carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, means substituted with one of the substituents independently selected from lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower carboxamidoalkylaryl, lower carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, lower aminocarboxamidoalkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkyloxyalkyl, provided that the substitution does not exceed the normal valence of the atom being considered and that the substitution results in a stable compound, i.e., a compound that is sufficiently robust to be isolated from a reaction mixture.

[0028] The term "alkyl" refers to a straight, branched, or cyclic chain hydrocarbon radical containing only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted.

[0029] The term "aryl" refers to an aromatic group having 5 to 14 ring atoms and at least one ring having a conjugated π-electron system; the term includes carbocyclic aryl, heterocyclic aryl, and biaryl groups, all of which may be optionally substituted.

[0030] Carbocyclic aryl groups are groups having 6 to 14 ring atoms, the ring atoms on the aromatic ring being carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds, such as optionally substituted naphthyl groups.

[0031] Heterocyclic aryl or heteroaryl groups are groups having 5 to 14 ring atoms, where 1 to 4 heteroatoms are ring atoms in an aromatic ring and the remainder are carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all of which may be optionally substituted.

[0032] The term "biaryl" refers to an aryl group having 5 to 14 atoms and containing two or more aromatic rings, including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.

[0033] The terms "substituted aryl" and "substituted heteroaryl" refer to aryl and heteroaryl groups substituted with one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.

[0034] The term "aralkyl" refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.

[0035] The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0036] The term "alkylaryl" refers to an aryl group substituted with an alkyl group. "Lower alkylaryl" refers to a group in which alkyl is lower alkyl.

[0037] The term "lower" as referred to herein in connection with organic radicals or compounds refers to 6 or fewer carbon atoms, respectively. Such groups may be straight-chained, branched, or cyclic.

[0038] The term "higher" as referred to herein in connection with organic radicals or compounds refers to seven or more carbon atoms, respectively. Such groups may be straight-chained, branched, or cyclic.

[0039] The terms "cyclic alkyl" or "cycloalkyl" refer to an alkyl group that is cyclic, having from 3 to 10 carbon atoms, and in one aspect, from 3 to 6 carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be optionally substituted.

[0040] The terms "heterocycle," "heterocyclealkyl," or "heterocycloalkyl" refer to a cyclic group of 3 to 10 atoms, in one embodiment 3 to 6 atoms including at least one heteroatom, and in a further embodiment 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. The heterocyclic group may be attached via a nitrogen or carbon atom in the ring. Heterocyclic alkyl groups include unsaturated cyclic groups, fused cyclic groups, and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.

[0041] The terms "arylamino" (a) and "aralkylamino" (b) each refer to the group -NRR', where (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R' is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl, or heterocycloalkyl, respectively.

[0042] The term "acyl" refers to -C(O)-R, where R is alkyl, heterocycloalkyl, or aryl.

[0043] The term "carboxy ester" refers to -C(O)-OR, where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.

[0044] The term "carboxyl" refers to -C(O)-OH.

[0045] The term "oxo" refers to =O in an alkyl or heterocycloalkyl group.

[0046] The term "amino" refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, and heterocycloalkyl, all except H being optionally substituted, and R and R' can form a ring system.

[0047] The term "carboxylamide" refers to -C(O)NR2, where each R is independently hydrogen or alkyl.

[0048] The term "sulfonylamido" or "-sulfonylamido" refers to -S(=O)2R2, where each R is independently hydrogen or alkyl.

[0049] The term "halogen" or "halo" refers to -F, -Cl, -Br and -I.

[0050] The term "alkylaminoalkylcarboxy" refers to the group alkyl-NR-alk-C(O)-O-, where "alk" is an alkylene group and R is H or lower alkyl.

[0051] The term "sulfonyl" or "sulfonyl" refers to -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0052] The term "sulfonate" or "sulfonate" refers to -SO2-OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0053] The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to an alkenyl group in which the double bond is between the first and second carbon atoms. When an 1-alkenyl group is bonded to another group, such as a W substituent bonded to a cyclic phosphonate, it is bonded to the first carbon.

[0054] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1-alkynyl" refers to an alkynyl group in which the triple bond is between the first and second carbon atoms. When an 1-alkynyl group is bonded to another group, such as a W substituent bonded to a cyclic phosphonate, it is bonded to the first carbon.

[0055] The term "alkylene" refers to a divalent straight-chain, branched-chain, or cyclic saturated aliphatic group. In one aspect, an alkylene group contains 10 or fewer atoms. In another aspect, an alkylene group contains 6 or fewer atoms. In a further aspect, an alkylene group contains 4 or fewer atoms. An alkylene group can be straight-chain, branched, or cyclic.

[0056] The term "acyloxy" refers to an ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

[0057] The term "aminoalkyl" refers to the group NR2-alk- where "alk" is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0058] The term "alkylaminoalkyl" refers to the group alkyl-NR-alk- where each "alk" is an independently selected alkylene and R is H or lower alkyl. "Lower alkylaminoalkyl" refers to groups in which the alkyl and alkylene groups are lower alkyl and lower alkylene, respectively.

[0059] The term "arylaminoalkyl" refers to the group aryl-NR-alk-, where "alk" is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In "lower arylaminoalkyl," the alkylene group is lower alkylene.

[0060] The term "alkylaminoaryl-" refers to the group alkyl-NR-aryl- where "aryl" is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl. In "lower alkylaminoaryl," the alkyl group is lower alkyl.

[0061] The term "alkoxyaryl" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl", the alkyl group is lower alkyl.

[0062] The term "aryloxyalkyl" refers to an alkyl group substituted with an aryloxy group.

[0063] The term "aralkyloxyalkyl" refers to the group aryl-alk-O-alk- where "alk" is an alkylene group. "Lower aralkyloxyalkyl" refers to groups where the alkylene group is lower alkylene.

[0064] The terms "alkoxy-" or "alkyloxy-" refer to an alkyl-O- group.

[0065] The term "alkoxyalkyl" or "alkyloxyalkyl" refers to the group alkyl-O-alk-, where "alk" is an alkylene group. In "lower alkoxyalkyl", each alkyl and alkylene is a lower alkyl and lower alkylene, respectively.

[0066] The term "alkylthio-" refers to an alkyl-S- group.

[0067] The term "alkylthioalkyl" refers to the group alkyl-5-alk-, where "alk" is an alkylene group. In "lower alkylthioalkyl", each alkyl and alkylene is a lower alkyl and lower alkylene, respectively.

[0068] The term "alkoxycarbonyloxy-" refers to alkyl-OC(O)-O-.

[0069] The term "aryloxycarbonyloxy-" refers to aryl-OC(O)-O-.

[0070] The term "alkylthiocarbonyloxy" refers to alkyl-SC(O)-O-.

[0071] The term "amide" includes NR2-C(O)-, RC(O)-NR 1 -, NR2-S(=O)2- and RS(=O)2-NR 1 - refers to an NR group adjacent to an acyl or sulfonyl group such as in -, where R and R 1 includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0072] The term "carboxamide" includes NR-C(O)- and RC(O)-NR 1 - where R and R 1includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl. This term does not include urea, -NR-C(O)-NR-.

[0073] The term "sulfonamide" or "sulfonamide" refers to NR2-S(=O)2- and RS(=O)2-NR 1 - where R and R 1 includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl. This term does not include sulfonylureas, -NR-S(=O)2-NR-.

[0074] The terms "carboxamidoalkylaryl" or "carboxamidoaryl" refer to aryl-alk-NR 1 -C(O) and ar-NR 1 -C(O)-alk-, where "ar" is aryl, "alk" is alkylene, and R 1 and R includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0075] The terms "sulfonamidoalkylaryl" or "sulfonamidoaryl" refer to aryl-alk-NR 1 -S(=O)2- and ar-NR 1 -S(=O)2-, where "ar" is aryl, "alk" is alkylene, and R 1 and R includes —H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0076] The term "hydroxyalkyl" refers to an alkyl group substituted with one --OH.

[0077] The term "haloalkyl" refers to an alkyl group substituted with a halo.

[0078] The term "cyano" refers to -CN.

[0079] The term "nitro" refers to -NO2.

[0080] The term "acylalkyl" refers to alkyl-C(O)-alk-, where "alk" is alkylene.

[0081] The term "aminocarboxamidoalkyl" refers to the group NR2-C(O)-N(R)-alk-, where R is an alkyl group or H, and "alk" is an alkylene group. "Lower aminocarboxamidoalkyl" refers to such groups where "alk" is lower alkylene.

[0082] The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0083] II. Compounds that inhibit PD-L1 activity One aspect of the present application relates to compounds that inhibit PD-L1 activity. In some embodiments, the compounds, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof, have the general structure as shown in Formula (I): [ka] During the ceremony, A and B are each independently selected from halogen, cyano, -N3, alkyl and substituted alkyl, amine, alkylamine, and alkoxy; Z1-CR 1 = or -N=, Z2-CR 2 = and Z3-CR 3 = or -N=, Z4-CR 4 = or -N=, Z5-CR 5 = and Z6-CR 6 = or -N=, R 1 and R 4are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 2 and R 5 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 3 and R 6 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; Y1 and Y2 are independently -C(R 7 )(R 8 )-, -CR 9 =, -NR 10 -, -O-, or -S-; X1 and X2 each independently represent -C(R 11 )(R 12 )-, -N=, -NR 13 -, -S- or -O-; R 7 , R 8 , R 9 , R 11 , and R 12 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R 10 and R 13 are each independently -H, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkenyl, alkynyl, aryl, alkylamine, or alkoxy; L1 and L2 are alkyl, substituted alkyl, or heteroatom chains containing m atoms between ring 3 and W1, and between ring 6 and W2, respectively, where m=0, 1, 2, 3, 4, 5, or 6, and when m is 0, W1 or W2 is directly bonded to the corresponding nitrogen in ring 3 or ring 6, respectively; W1 and W2 are each independently hydrogen, a 5-membered heterocycle or a substituted 5-membered heterocycle, a 6-membered heterocycle or a substituted 6-membered heterocycle, a carboxylalkyl group or a substituted carboxylalkyl group, a cyanoalkyl group or a substituted cyanoalkyl group, an aminoalkyl group or a substituted aminoalkyl group, a hydroxyalkyl group or a substituted hydroxyalkyl group, an amino acid, an amino acid ester, an amino acid amide, a non-natural amino acid, a non-natural amino acid ester, or a non-natural amino acid amide.

[0084] The compounds of formula (I) may be symmetrical about the axis DD (i.e., the left-hand portion of formula (I) is a mirror image of the right-hand portion of formula (I)) or asymmetrical (i.e., the left-hand portion of formula (I) is different from the right-hand portion of formula (I)).

[0085] Preferred Core Structure In some embodiments, the compound of Formula (I) comprises a core structure selected from the group consisting of Formulas (II)-(XXIII). [ka] [ka] [ka]

[0086] In some embodiments, the compound of formula (I) is [ka] Contains the core structure of

[0087] In some embodiments, L1 and L2 are each independently selected from -CH2-, (CH2)2-, and -(CH2)3-.

[0088] In some embodiments, L1 and L2 are each independently selected from -CH(CH3)-, -CH2-, and -CH2-CH(CH3)-.

[0089] Type I side chain In some embodiments, W1 and / or W2 are each independently a type I side chain. As used herein, the term "type I side chain" refers to a structure that includes (1) a 5-membered heterocyclic ring having at least one nitrogen atom as a ring atom, or a substituted 5-membered heterocyclic ring having at least one nitrogen atom as a ring atom, or (2) a 6-membered heterocyclic ring having at least one nitrogen atom as a ring atom, or a substituted 5-membered heterocyclic ring having at least one nitrogen atom as a ring atom, where a linker L1 or L2 is directly attached to a ring atom in the 5- or 6-membered heterocyclic ring.

[0090] In some embodiments, W1 and / or W2 are each independently a heterocycle. In some embodiments, W1 and / or W2 are each independently a 5-membered heterocycle having at least one nitrogen atom as a ring atom. In some embodiments, W1 and / or W2 are each independently a 6-membered heterocycle having at least one nitrogen atom as a ring atom.

[0091] In some embodiments, W1 and / or W2 are each independently selected from the group of Type I side chains listed below. [ka]

[0092] Type 2 side chain In some embodiments, W1 and / or W2 are each independently a Type II side chain. As used herein, the term "Type II side chain" refers to a group having the general formula [ka] W1 structure and general formula [ka] It refers to a W2 structure having In the formula, R 14 and R 16are each independently -H, alkyl, substituted alkyl, hydroxyalkyl or substituted hydroxyalkyl, hydroxycarboxylic acid or a salt or ester thereof, substituted hydroxycarboxylic acid or a salt or ester thereof, carboxylic acid or a salt or ester thereof, or an alkyl ether thereof, substituted carboxylic acid or a salt or ester thereof, or an alkyl ether thereof, carboxamide, or lactone; R 15 and R 17 are each independently —H, alkyl, or substituted alkyl.

[0093] In some embodiments, R 14 or R 16 or both have the general formula -L3-C(O)-Q2R 18 wherein L3 is alkyl, substituted alkyl, alkylamino, or alkylaminoalkyl; Q2 is —O— or —CH2—; and R 18 is —H, alkyl or substituted alkyl.

[0094] In some embodiments, R 14 or R 16 or both are independently selected from the group consisting of: [ka]

[0095] In some embodiments, each W1 or W2 is independently an amino acid.

[0096] In some embodiments, the side chain W1 or W2 is L-serine.

[0097] In some embodiments, the side chain W1 or W2 is an L-serine ester.

[0098] In some embodiments, the side chains W1 and W2 are both L-serine.

[0099] In some embodiments, the side chains W1 and W2 are both L-serine esters.

[0100] Other side chains In some embodiments, each W1 or W2 is independently -C(O)-ONa, -CN, -CH2OH, or -CH2NH2.

[0101] Exemplary Compounds In some embodiments, the compounds of formula (I) comprise the following core structure: [ka]

[0102] In some embodiments, the compounds of formula (I) comprise the following core structure: [ka]

[0103] In some embodiments, the compound of formula (I) comprises two identical core structures linked together. [ka] It consists of:

[0104] In some embodiments, the compound of formula (I) comprises two identical core structures linked together. [ka] It consists of:

[0105] In some embodiments, the compounds of formula (I) comprise a core structure linked together. [ka] and core structure [ka] It consists of:

[0106] In some embodiments, the side chains W1 and / or W2 are independently selected from the group consisting of: [ka]

[0107] In some embodiments, the compound of Formula (I) comprises only one side chain, wherein: W1 is [ka] and W2 is H and L2 is absent (i.e., m=0). In other words, there is no side chain on the nitrogen atom of ring 6. In a further embodiment, L1 is C1-C3 alkyl.

[0108] In some embodiments, the compounds of formula (I) comprise side chains that are asymmetric about the axis DD.

[0109] In some embodiments, W1 is [ka] and W2 is selected from Type I and Type II side chains. In further embodiments, L1 and L2 are each independently C1-C3 alkyl.

[0110] In some embodiments, W1 is [ka] and W2 is selected from Type I and Type II side chains. In further embodiments, L1 and L2 are each independently C1-C3 alkyl.

[0111] In some embodiments, W1 is [ka] and W2 is selected from Type I and Type II side chains. In further embodiments, L1 and L2 are each independently C1-C3 alkyl.

[0112] In some embodiments, W1 is [ka] and W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0113] In some embodiments, W1 is [ka] and W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0114] In some embodiments, W1 is [ka] and W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0115] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0116] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0117] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0118] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0119] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0120] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0121] In some embodiments, the side chain W1 is [ka] and the side chain W2 is [ka] In a further embodiment, L1 and L2 are each independently C1-C3 alkyl.

[0122] Specific embodiments of the compounds disclosed herein are listed in Table 1 (or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof), but are not limited to these.

[0123] [Table 1-01]

[0124] [Table 1-02]

[0125] [Table 1-03]

[0126] [Table 1-04]

[0127] [Table 1-05]

[0128] [Table 1-06]

[0129] [Table 1-07]

[0130] [Table 1-08]

[0131] [Table 1-09]

[0132] [Table 1-10]

[0133] [Table 1-11]

[0134] The present application further includes isotopically substituted compounds of the present disclosure. "Isotopically substituted" compounds are compounds of the present application in which one or more atoms have been replaced or substituted by atoms having the same atomic number but a different atomic mass or mass number, e.g., an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). It is understood that a "radiolabeled" compound is a compound incorporating at least one radioactive isotope (e.g., a radionuclide).

[0135] III. Uses of the Compounds of Formula (I) Another aspect of the present application relates to the use of compounds of formula (I), which inhibit the interaction between PD-L1 and PD-1 and are therefore useful in the treatment of diseases and disorders associated with the activity of PD-1, as well as diseases and disorders associated with PD-L1.

[0136] In some embodiments, compounds of Formula (I) promote the formation of PD-L1 dimers, thus inhibiting the interaction between PD-L1 and PD-1. In certain embodiments, compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, are useful for therapeutic administration to enhance, stimulate, and / or increase immunity in cancer, chronic infection, or sepsis, including enhancing responses to vaccination. In some embodiments, the present disclosure provides a method for inhibiting PD-1 / PD-L1 protein / protein interaction. The method comprises administering to an individual or patient an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. The compound of Formula (I) can be used alone, in combination with other drugs or therapies, or as an adjuvant or neoadjuvant, for the treatment of diseases or disorders, including cancer or infectious diseases. Any of the compounds of the present disclosure (including any of their embodiments) can be used for the uses described herein.

[0137] The compounds of the present application inhibit the PD-1 / PD-L1 protein / protein interaction, thereby blocking the PD-1 pathway. Blocking PD-1 enhances immune responses to cancer cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides in vivo treatment of an individual or patient using a compound of any of the formulas herein, or a salt or stereoisomer thereof, to inhibit the growth of cancerous tumors. A compound of any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors. Alternatively, a compound of any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used in combination with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting tumor cell growth in vitro. The method comprises contacting tumor cells in vitro with a compound of any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt or stereoisomer thereof. In another embodiment, the present disclosure provides a method of inhibiting tumor cell growth in an individual or patient, comprising administering to the individual or patient in need of treatment a therapeutically effective amount of a compound of any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt or stereoisomer thereof.

[0138] In some embodiments, provided herein are methods of treating cancer. The methods include administering to a patient in need of treatment a therapeutically effective amount of a compound listed in any of the formulas described herein, any of the claims, and described herein, or a salt thereof. Examples of cancers include cancers whose growth can be inhibited using compounds of the present disclosure and cancers that typically respond to immunotherapy.

[0139] Examples of cancers that can be treated using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, and ovarian cancer. These cancers include leukemia, acute lymphocytic leukemia, chronic or acute leukemia including chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos-induced cancer, and combinations of the above cancers. The compounds of the present disclosure are also useful for treating metastatic cancers, particularly metastatic cancers that express PD-L1.

[0140] In some embodiments, cancers treatable using the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, cutaneous melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer (e.g., invasive breast cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma (e.g., squamous cell carcinoma of the head and neck), urothelial cancer (e.g., bladder cancer, non-muscle-invasive bladder cancer (NMIBC)), and microsatellite instability-high (MSIhlgh) cancers.

[0141] Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0142] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the above cancers.

[0143] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, biliary tract cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, mouth cancer, pharyngeal cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0144] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0145] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0146] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0147] Exemplary lung cancers include non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0148] Exemplary gastrointestinal cancers include esophageal cancer (carcinoma, squamous cell, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer (e.g., colorectal adenocarcinoma).

[0149] Exemplary genitourinary cancers include kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma). In some embodiments, the cancer is a urological cancer (e.g., papillary renal carcinoma, testicular germ cell carcinoma, chromophobe renal cell carcinoma, clear cell renal carcinoma, or prostate adenocarcinoma).

[0150] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0151] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0152] Exemplary nervous system cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cancer (neurofibroma, meningioma, glioma, sarcoma), and neuroblastoma and Lhermitte-Duclos disease.

[0153] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonic rhabdomyosarcoma)), and fallopian tube cancer (carcinoma).

[0154] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial cancer.

[0155] Blockade of the PD-1 pathway by compounds of the present disclosure can also be used to treat infectious diseases, such as viral, bacterial, fungal, and parasitic infections. In some embodiments, provided herein are methods for treating infectious diseases. The methods include administering to a patient in need of treatment a therapeutically effective amount of a compound, or salt thereof, listed in any of the formulas, claims, and described herein. Examples of viruses that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, coronavirus, severe acute respiratory syndrome virus, Ebola virus, and measles virus. In some embodiments, viruses causing infections treatable by the methods of the present disclosure include, but are not limited to, hepatitis viruses (types A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, CMV, and Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, Mycobacterium tuberculosis, and arboviral encephalitis virus.

[0156] The present disclosure provides a method for treating a bacterial infection. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic bacteria causing infections treatable by the methods of the present disclosure include chlamydia, rickettsia, mycobacteria, staphylococcus, streptococcus, pneumococcus, meningococcus, gonococcus, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulinum, anthrax, plague, leptospira, and lyme disease bacteria.

[0157] The present disclosure provides a method for treating a fungal infection. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic fungi causing infections treatable by the methods of the present disclosure include Candida (e.g., Candida albicans, Krusei, Glabrata, Tropicalis), Cryptococcus neoformans, Aspergillus (e.g., Fumigatus, Niger), Mucorales (Mucor, Absidia, Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0158] The present disclosure provides a method for treating a parasitic infection. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic parasites causing infections treatable by the methods of the present disclosure include Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lamblia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Nippostrongylus brasiliensis.

[0159] In some embodiments, provided herein are methods of treating inflammation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof.

[0160] In some embodiments, provided herein are methods of treating an autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof.

[0161] It is believed that the compounds of formula (I) or any of its embodiments may have satisfactory pharmacological profiles and promising biopharmaceutical properties, such as toxicological profiles, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biopharmaceutical properties, such as determining cytotoxicity in cells or determining the inhibition of specific targets or channels to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0162] In some embodiments, the compounds of the present application are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, for example, for preventing or reducing the risk of developing a disease, condition or disorder in individuals who may have a predisposition to the disease, condition or disorder but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0163] In some embodiments, the present disclosure provides a method of enhancing, stimulating, and / or increasing an immune response in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition listed in any of the formulas described herein, any of the claims, and described herein, or a salt thereof.

[0164] Combination therapy The compounds of the present disclosure can be used in combination with one or more other therapies for the treatment of diseases such as cancer or infectious diseases. Examples of diseases and indications that can be treated with combination therapy include those described herein.

[0165] Examples of cancer include solid tumors and non-solid tumors, such as liquid tumors, blood cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure can be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, BCL2, CDK, TGF-PR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFotR, PDGi′PR, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-1I, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, I RKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR / FH2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infectious diseases. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCY54828), INCB62079), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), IDO inhibitors (e.g., epacadostat, N LG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., palsaclisib (INCB50465) and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pirn inhibitors (e.g., INCB53914), EGFR inhibitors (also known as ErB-1 or HER-1).e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, axitinib, vandetanib, ramucirumab, lenvatinib, dib-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, talazoparib, or niraparib), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CC1 receptor antagonists), R2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDACs) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo- and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643), arginase inhibitors (INCB001158), PARP inhibitors (such as rucaparib or olaparib), sitravatinib, combinations of B-Raf inhibitors and MEK inhibitors (such as encorafenib and binimetinib, dabrafenib and trametinib, or cobimetinib and vemurafenib), adenosine receptor antagonists, or combinations thereof.

[0166] In some embodiments, compounds of the present disclosure can be combined with a TLR7 agonist (eg, imiquimod).

[0167] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, STING agonists, RIG-I agonists, oncolytic virotherapy, and immunomodulatory small molecules (including thalidomide or JAK1 / 2 inhibitors, PI3K6 inhibitors, etc.). The compounds can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitonin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, Eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hitorelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosilate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,Mitoxantrone, nandrolone phenylpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, strontium iodide ... Examples of the anti-cancer drugs include leptozocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0168] Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies against PD-1 and PD-L1, or antibodies against cytokines (e.g., IL-10, TGF-b, etc.). Examples of antibodies against PD-1 and / or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infectious diseases, such as viral, bacterial, fungal, and parasitic infections, include, but are not limited to, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and SHR-1210.

[0169] The compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases.

[0170] Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CBL-B, CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0171] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0172] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is pembrolizumab.

[0173] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0174] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0175] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0176] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0177] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0178] The compounds of the present disclosure may also be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

[0179] A compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof, can be combined with another immunogenic substance, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include tumor cells transfected to express peptides of melanoma antigens (such as peptides of gplOO, MAGE antigens, Trp-2, MARTI, and / or tyrosinase), or the cytokine GM-CSF.

[0180] A compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof, can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, a compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof can be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0181] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target effector cells expressing Fe alpha or Fe gamma receptors to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate the host's immune responsiveness.

[0182] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0183] A compound of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof, can be used in combination with a vaccine to stimulate an immune response against pathogens, toxins, and self-antigens.

[0184] When two or more agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for three or more agents).

[0185] Formulations, dosage forms and routes of administration When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. Accordingly, the present disclosure provides compositions comprising a compound of any of the formulas described herein, any of the compounds listed in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powder or aerosol by nebulizer, intratracheal, or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration.

[0186] Parenteral administration may be in the form of a single bolus dose or may be, for example, administered by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0187] The present application also includes pharmaceutical compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the compositions are suitable for topical administration. When preparing the compositions of the present application, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material and serves as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0188] When preparing formulation, active compound can be milled to provide suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to provide substantially uniform distribution (for example, about 40 mesh) in formulation.

[0189] To obtain a particle size suitable for tablet formation and other formulation types, the compounds of the present application can be milled using known milling procedures, such as wet milling. Finely divided (nanoparticulate) preparations of the compounds of the present application can be prepared by processes well known in the art (see, for example, WO 2002 / 000196).

[0190] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl benzoate and propyl hydroxybenzoate, sweeteners, and flavoring agents. The compositions of the present application can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to a patient by using procedures well known in the art.

[0191] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide (w / w).

[0192] In some embodiments, the composition is a sustained-release composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (e.g., Poly ox WSR 1105™).

[0193] In some embodiments, the compositions are manufactured using a wet granulation process. In some embodiments, the compositions are manufactured using a dry granulation process.

[0194] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary administration for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients.

[0195] The ingredients used to formulate pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). For human consumption in particular, compositions are preferably manufactured or formulated in accordance with good manufacturing practice as defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all U.S. Food and Drug Administration good manufacturing practice regulations.

[0196] The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0197] Therapeutic dosages of the compounds of the present application may vary depending, for example, on the particular application for which the treatment is given, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in a pharmaceutical composition may vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 pg to about 1 g per kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg to about 100 mg per kg of body weight per day. The dosage may depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0198] To prepare solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present application. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into similarly effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present application.

[0199] The tablets or pills of the present application can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which resists disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0200] Liquid forms into which the compounds and compositions of the present application can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0201] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized using an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0202] Topical formulations can include one or more conventional carriers. In some embodiments, ointments can include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions can be based on water in combination with glycerol and one or more other ingredients, such as glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, appropriately combined with other ingredients such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present application. Topical formulations can be suitably packaged, for example, in 100g tubes, optionally accompanied by instructions for the treatment of a selected indication, such as psoriasis or other skin conditions.

[0203] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and the judgment of the attending physician, depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0204] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulations is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0205] Therapeutic dosages of the compounds of the present application may vary depending, for example, on the particular application for which the treatment is given, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in a pharmaceutical composition may vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 pg to about 1 g per kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg to about 100 mg per kg of body weight per day. The dosage may depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0206] The present application is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents, and published patent applications, as well as figures and tables, cited throughout this application are hereby incorporated by reference. [Example]

[0207] Example 1 Preparation of (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Intermediate SM1) [ka]

[0208] A solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (0.100 g, 0.869 mmol, 1 equiv), TsCl (0.182 g, 0.954 mmol, 1.10 equiv), TEA (0.132 g, 1.306 mmol, 1.5 equiv), and DMAP (0.006 g, 0.049 mmol, 0.05 equiv) in DCM (2 mL) was stirred at room temperature for 16 h, followed by the slow addition of 1 N HCl (5 mL), extraction with DCM, and concentration of the organics to give SM1 (0.170 g, 73%).

[0209] Example 2 Preparation of 2,2′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (Intermediate SM2) [ka]

[0210] Step 1 and Step 2 To a 500 mL round-bottom flask were added 3-bromo-2-chlorophenol (12.4 g, 0.060 mol, 1.0 equiv.), B2Pin2 (16.4 g, 0.065 mol, 1.08 equiv.), KOAc (20.5 g, 0.210 mol, 3.5 equiv.), and Pd(dppf)Cl·DCM (4.1 g, 5.1 mmol, 0.085 equiv.), followed by the solvent dioxane (300 mL). The final mixture was backfilled with N and stirred at 95 °C for 3 h. The reaction mixture was then cooled to room temperature, filtered, the filter cake washed with dioxane (100 mL), and the filtrate was used directly in the next step.

[0211] To the previous filtrate, 3-bromo-2-chlorophenol (12.0 g, 0.059 mol, 0.99 equiv.), K2CO3 (24.8 g, 0.180 mol, 3.0 equiv.), and Pd(dppf)Cl2·DCM (2.1 g, 2.40 mmol, 0.042 equiv.) were added, followed by HO (80 ml). The final mixture was backfilled with N2 and stirred at 85 °C for 3.5 h. The reaction mixture was then cooled to room temperature, filtered, and the filter cake was washed with EA (300 ml). Brine (300 ml) was added to the filtrate and separated. The aqueous phase was extracted with EA (100 ml × 2), and the combined organic phases were decolorized with activated carbon at room temperature overnight. The mixture was filtered through a pad of Celite, the filter cake was washed with EA, and the combined organic phases were concentrated in vacuo. The residue was purified by recrystallization from DCM / PE=1.5 / 1 to give the desired product (10.1 g, yield: 46%) as a pale yellow solid.

[0212] Step 3 To a stirred mixture of SM2-02 (10.1 g, 0.039 mol, 1.0 equiv.) in DCM (200 ml), DIPEA (19.4 g, 0.151 mol, 3.8 equiv.) was added at 0 °C after dissolution of SM2-02, followed by TfO (26.8 g, 0.095 mol, 2.4 equiv.) at the same temperature. The mixture was then allowed to warm to room temperature and stirred for an additional 2 h. Water (100 ml) was added to work up the reaction, followed by separation, and the aqueous phase was extracted with DCM (100 ml). The combined organic phase was washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by recrystallization from 1:1 EtOH / H2O to give the desired product (18.3 g, 89% yield) as a pale yellow solid.

[0213] Step 4 To a stirred solution of SM2-03 (14.2 g, 0.027 mol, 1.0 equiv.) in dioxane (80 mL), B2Pin2 (27.8 g, 0.109 mol, 4.0 equiv.), KOAc (16 g, 0.164 mol, 6.0 equiv.), and Pd(dppf)Cl₂·DCM (3.3 g, 4.1 mmol, 0.15 equiv.) were added at room temperature, followed by a nitrogen atmosphere and stirring at 85 °C for 2 h. After cooling to room temperature, EA (150 mL) and water (150 mL) were added to the mixture, which was then separated. The aqueous phase was extracted with EA (100 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EA (50 ml), and then PE (300 ml) was slowly added to the solution to form a black suspension. After stirring for 30 minutes, it was filtered, the filter cake was washed with 140 ml (PE / EA = 6 / 1), and the filtrate was concentrated under vacuum. The residue was recrystallized with EtOH (150 ml) to give the desired product (9.5 g, yield: 75%) as an off-white solid.

[0214] Example 3 Preparation of 2,2′-((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))diacetaldehyde (Intermediate SM3) [ka]

[0215] Step 1 A solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (5.00 g, 21.93 mmol, 1 equiv.), bromoacetaldehyde dimethyl acetal (5.55 g, 32.89 mmol, 1.5 equiv.), and CsCO (14.29 g, 43.86 mmol, 2.0 equiv.) in DMF (60 mL) was stirred at 60 °C for 16 h, followed by the addition of 180 mL of HO. Extraction with EA was performed. The organic layer was collected and purified on silica gel to give 7-bromo-4-(2,2-dimethoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5.40 g, 78%).

[0216] Step 2 Compound SM2 (2.50 g, 5.26 mmol, 1 equiv.), 7-bromo-4-(2,2-dimethoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (3.49 g, 11.04 mmol, 2.1 equiv.), K2CO3 (2.90 g, 21.04 mmol, 4.0 equiv.), and Pd(dppf)Cl2.DCM (0.21 g, 0.263 mmol, 0.05 equiv.) were dissolved in dioxane ( A solution of 7,7'-(2,2'-dichloro-[1,1'-biphenyl]-3,3'-diyl)bis(4-(2,2-dimethoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one) (3.10 g, 85%) was obtained.

[0217] Step 3 A solution of 7,7′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(4-(2,2-dimethoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one) (3.10 g, 4.47 mmol, 1 equiv) in 1 N aqueous HCl / dioxane (15 ml / 30 ml) was stirred at 80° C. for 1 h, 30 mL of HO was added, extracted with EA, and the organic layer was washed with NaHCO and concentrated to give the title compound SM3 (2.91 g, crude).

[0218] Preparation of 3,3′-((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))dipropanal (Intermediate SM4) [ka]

[0219] Compound SM4 can be prepared following the same procedure as SM3 using 3-bromo-1,1-dimethoxypropane as a reactant.

[0220] Example 4 Preparation of 7,7′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(2H-benzo[b][1,4]oxazin-3(4H)-one) (Intermediate SM5) [ka]

[0221] Referring to the reaction scheme below, SM2 (0.05 g, 0.11 mmol, 1 equiv.), 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (0.062 g, 0.27 mmol, 2.5 equiv.), Pd(dppf)Cl2 (0.008 g, 0.01 mmol, 0.1 equiv.), and potassium carbonate (0.058 g, 0.42 mmol, 4 equiv.) were dissolved in dioxane / HO (3 mL, v / v = 5:1). The reaction was carried out at 85 °C for 2 h under a N2 atmosphere. After cooling, 10 ml of water and 10 ml of EA were added for extraction, and the organic phase was concentrated and purified by preparative TLC (eluting with DCM / MeOH=10 / 1) to obtain compound SM5, 7,7′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(2H-benzo[b][1,4]oxazin-3(4H)-one) (13 mg, yield: 15.6%).

[0222] Example 5 (Preparation for reductive amination) 5A. Preparation of 1-(2-(7-(2,2′-dichloro-3′-(4-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-[1,1′-biphenyl]-3-yl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)pyrrolidine-3-carboxylic acid [ka]

[0223] To a stirred solution of compound SM3 (0.015 g, 0.024 mmol, 1 equiv.), pyrrolidine-3-carboxylic acid (0.0035 g, 0.03 mmol, 1.3 equiv.), (S)-pyrrolidin-3-ol hydrochloride (0.004 g, 0.032 mmol, 1.3 equiv.), and 1 drop of AcOH in CHCl / MeOH (1 mL / 0.5 mL) was added sodium triacetoxyborohydride (0.051 g, 0.24 mmol, 10 equiv.) at room temperature. After 4 h, the mixture was directly concentrated, 0.5 mL of HO and 3 mL of MeOH were added, and the mixture was purified by reverse-phase HPLC (0.1% trifluoroacetic acid in water / acetonitrile) to give GLC01-481 (6 mg, 31%). 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.19 (d, 2H), 7.14 (d, J = 2.0 Hz, 2H), 5.53 (s, 2H), 4.75 (s, 4H), 4.49-4.43 (m, 2H), 4.34-4.26 (m, 4H), 3.75-3.67 (m, 4H), 3.24-3.17 (m, 4H), 2.34-2.16 (m, 4H), 1.57-1.35 (m, 4H). LCMS(ESI):C 41 H 40 Calculated for Cl2N4O7; [M+H]+ :771.23, Actual value:771.50

[0224] 5B. Using amine substrates different from SM3 or SM4, the following compounds could be prepared:

[0225] [ka] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.14 (s, 2H), 4.75 (s, 4H), 4.29 (s, 4H), 3.66 (s, 2H) 3.35-3.29 (m, 8H), 2.29-2.20 (m, 8H). LCMS(ESI):C 36 H 36 Calculated for Cl2N4O6; [M+H] + :691.2, Actual value:691.2

[0226] [ka] 1 H NMR (500 MHz, DMSO-d6) δ 7.62 (s, 2H), 7.52-7.44 (m, 5H), 7.38 (dd, J = 17.4 Hz, 7.9 Hz, 4H), 7.16 (d, J = 8.4 Hz, 2H), 7.10 (s, 2H), 4.70 (s, 4H), 3.99 (td, J = 14.8 Hz, 7.5 Hz, 4H), 3.55 (dd, J = 12.1 Hz, 6.0 Hz, 2H), 2.76 (s, 4H), 2.55 (d, J = 5.7 Hz, 4H), 2.15-1.96 (m, 8H), 1.71-1.61 (m, 2H). LCMS(ESI):C42 H 42 Calculated value for Cl2N4O6; [M+H] + : 797.3, Measured value: 797.3

[0227]

Chem.

[0228]

Chem.

[0229]

Chem.

[0230]

Chem.

[0231]

Chem.

[0232] <0001​​​​​1H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.14 (s, 2H), 4.75 (s, 4H), 4.30 (s, 4H), 3.50 - 3.30 (m, 14H), 2.20 (d, J = 63.2 Hz, 4H) LCMS(ESI): C 42 H 40 Calculated for Cl2N4O8; [M+H] + : 799.2, Found: 799.2

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[0256] [[ID=**33**]] [[ID=**34**]] [[ID=**35**]]

Chem.

化

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Chemistry

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Chemical Structure

[0262] Notes: 1. In the original text, there seems to be a missing digit in the chemical formula in and . I've added the missing " 38 " and " 40 " according to the context. 2. I've translated

化

Chemical Structure

[0263] [Chemical] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.6 Hz, 2H), 7.46 (dd, J = 7.8, 1.8 Hz, 2H), 7.40 (dd, J = 7.4, 1.9 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (dd, J = 8.1, 2.0 Hz, 2H), 7.13 (d, J = 2.0 Hz, 2H), 5.47 (s, 2H), 4.73 (s, 4H), 4.39 - 4.34 (m, 2H), 4.28 - 4.19 (m, 4H), 4.01 (t, J = 7.0 Hz, 4H), 3.71 - 3.67 (m, 2H), 3.24 - 3.20 (m, 2H), 2.68 - 2.56 (m, 2H), 2.46 - 2.34 (m, 2H), 2.20 - 2.11 (m, 4H) LCMS(ESI):C 44 H 44 Cl2N4O 10 Calculated value for [M+H] + :859.24, Actual value:859.50

[0264] [ka] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.6 Hz, 2H), 7.46 (dd, J = 7.8, 1.8 Hz, 2H), 7.40 (dd, J = 7.4, 1.9 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (dd, J = 8.1, 2.0 Hz, 2H), 7.13 (d, J = 2.0 Hz, 2H), 4.73 (s, 4H), 4.13 (t, J = 7.5 Hz, 4H),4.07 (q, J = 7.1 Hz, 4H), 4.01 (t, J = 7.0Hz, 4H), 3.31-3.29 (m, 2H),3.04-3.00 (m, 4H), 1.97 (t, J = 8.1 Hz, 4H), 1.19-1.14 (t, J = 7.1 Hz, 6H). LCMS(ESI):C 44 H 48 Cl2N4O 10 Calculated value for [M+H] + :863.27, Actual value:863.50.

[0265] Example 6 Preparation of (2S,2′S)-2,2′-(((2R,2′R)-((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))bis(propane-1,2-diyl))bis(azanediyl))bis(3-hydroxypropanoic acid) [ka] [ka]

[0266] Synthesis of intermediate 2 A solution of compound SM4 (0.515 g, 2.258 mmol, 1 equiv), 1-bromopropan-2-one (0.340 g, 2.48 mmol, 1.10 equiv), and CsCO (0.960 g, 2.93 mmol, 1.30 equiv) in DMF (5 mL) was stirred at room temperature for 1 h, 15 mL of HO was added slowly, and the solid was collected and dried to give the title compound 2 (0.400 g, 62%).

[0267] Synthesis of intermediate 4 To a solution of compound SM2 (0.300 g, 1.056 mmol, 1 equiv.), compound 3 (0.315 g, 2.024 mmol, 1.90 equiv.), DIEA (0.274 g, 2.124 mmol, 2.01 equiv.), 4A, and 2 drops of AcOH in DCM (6 mL) was added NaBH(OAc) (1.00 g, 4.73 mmol, 4 equiv.) at room temperature. After 3–4 h, 10 mL of HO was added, followed by extraction with DCM. The organic layer was collected and purified on silica gel to give the title compound 4 (0.07 g, 17%).

[0268] Synthesis of intermediate 6 A solution of compound SM2 (0.043 g, 0.09 mmol, 1 equiv), compound 4 (0.07 g, 0.18 mmol, 2.0 equiv), K2CO3 (0.05 g, 0.36 mmol, 4.0 equiv), and Pd(dppf)Cl2.DCM (0.008 g, 0.009 mmol, 0.1 equiv) in dioxane (3 mL) and HO (0.5 mL) was stirred at 80 °C under N2 for 2 h, 5 mL of HO was added, extracted with EA, and the organic layer was collected and purified by preparative TLC to give the title compound 6 (0.05 g, 66%).

[0269] Synthesis of GLC01-563 To a stirred solution of compound 6 (0.025 g, 0.030 mmol, 1 equiv.) in MeOH (2 mL) was added a solution of NaOH (0.020 g, 0.50 mmol, 16.6 equiv.) in HO (0.5 mL) at room temperature. After 1 h, the mixture was purified by reverse-phase HPLC (0.1% trifluoroacetic acid in water / acetonitrile) to give GLC01-563 (12 mg, 50%). 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 8.0 Hz, 4H), 7.14 (d, J = 8.5 Hz, 2H), 7.11 (d, 2H), 4.71 (s, 4H), 4.12-4.07 (m, 2H), 4.00-3.96 (m, 2H), 3.63-3.57 (m, 6H), 3.24-3.22 (m, 2H), 1.08 (d, J = 6.4 Hz, 6H). LCMS(ESI):C 40 H 40 Cl2N4O 10 Calculated value for [M+H] + :807.21, Actual value:807.43

[0270] The same procedure was used to prepare GLC01-550. [ka] 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 8.0 Hz, 4H), 7.14 (d, J = 8.5 Hz, 2H), 7.11 (d, 2H), 4.71 (s, 4H), 4.12-4.07 (m, 2H), 4.00-3.96 (m, 2H), 3.63-3.57 (m, 6H), 3.24-3.22 (m, 2H), 1.08 (d, J = 6.4 Hz, 6H). LCMS(ESI):C40 H 40 Cl2N4O 10 Calculated value for [M+H] + :807.21, Actual value:807.43

[0271] Example 7 7A. Preparation of diethyl 2,2′-((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(6-fluoro-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))bis(ethane-2,1-diyl))bis(azanediyl))(2S,2′S)-bis(3-hydroxypropanoate) and (2S,2′S)-2,2′-((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(6-fluoro-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxypropanoate) [ka] [ka]

[0272] Synthesis of intermediate 2 A solution of compound 1 (0.100 g, 0.598 mmol, 1.00 equiv), NBS (0.115 g, 0.646 mmol, 1.08 equiv), and 1 drop of AcOH in CHCN (1.5 ml) was stirred at 50 °C for 16 h, HO (5 ml) was added slowly, extracted with EA, and the organics were concentrated to give the title compound 2 (0.100 g, 68%).

[0273] Synthesis of intermediate 3 A solution of compound 2 (1.50 g, 6.09 mmol, 1.00 equiv), 2-bromo-1,1-dimethoxyethane (2.00 g, 11.83 mmol, 1.94 equiv), and CsCO (5.00 g, 15.33 mmol, 2.51 equiv) in DMF (15 mL) was stirred at 60 °C for 16 h, 45 mL of HO was added slowly, and the solid was collected and dried in vacuo to give compound 3 (0.65 g, 32%).

[0274] Synthesis of intermediate 5 A solution of compound SM2 (0.280 g, 0.589 mmol, 1.00 equiv), compound 3 (0.400 g, 1.197 mmol, 2.03 equiv), K2CO3 (0.350 g, 2.536 mmol, 4.3 equiv), and Pd(dppf)Cl2.DCM (0.030 g, 0.036 mmol, 0.06 equiv) in dioxane (3 mL) and HO (0.5 mL) was stirred at 80 °C for 2 h under N2, 5 mL of HO was added, and the mixture was extracted with EA. The organic layer was concentrated and purified on silica gel (PE:EA = 3:1 to 1:1) to give compound 5 (0.330 g, 77%).

[0275] Synthesis of intermediate 6 A solution of compound 5 (0.340 g, 0.466 mmol, 1 equiv) in dioxane / 1 N HCl (4 ml / 2 ml) was stirred at 80 °C for 0.5 h, 10 mL of HO was added, extracted with EA, and the organic layer was concentrated to give compound 6 (0.330 g, crude product).

[0276] Synthesis of GLC01-589 To a solution of compound 6 (0.330 g, 0.520 mmol, 1.0 equiv.), compound 7 (0.440 g, 2.59 mmol, 5.0 equiv.), DIEA (0.351 g, 2.72 mmol, 5.2 equiv.), 4A, and AcOH (0.155 g, 2.59 mmol, 5.0 equiv.) in DCM (7 mL) was added NaBH(OAc) (0.500 g, 2.37 mmol, 4.5 equiv.) at room temperature. After 3–4 h, 10 mL of HO was added, followed by extraction with DCM. The organic layer was collected and purified on silica gel (DCM:MeOH = 50:1–20:1) to give GLC01-589 (0.200 g, 44%). 1 H NMR (500 MHz, DMSO-d6) δ 7.53 (t, J = 7.6 Hz, 2H), 7.49-7.43 (m, 4H), 7.37 (d, J = 11.2 Hz, 2H), 7.04 (d, J = 6.8 Hz, 2H), 4.81 (t, J = 5.6 Hz, 2H), 4.68 (s, 4H), 4.07 (q, J = 7.1 Hz, 4H), 4.00-3.90 (m, 4H), 3.60-3.49 (m, 4H), 3.37-3.33 (m, 2H), 2.87-2.77 (m, 2H), 2.68-2.62 (m, 2H), 1.19-1.14 (t, J = 7.1 Hz, 6H). LCMS(ESI):C 42 H 42 Cl2F2N4O 10 Calculated value for [M+H] + :871.22, Actual value:871.50

[0277] Synthesis of GLC01-554 To a solution of GLC01-589 (0.015 g, 0.017 mmol, 1 equiv.) in MeOH (0.2 mL) was added a solution of NaOH (0.020 g, 0.5 mmol, 29 equiv.) in HO (0.1 mL) at room temperature. After 1 h, the mixture was purified by reverse-phase HPLC (0.1% trifluoroacetic acid in water / acetonitrile) to give GLC01-554 (7.7 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ 7.53 (t, J = 7.6 Hz, 2H), 7.48-7.39 (m, 6H), 7.06 (d, J = 6.9 Hz, 2H), 4.70 (s, 4H), 4.13 (t, J = 7.5 Hz, 4H), 3.72-3.65 (m, 4H), 3.31-3.29 (m, 2H), 3.07-3.03 (m, 2H), 3.02-2.97 (m, 2H). LCMS(ESI):C 38 H 34 Cl2F2N4O 10 Calculated value for [M+H] + :815.16, Actual value:815.33

[0278] 7B. The following compounds could be prepared using different starting materials:

[0279] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.49 (d, J = 4 Hz, 2H), 7.43 (d, J = 4.0Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 7.06 (s, 2H), 4.72 (s, 4H), 4.26 (m, 4H), 4.14 (s, 2H), 3.90 (m, 4H), 3.34 (m, 4H). LCMS(ESI):C 38 H 34 F2Cl2N4O 10 Calculated value for [M+H] + :815.16, Actual value:815.16

[0280] [ka] 11H NMR (400 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.49 (d, J = 4 Hz, 2H), 7.43 (d, J = 4.0Hz, 2H), 7.30 (d, J = 8 Hz, 2H), 7.06 (s, 2H), 4.72 (s, 4H), 4.26 (m, 4H), 4.14 (s, 2H), 3.90 (m, 4H), 3.34 (m, 4H). LCMS(ESI):C 38 H 34 F2Cl2N4O 10 Calculated value for; [M+H] + :815.16, Measured value: 815.16

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Chemical Structure

[0282]

Chemical Structure

[0284] Example 8 8A. Preparation of diethyl 2,2′-((((2,2′-difluoro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))bis(ethane-2,1-diyl))bis(azanediyl))(2S,2′S)-bis(3-hydroxypropanoate) and (2S,2′S)-2,2′-((((2,2′-difluoro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))bis(ethane-2,1-diyl))bis(azanediyl))bis(3-hydroxypropanoate) [ka] [ka]

[0285] Synthesis of intermediate GLC01-612-04 To a stirred solution of GLC01-612-03 (100 mg, 0.206 mmol, 1.0 equiv.) and SM (164 mg, 0.453 mmol, 2.2 equiv.) in 4 mL of 1,4-dioxane and 0.8 mL of water, K2CO3 (114 mg, 0.826 mmol, 4.0 equiv.) and Pd(dppf)Cl2.DCM (33 mg, 0.04 mmol, 0.2 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was then heated at 85 °C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EA (3 × 15 mL). The combined organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA = 2 / 1) to give the desired product (70 mg, 52% yield) as a pale yellow solid.

[0286] Synthesis of GLC01-612 To a stirred mixture of GLC01-612-04 (50 mg) in ACN (3 mL) and water (3 mL) was added TFA (0.3 mL) at ambient temperature. After stirring at 80 °C for 1 h, the resulting solution was adjusted to pH 8-9 with aqueous KCO, extracted with EA, washed with brine, and the organic phase was concentrated under reduced pressure. The residue (43 mg, 100% yield) was used directly in the next step. The reductive amination step was carried out according to the procedure described above. 1 H NMR (500 MHz, DMSO) δ 7.53-7.31 (m, 8H), 7.12 (dd, J = 31.2, 8.5 Hz, 4H), 4.81 (t, J = 5.5 Hz, 2H), 4.68 (s, 4H), 4.10-4.03 (m, 4H), 3.98 (ddd, J = 21.0, 14.1, 7.1 Hz, 4H), 3.54 (ddt, J = 16.0, 10.5, 5.2 Hz, 4H), 2.83 (dt, J = 14.1, 7.1 Hz, 2H), 2.69-2.63 (m, 2H), 1.22-1.12 (m, 6H). LCMS(ESI):C 42 H 44 Cl2N4O 10 Calculated value for [M+H] + :803.3, Actual value:803.3

[0287] Synthesis of GLC01-613 The hydrolysis reaction was carried out according to the procedure described above. 1 H NMR (500 MHz, DMSO) δ 7.52 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.6, 1.8 Hz, 2H), 7.43-7.34 (m, 4H), 7.19 (dd, J = 8.4, 1.9 Hz, 2H), 7.13 (d, J = 1.9 Hz, 2H), 4.73 (s, 4H), 4.31-4.20 (m, 4H), 4.10-4.01 (m, 2H), 3.90-3.81 (m, 4H), 3.25-3.19 (m, 4H). LCMS(ESI):C38 H 36 Cl2N4O 10 Calculated value for [M+H] + :747.3, Actual value:747.3

[0288] Example 9 (different core, same side preparation) 9A. Preparation of 6,6′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(1-(((S)-5-oxopyrrolidin-2-yl)methyl)-3,4-dihydroquinolin-2(1H)-one) [ka] [ka]

[0289] Substrate A was prepared using the same procedure as for SM5.

[0290] A mixture of compound A (100 mg, 1 equiv.), CsCO (253 mg, 4.0 equiv.), and SM1 (157 mg, 3.0 equiv.) in DMF was stirred at 40° C. for 2 hours. The reaction mixture was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the title compound 281 (98 mg, yield: 71%). 1 H NMR (500 MHz, Chloroform-d) δ 7.46-7.37 (m, 3H), 7.36 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 7.4, 2.0 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 5.89 (s, 1H), 4.20-3.98 (m, 3H), 2.99 (t, J = 7.5 Hz, 2H), 2.83-2.66 (m, 2H), 2.40-2.30 (m, 2H), 2.10-1.85 (m, 2H). LCMS(ESI):C 40 H 36Calculated for Cl2N4O4 [M+H] + :707.22, Actual value:707.43.

[0291] 9B. The following compounds could be prepared using different bromide substrates:

[0292] [ka] 1 H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 8.7, 2.1 Hz, 2H), 7.71 (s, 2H), 7.60-7.54 (m, 4H), 7.51-7.47 (m, 2H), 3.91-3.82 (m, 2H), 3.61-3.53 (m, 4H), 3.41-3.33 (m, 4H), 2.85-2.76 (m, 4H), 2.39-2.26 (m, 4H), 2.25-2.06 (m, 6H), 1.92-1.84 (m, 2H) LCMS(ESI):C 40 H 40 Calculated for Cl2N4O2 [M+H] + :679.25, Actual value:679.45

[0293] [ka] 11H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.7, 1.7 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 2.0 Hz, 2H), 4.71 (s, 4H), 4.06 - 3.89 (m, 6H), 2.34 - 2.24 (m, 2H), 2.20 - 2.07 (m, 4H), 1.84 - 1.72 (m, 2H).. LCMS(ESI): C 38 H 32 Calculated for Cl2N4O6; [M + H] + : 711.17, Found: 711.47

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Chem.

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Chem.

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[0310] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 2H), 7.92 (s, 2H), 7.62-7.75 (m, 6H), 4.78 (s, 4H), 4.22 (m, 2H), 4.06 (dd, J = 4 Hz, 2H), 3.95 (m, 2H), 2.32 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H) 1.80 (m, 2H). LCMS(ESI):C 34 H 28 Calculated for Cl2N8O6; [M+H] + :715.15,Actual value:715.15.

[0311] Example 10 (Preparation of Same Core, Different Sides) 10A. Preparation of 2,2′-((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-7,4-diyl))diacetonitrile [ka] [ka]

[0312] A mixture of compound SM5 (100 mg, 1 equiv.), CsCO (251 mg, 4.0 equiv.), and bromoacetonitrile (69 mg, 3.0 equiv.) in DMF was stirred at 40° C. for 2 hours. The reaction mixture was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give title compound 397 (92 mg, yield: 67.6%). 1 H NMR (500 MHz, DMSO-d6) δ 7.54-7.46 (m, 2H), 7.44-7.38 (m, 2H), 7.25 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 5.15 (s, 2H), 4.84 (s, 2H). LCMS(ESI):C 32 H 20 Calculated for Cl2N4O4 [M+H] + :595.09, Actual value:595.40.

[0313] 10B. Following the procedure above, compounds could be prepared with different bromide side chains.

[0314] [ka] 11H NMR (500 MHz, DMSO-d6) δ 7.55 (broad singlet, 1H), 7.52 - 7.45 (multiplet, 2H), 7.41 - 7.36 (multiplet, 2H), 7.16 (doublet of doublets, J = 8.4, 2.0 Hz, 1H), 7.12 (doublet, J = 2.0 Hz, 1H), 4.73 (singlet, 2H), 4.11 - 3.98 (multiplet, 2H), 3.34 - 3.28 (multiplet, 1H), 3.06 - 2.99 (multiplet, 1H), 2.83 - 2.74 (multiplet, 1H), 2.30 - 2.22 (multiplet, 1H), 2.02 - 1.95 (multiplet, 1H). LCMS(ESI): C 38 H 32 Calculated for C 1 Cl2N4O6; [M + H] + <"0000405">:​​​​​​​​​​​​​​​​​​​​​​​​​​​1H NMR (500 MHz, DMSO-d6) δ 7.74 (d, J = 1.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.41 (m, 2H), 7.39 (dd, J = 7.4, 1.8 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.18 (t, J = 2.0 Hz, 1H), 4.68 (d, J = 1.4 Hz, 2H), 4.40 (t, J = 6.2 Hz, 2H), 4.28 (t, J = 6.2 Hz, 2H). LCMS(ESI):C 38 [[ID=H]]H 30 Calculated for Cl2N6O4; [M + H] + : 705.18, found: 705.42.

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[0327] Example 11 (same core, different sides) 11A. Preparation of 7,7′-(2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(4-(((S)-pyrrolidin-2-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one) [ka] [ka]

[0328] 1. [ka] To a stirred solution of 411-01 (500 mg, 2.49 mmol, 1.0 equiv) in DCM (5 mL), TosCl (567 mg, 2.98 mmol, 1.2 equiv) and TEA (502 mg, 4.97 mmol, 2.0 equiv) were added, followed by DMAP (30 mg, 0.249 mmol, 0.1 equiv) at room temperature and stirring for 4 h. Water and DCM were added to the reaction mixture, which was then separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue (950 mg, 107% yield) was used directly in the next step.

[0329] 2. [ka] To a stirred solution of SM4 (117 mg, 0.51 mmol, 1.0 equiv) in DMF (2 ml) was added 411-02 (219 mg, 0.62 mmol, 1.2 equiv) and CS2CO3 (337 mg, 1.03 mmol, 2.0 equiv) at ambient temperature. The resulting mixture was then stirred at 70 °C overnight. The reaction was quenched with water and extracted with EA. The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA = 4 / 1) to give the desired product (105 mg, yield: 50%) as a pale yellow oil.

[0330] 3. [ka] To a solution of 411-03 (105 mg, 0.26 mmol, 2.2 equiv) and SM2 (55 mg, 0.12 mmol, 1.0 equiv) in dioxane (2.5 mL) and HO (0.5 mL) under a N atmosphere, Pd(dppf)Cl·DCM (19 mg, 0.024 mmol, 0.2 equiv) and KCO (64 mg, 0.48 mmol, 4.0 equiv) were added. The final mixture was then heated to 80 °C and stirred for 2 h. After cooling to room temperature, water was added and extracted twice with EA. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the desired product (50 mg, yield: 49%) as a white solid.

[0331] 4. [ka] To a solution of 411-03 (50 mg, 0.056 mmol, 1.0 equiv) in MeOH (1 mL), a 4 M solution of HCl in dioxane (1 mL) was added, and the solution was stirred at room temperature for 2 h. After completion of the reaction, the solvent was evaporated under reduced pressure and lyophilized to give the desired product (36 mg, yield: 95%). 1 H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 2H), 8.72 (s, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.48-7.43 (m, 4H),7.41 (d, J = 7.4 Hz, 2H), 7.19-7.12 (m, 4H), 4.78 (t, J = 8.6 Hz, 4H), 4.35 (dd, J = 15.0, 7.8 Hz, 2H), 4.24 (dd, J = 14.9, 5.0 Hz, 2H), 3.71 (s, 2H), 3.28 (s, 2H), 3.11 (s, 2H), 2.17 (d, J = 6.7 Hz, 2H), 2.02-1.88 (m, 4H), 1.71 (dt, J = 18.8, 9.3 Hz, 2H). LCMS(ESI):C 38 H 36Calculated value for Cl2N4O4 (free form); [M+H] + : 683.2, measured value: 683.2

[0332] 11B. The following compounds can also be prepared.

[0333]

Chemical formula

[0334]

Chemical formula

[0335]

change

[0336]

Chem.

[0337]

Chem.

[0338]

change

[0339]

change

[0340]

change

[0341] [[]] [[]] [[]] [[]] [[]] [[]] [[]] [[]]

[0342] [[]] [[]] [[]] [[]] [[]] [[]] [[]] [[]]

[0343] [[]] [[]] [[]] [[]] [[]] [[]] [[]] [[]]

[0344] [[]] [[]] [[]] [[]] [[]] [[]] [[]] [[]]

[0345] [[]] [[]] [[]] [[]] [[]] [[]] [[]] [[]]

[0346] [[]]<0​​​​​​​​​​​​​​​​​​​​​ [Chemical formula] 1 1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.4 Hz, 2H), 7.53 - 7.44 (m, 4H), 7.40 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.10 (s, 2H), 4.78 - 4.64 (m, 4H), 4.24 (dd, J = 24.9, 11.7 Hz, 4H), 3.74 (d, J = 10.6 Hz, 2H), 3.52 (t, J = 9.0 Hz, 2H), 3.38 (dd, J = 17.3, 9.7 Hz, 2H), 2.09 - 2.01 (m, 2H), 1.94 (s, 6H), 1.92 - 1.87 (m, 2H), 1.80 - 1.70 (m, 4H). LCMS(ESI): C 42 H 40 Calculated value for C12H12Cl2N4O6; [M + H] + : 767.2, Measured value: 767.2

[0342] [Chemical formula] 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.76 (br s, 1H), 7.54 - 7.49 (m, J = 7.6 Hz, 1H), 7.46 (dd, J = 9.0, 3.1 Hz, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.16 (dd, J = 8.2, 2.1 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 4.77 (s, 2H), 4.38 - 4.25 (m, 2H), 3.70 (s, 1H), 3.31 - 3.04 (m, 2H), 2.20 - 1.95 (m, 2H), 1.94 - 1.66 (m, 2H). LCMS(ESI): C [[ID=...]] 38 H 36Calculated value for Cl2N4O4; [M+H] + : 683.22, measured value: 683.49.

[0343]

Chem.

[0344]

Chem.

[0345] [ka] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 6H), 7.52 (t, J = 6 Hz, 2H), 7.45 (d, J = 4.0 Hz, 2H), 7.40 (d, J = 4 Hz, 2H), 7.35 (d, J = 4 Hz, 2H), 7.17 (d, J = 4.0 Hz, 2H), 7.13 (s, 2H), 4.73 (s, 4H), 4.19 (t, J = 6 Hz, 4H), 3.09 (t, J = 6 Hz, 4H). LCMS(ESI):C 32 H 28 Calculated for Cl2N4O4 [M+H] + :603.15,Actual value:603.15.

[0346] Example 12 (Asymmetric, Asymmetric) Preparation of (S)-7-(2,2′-dichloro-3′-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-[1,1′-biphenyl]-3-yl)-4-((5-oxopyrrolidin-2-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] [ka]

[0347] SM5 (20.0 mg, 1 equivalent), SM1 (10.4 mg, 1 equivalent), and cesium carbonate (25 mg, 2 equivalents) were dissolved in DMF (1 ml). The reaction was carried out at 40 °C for 2 hours. After cooling, 5 ml of water and 5 ml of EA were added for extraction, and the organic phase was washed with water and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to give the title compound 429 (11 mg, yield: 46.3%). 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.76 (s, 1H), 7.52-7.46 (m, 2H), 7.46-7.41 (m, 2H), 7.41-7.36 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.07-7.02 (m, 2H), 6.98 (d, J = 7.9 Hz, 1H), 4.71 (s, 2H), 4.63 (s, 2H), 4.04-3.92 (m, 3H), 2.34-2.23 (m, 1H), 2.21-2.05 (m, 2H), 1.83-1.74 (m, 1H). LCMS(ESI):C 33 H 25 Calculated for Cl2N3O5; [M+H] + :614.13, Actual value:614.41

[0348] Following the procedure above, the title compound 385 was obtained by the same procedure. [ka] 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.52-7.45 (m, 3H), 7.43 (dd, J = 7.7, 1.8 Hz, 1H), 7.40-7.36 (m, 3H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.07-7.02 (m, 2H), 6.98 (d, J = 7.9 Hz, 1H), 4.68 (s, 2H), 4.62 (s, 2H), 4.05 (t, J = 6.5 Hz, 2H), 3.46-3.41 (m, 2H), 3.31 (t, J = 6.5 Hz, 2H), 3.19-3.14 (m, 2H). LCMS(ESI):C 33 H 26 Calculated for Cl2N4O5; [M+H] + :629.14, Actual value:629.44

[0349] Example 13 13A. Preparation of (2-(7-(2,2′-dichloro-3′-(3-oxo-4-(((S)-pyrrolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-[1,1′-biphenyl]-3-yl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)-L-serine [ka]

[0350] (a) Referring to the following reaction scheme, compound 1A-1 (0.35 g, 1.54 mmol, 1 equivalent), compound 1A-2 (1.10 g, 3.07 mmol, 2.0 equivalents), and cesium carbonate (0.75 g, 2.30 mmol, 1.5 equivalents) were dissolved in DMF (10 ml). The reaction was carried out at 60 °C for 5 hours. After cooling, 10 ml of water and 10 ml of EA (ethyl acetate) were added for extraction. The organic phase was washed with water and purified on silica gel. The mixture was eluted with PE / EA (v / v, 8:1) to obtain compound 1A, tert-butyl (S)-2-((7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)pyrrolidine-1-carboxylate (0.35 g, yield: 55.5%).

[0351] [ka]

[0352] (b) Referring to the reaction scheme below, compound 1B (25 mg) was dissolved in dioxane (0.5 ml), and then 1N HCl solution (0.5 ml) was added dropwise. The temperature was raised to 85°C, and the reaction was carried out for 0.5 hours. The pH of the reaction solution was adjusted to 7-8 by adding saturated Na2CO3 solution, and 10 ml of EA was added for extraction. The organic phase was concentrated to obtain 1B (25 mg, yield: 107.0%). [ka]

[0353] (c) Referring to the reaction scheme below, compound 1C (25 mg, 0.09 mmol, 1 eq.), 1D (29 mg, 0.19 mmol, 2 eq.), TEA (19 mg, 0.19 mmol), and 1 drop of AcOH were dissolved in DCM (3 ml), and the resulting mixture was stirred at room temperature for 1 hour. NaBH(OAc) (37 mg, 0.45 mmol, 5 eq.) was then added, and the reaction was carried out for 1 hour. Next, 10 ml of HO and 10 ml of DCM were added for extraction. The organic phase was concentrated to give 1C (25 mg, yield: 72%). [ka]

[0354] (d) Referring to the following reaction scheme, compounds 1F (0.05 g, 0.11 mmol, 1 equiv.), 1A (0.043 g, 0.11 mmol, 1 equiv.), 1E (0.04 g, 0.11 mmol, 1 equiv.), Pd(dppf)Cl (0.008 g, 0.01 mmol, 0.1 equiv.), and potassium carbonate (0.058 g, 0.42 mmol, 4 equiv.) were dissolved in dioxane / HO (3 mL, v / v = 5:1). The reaction was carried out at 85 °C for 2 hours under a N atmosphere. After cooling, 10 ml of water and 10 ml of EA were added for extraction, and the organic phase was concentrated and purified by preparative TLC (PE / EA=1 / 1 elution) to give compound 1G, tert-butyl (S)-2-((7-(2,2′-dichloro-3′-(4-(2-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)amino)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-[1,1′-biphenyl]-3-yl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)pyrrolidine-1-carboxylate (0.017 g, yield: 20%). LCMS(ESI):C 44 H 46 Calculated for Cl2N4O9 [M+H] + :845.26,Actual value:845.26. [ka]

[0355] (e) Referring to the reaction scheme below, 1N HCl (1 mL) was added to a solution of compound 1G (17 mg, 0.02 mmol) in dioxane (1 mL) and stirred at room temperature for 3 hours. NaCO (aq) was then added to the reaction mixture to neutralize unreacted HCl. The reaction mixture was extracted with EA and water. The organic phase was concentrated and purified by preparative HPLC to give 1F (10 mg, yield: 67%). [ka]

[0356] (f) Referring to the reaction scheme below, NaOH (0.5 ml, 0.26 M in water) was added to a solution of 1F (10 mg, 0.013 mmol) in MeOH / THF (3 mL, 2:1), followed by stirring at room temperature for 1 h. HCl (1 M) was then added to the reaction mixture to neutralize unreacted NaOH. The reaction mixture was purified by preparative HPLC to give the title compound 1 (7.4 mg, yield: 75.5%). 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.43 (s, 1H), 7.53-7.36 (m, 8H), 7.19-7.12 (m, 4H),5.58 (s, 1H), 4.78 (s, 2H), 4.71 (s, 2H), 4.36 (m, 1H), 4.32-4.13 (m, 3H), 4.04 (m, 1H), 3.87 (s, 2H), 3.72 (m, 1H), 3.21 (m, 2H), 3.12 (m, 2H), 2.20 (m, 1H), 1.94 (m, 2H), 1.70 (m, 1H). LCMS(ESI):C 40 H 36 Calculated for Cl2N4O8; [M+H] + :731.21,Actual value:731.21. [ka]

[0357] 13B. Using the same procedure, the following compounds were prepared:

[0358] [ka] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.64 (s, 2H), 8.44 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.45 (d, J = 4.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.36 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.14 (s, 2H), 4.75 (s, 2H), 4.71 (s, 2H), 4.36 (m, 1H), 4.24 (t, J = 4.0 Hz, 2H), 419 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 3.72 (m, 1H), 3.31 (m, 3H), 3.23 (m, 2H), 3.12 (m, 1H), 3.06 (m, 2H), 2.20 (m, 1H), 1.97 (m, 2H), 1.85 (s, 3H), 1.70 (m, 1H) LCMS(ESI): C 39 H 39 Calculated for Cl2N5O5; [M+H][[ID=*]] + : 728.23, Found: 728.23.

[0359]

Chemical Structure

化

[0360]

Chem.

[0361]

Chem.

[0362]

Chemical Structure

[0363]

Chemical Structure

[0364]

Chem.

[0365]

Chem.

[0366] Example 14 PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay

[0367] Assays were performed in standard black 384-well polystyrene plates with a final volume of 20 μL. Inhibitors were first serially diluted in DMSO and then added to the plate wells prior to the addition of other reaction components. The final concentration of DMSO in the assay was 1%. Assays were performed at 25°C in PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a C-terminal His tag was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with a C-terminal Fe tag was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in assay buffer, and 10 μL was added to the plate wells. The plate was centrifuged, and the proteins were pre-incubated with the inhibitors for 40 minutes. Following incubation, 10 μL of HTRF detection buffer supplemented with Fe-specific europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) and anti-His antibody conjugated to SureLight® allophycocyanin (APC, PerkinElmer-AD0059H) was added. After centrifugation, the plate was incubated at 25°C for 60 minutes and then read on a PHERAstar FS plate reader (665 nm / 620 nm ratio). Final concentrations in the assay were 3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG, and 20 nM anti-His-allophycocyanin. IC was determined by curve fitting of percent control activity versus the logarithm of inhibitor concentration. 50 Measurements were carried out.

[0368] [Table 2]

[0369] Example 15 PD-L1 internalization

[0370] 1. Experimental Protocol Day 1. Cell seeding: PD-L1 / CHO-K1 cells were digested with trypsin in a flask, then the cells were counted and diluted to 1x105 cells / ml. The cells were seeded into a 6-well plate (Corning, #3516) at 2mL / well. The plate was incubated at 37°C in a 5% CO2 incubator for 24 hours.

[0371] Day 2. Preparation of compounds and treated cells: GLC01-258 was diluted from 15 mM to 0.5 mM using DMSO, and the 15 mM compounds were serially diluted from 15 mM to 15 nM in DMSO, followed by a 500-fold dilution of the compounds using assay buffer. 0.2% DMSO was prepared in assay buffer to be used for the vehicle and low controls. The plate was removed, and the medium was aspirated and discarded. 2 mL of diluted compound, vehicle, and low controls were added to the corresponding wells. The plate was then incubated at 37°C in a 5% CO2 incubator for 17 hours.

[0372] Day 3. Preparation of samples for FACS: After 17 hours of incubation, the medium was discarded and washed with PBS. The cells in each well were digested with trypsin. After centrifugation, the supernatant was discarded and the cells were resuspended in DPBS (Ca). 2+ , Mg 2+The cells are washed twice with DPBS (without PBS). The antibody (PE-conjugated mouse anti-human CD274) is diluted 10-fold in DPBS, and then the staining solution is added to the compound-treated and vehicle control samples. For the low control, only DPBS is added without antibody. The plate is incubated at room temperature for 20 minutes, protected from light. After 20 minutes, the samples are washed twice with DPBS. They are then centrifuged and the supernatant is discarded. The cells are resuspended in 300uL of DPBS, and the samples are transferred to 5mL polystyrene round-bottom tubes (Falcon, #352054) and run on a BD FACSCanto. Run the samples on a BD FACSCanto.

[0373] 2. Data analysis The PD-L1 signal of the vehicle control is set to 100% and the PD-L1 signal of the low control is set to 0%. The PD-L1 signal of the compound-treated samples is then calculated. 0% PD-L1 signal: low control stained without anti-CD274 100% PD-L1 signal: vehicle control stained with anti-CD274 % activation of PD-L1 internalization = 1 - PD-L1 signal of compound.

[0374] [Table 3]

[0375] Example 16 PD-L1 dimerization To determine whether the compounds could specifically dimerize the extracellular domain of PD-L1, the compounds were tested in a biochemical protein-protein interaction assay.

[0376] (1) For each column of 10+0 pts, serially dilute the compounds 1:3 in DMSO (see dilution plate map). (2) Use Echo to transfer 0.2 µL of compound solution from each column to a 384-well assay plate, with each column containing two replicates (see assay plate map). (3) 20 μL of the prepared mixture containing the PDL1-Eu and PDL1-A2 solutions is added to the assay plate and centrifuged at 1000 rpm for 1 minute. (4) Incubate at 25°C for 120 minutes. (5) Read the fluorescent signal using an Envision 2104 plate reader. (6) Read the ratio (665nm / 615nm) signal on Envision. (7) Analyze the raw data using equations (V. Data Analysis).

[0377] [Table 4]

[0378] Example 17 PDL1 Jurkat-NFAT reporter assay

[0379] a. Preparation of Hep3B-OS8-hPDL1 1. Hep3B-OS8-hPDL1 cells were cultured in 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and also containing 100 μg / mL of G418 and hygromycin B. 2. The cells were resuspended in RPMI1640 medium containing 10% FBS, and the cell density was adjusted to 1.25E5 cells / mL. 3. Cells were seeded into 96-well flat-bottom plates (1.25E4 cells / 100 μL / well).

[0380] b. Preparation of compound solutions 4. Remove the medium from the pre-plated Hep3B-OS8-PDL1 cells and wash once with 200 μL of assay medium. 5. Prepare compound dilutions in RPMI 1640 medium with 10% FBS according to layout. 6. Nine concentrations of compound (3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, and 0.0003 μM) are added to each well in a volume of 50 μL. Include Keytruda at a concentration of 5 μg / mL as a positive control. 7. Incubate at 37°C, 5% CO2 for 20-30 minutes.

[0381] c. Preparation of Jurkat-NFAT-PD1 8. Jurkat-NFAT-PD1 cells were cultured in 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and also supplemented with 1000 μg / mL hygromycin B and 0.3 μg / mL puromycin. 9. On the second day of the assay, the cells were resuspended in RPMI 1640 medium containing 10% FBS and the cell density was adjusted to 2.5E5 cells / mL. 10. Cells were seeded into 96-well flat-bottom plates (1.25E4 cells / 50 μL / well). 11. Incubate the assay plate in a humidified 37°C, 5% CO2 incubator for 6 hours. 12. Equilibrate the cultured cells at room temperature for 5-10 minutes. 13. Add an equal volume (100 μL / well) of ONE-Glo™ Luciferase Assay System to each well, wait at least 3 minutes for cells to completely lyse, and measure in a luminometer.

[0382] [Table 5]

[0383] Example 18 a. Co-culture assay of Hep3B-OS8-hPDL1 and T cells Tumor preparation 1. Hep3B-OS8-hPDL1 cells were cultured in 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and also containing 100 μg / mL of G418 and hygromycin B. 2. Hep3B-OS8-hPDL1 cells were harvested and treated with 10 μg / mL mitomycin C at 37°C for 1.5 hours, after which the cells were thoroughly washed four times with PBS. 3. The cells were resuspended in RPMI1640 medium containing 10% FBS, and the cell density was adjusted to 5E5 cells / mL. 4. Cells were seeded into 96-well flat-bottom plates (2.5E4 cells / 50 μL / well).

[0384] b. CD3+ T Cell Isolation (30 mL of blood) 5. Human blood samples from individual donors are diluted with an equal volume of sterile PBS, for example, 25 mL of sterile PBS is added to 25 mL of fresh whole blood and mixed thoroughly by gentle shaking. 6. Transfer 15 mL of Lymphoprep medium to a new 50 mL centrifuge tube. 7. Add the diluted blood sample as gently as possible to the surface of the Ficoll medium, ensuring that there is a clear boundary between the two liquids, and achieve a volume ratio of 1:2 between Ficoll and diluted blood (30 mL). 8. Gently agitate the tube and centrifuge at 1000 x g for 25 minutes at 20°C with acceleration (5) and minimum deceleration (0) during centrifugation. 9. After centrifugation, a total of four interfaces can be observed: plasma, mononuclear cells, Ficoll medium, and RBC layers from top to bottom. Then, gently move the tube to keep the four interfaces separate. Carefully aspirate the second layer of mononuclear cells and transfer them to another sterile centrifuge tube. If necessary, aspirate a certain amount of plasma instead of the Ficoll medium. 10. Add 3x the volume of sterile PBS to the tube containing the PBMCs. 11. Wash the cells twice with 5-10 mL of PBS and then count them using a cytometer. Centrifuge at 350 x g for 10 minutes at 20°C with an acceleration and deceleration setting of 5. 12. Resuspend cells in the recommended medium and adjust the PBMC density to a final concentration of 5E7 cells / mL. 13. CD3+ T cells were isolated using the EasySep™ Human T Cell Isolation Kit (STEMCELL Technologies #17951) and seeded into 96-well flat-bottom plates (5E4 cells / 100 μL / well).

[0385] c. Preparation of compound solutions 14. Prepare compound dilutions in RPMI 1640 medium with 10% FBS according to layout. 15. Add compounds to each well in a volume of 50 μL {three compounds (GLC01-258, GLC01-269, GLC01-465) at seven concentrations (0.03, 0.1, 0.3, 1, 3, 10, and 30 μM), and six compounds (GLC01-411, GLC01-292, GLC01-445, GLC01-475, GLC01-470, and GLC01-468) at the same concentration (1 μM)}. 16. Include Keytruda as a positive control at a concentration of 5 μg / mL. 17. Incubate at 37°C, 5% CO2 for 72 hours. 18. Collect the supernatant by centrifugation and measure IFN-γ by ELISA.

[0386] [Table 6]

[0387] Example 19 Mouse PK study (1) Compounds were weighed and dissolved in a vehicle of 5% saline solution at 1 mg / mL, shaken vigorously, and sonicated to form a clear, colorless solution, which was orally administered at a dose of 10 mg / kg to groups of three overnight-fasted mice. (2) Blood samples were collected from the submandibular vein using sodium heparin as an anticoagulant. After collection, the blood was placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours. (3) The samples were stored in a -20°C freezer. 160 μL of ice-cold acetonitrile containing the internal standard was added to 40 μL of plasma sample, vortexed for 3 minutes, and centrifuged at 11,000 rpm for 5 minutes. 100 μL of the supernatant was added to 100 μL of water, and 5 μL of the supernatant was injected into the LC / MS / MS system to detect the compound (if the compound was an ester, the acid was detected).

[0388] Display the data 7 Shown below. [Table 7]

[0389] While various embodiments have been described above, it should be understood that such disclosure is presented by way of example only, and not limitation. Thus, the breadth and scope of the subject compositions and methods should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0390] The above description is intended to teach those skilled in the art how to practice the present application and is not intended to detail all obvious modifications and variations that will become apparent to those skilled in the art upon reading the present description. However, all such obvious modifications and variations are intended to be included within the scope of the present application as defined by the claims that follow. The claims are intended to cover any sequence of components and steps that is effective to achieve the intended purpose, unless the context specifically indicates to the contrary.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof. [Chemical Formula 1] (In the formula, A and B each independently represent a halogen, a cyano, or —N ３ , alkyl and substituted alkyl, amine, alkylamine, alkoxy; Z １ Ha-CR １ = or -N=, Z ２ Ha-CR ２ = and Z ３ Ha-CR ３ = or -N=, Z ４ Ha-CR ４ = or -N=, Z ５ Ha-CR ５ = and Z ６ Ha-CR ６ = or -N=, R １ and R ４ are each independently —H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R ２ and R ５ are each independently —H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R ３ and R ６ are each independently —H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; Y １ and Y ２ are each independently -C(R ７ ) (R ８ ) -, -CR ９ =, -NR １０ -, -O- or -S-; X １ and X ２ are each independently -C(R １１ ) (R １２ )-, -N=, -NR １３ -, -S- or -O-; R ７ , R ８ , R ９ , R １１ , and R １２ are each independently —H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy; R １０ and R １３ are each independently —H, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, alkylamine, or alkoxy; L １ and L ２ are rings 3 and W, respectively. １ Between ring 6 and W ２ and wherein said alkyl, said substituted alkyl or said heteroatom chain each contains m atoms, where m=0, 1, 2, 3, 4, 5 or 6; and when m is 0, W １ Or W ２ are each directly attached to the corresponding nitrogen atom in ring 3 or ring 6, W １ and W ２ are each independently hydrogen, a 5-membered heterocycle or a substituted 5-membered heterocycle, a 6-membered heterocycle or a substituted 6-membered heterocycle, a carboxylalkyl group or a substituted carboxylalkyl group, a cyanoalkyl group or a substituted cyanoalkyl group, an aminoalkyl group or a substituted aminoalkyl group, a hydroxyalkyl group or a substituted hydroxyalkyl group, an amino acid, an ester of an amino acid, or an amide of an amino acid.

2. A and B are each independently selected from halogen, alkyl and substituted alkyl, cyano, and —N ３ is selected from Z １ Ha-CR １ = or -N=, Z ２ Ha-CR ２ = and Z ３ Ha-CR ３ = or -N=, Z ４ Ha-CR ４ = or -N=, Z ５ Ha-CR ５ = and Z ６ Ha-CR ６ = or -N=, R １ and R ４ are each independently —H or —F, —Cl, or —CH ３ and R ２ and R ５ are each independently —H, —Cl, —F, or —CH ３ , or -NH ２ and R ３ and R ６ are each independently —H, —Cl, —F, or —CH ３ , or -NH ２ and X １ and X ２ are each independently -C(R １１ ) (R １２ )-, -N=, -NH-, -N(R １３ )- or -O-; Y １ and Y ２ are each independently -CH ２ -, -CH=, -NH-, -O-, -C(R ７ ) (R ８ ) - and R ７ , R ８ , R １１ and R １２ are each independently —H, —F, —Cl, or —CH ３ and L １ and L ２ are each an alkyl containing m carbon atoms or a substituted alkyl containing m carbon atoms, where m=0, 1, 2, 3, 4, 5, or 6; when m is 0, W １ Or W ２ are each directly attached to the corresponding nitrogen atom in ring 3 or ring 6, W １ and W ２ are each independently hydrogen, a 5-membered heterocycle or a substituted 5-membered heterocycle, a 6-membered heterocycle or a substituted 6-membered heterocycle, a carboxylalkyl group or a substituted carboxylalkyl group, a cyanoalkyl group or a substituted cyanoalkyl group, an aminoalkyl group or a substituted aminoalkyl group, a hydroxyalkyl group or a substituted hydroxyalkyl group, an amino acid, an ester of an amino acid, or an amide of an amino acid.

3. The compound comprises a core structure selected from the group consisting of Formula (II) and Formulas (IV)-(XXIII): 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 The compound according to claim 1 , wherein the core structure is a structure consisting of rings 1, 2 and 3 or a structure consisting of rings 4, 5 and 6.

4. 4. The compound of claim 3, wherein the compound comprises the core structure: 【Chemistry 6】

5. L １ and L ２ are each independently １ ~C ３ The compound of claim 3, wherein the aryl group is alkyl.

6. W １ and W ２ are each independently a type I side chain, the type I side chain consisting of: 【Chemistry 7】

7. W １ and W ２ are each independently a type II side chain; W １ The type II side chain of has the general formula: 【Chemistry 8】 In the formula, R １４ is alkyl or substituted alkyl, and R １５ is —H, alkyl, or substituted alkyl; W ２ The type II side chain of has the general formula: 【Chemistry 9】 In the formula, R １６ is alkyl or substituted alkyl, and R １７ The compound of any one of claims 1 to 5, wherein is -H, alkyl, or substituted alkyl.

8. R １４ is one of the following: 【Chemistry 10】 R １５ is independently —H, alkyl, or substituted alkyl; R １６ is one of the following: 【Chemistry 11】 R １７ The compound of claim 7, wherein is independently -H, alkyl, or substituted alkyl.

9. R １４ and R １６ are each independently selected from the group consisting of: 【Chemistry 12】

10. W １ Or W ２ The compound according to any one of claims 1 to 5, wherein is L-serine.

11. W １ and W ２ and are both L-serine.

12. W １ Or W ２ The compound according to any one of claims 1 to 5, wherein is an ester of L-serine.

13. W １ and W ２ The compound according to any one of claims 1 to 5, wherein both are esters of L-serine.

14. W １ and / or W ２ The compound according to any one of claims 1 to 5, wherein is an ester of L-serine.

15. W １ and W ２ is independently selected from the group consisting of: 【Chemistry 13】

16. W １ teeth 【Chemistry 14】 and W ２ is H and L ２ The compound according to any one of claims 1 to 5, wherein is absent.

17. W １ teeth 【Chemistry 15】 and W ２ is a type I or type II side chain, Type I side chains consist of: 【Chemistry 16】 W ２ Type II side chains have the general formula: 【Chemistry 17】 In the formula, R １６ is alkyl or substituted alkyl, and R １７ The compound of any one of claims 1 to 5, wherein is -H, alkyl, or substituted alkyl.

18. W １ teeth 【Chemistry 18】 and W ２ is a type I or type II side chain, Type I side chains consist of: 【Chemistry 19】 W ２ Type II side chains have the general formula: 【Chemistry 20】 In the formula, R １６ is alkyl or substituted alkyl, and R １７ The compound of any one of claims 1 to 5, wherein is -H, alkyl, or substituted alkyl.

19. W １ teeth 【Chemical 21】 and W ２ is a type I or type II side chain, Type I side chains consist of: 【Chemical 22】 W ２ Type II side chains have the general formula: 【Chemical 23】 In the formula, R １６ is alkyl or substituted alkyl, and R １７ The compound of any one of claims 1 to 5, wherein is -H, alkyl, or substituted alkyl.

20. W １ teeth 【Chemistry 24】 and W ２ is a type I or type II side chain, Type I side chains consist of: 【Chemistry 25】 W ２ Type II side chains have the general formula: 【Chemical 26】 In the formula, R １６ is alkyl or substituted alkyl, and R １７ The compound of any one of claims 1 to 5, wherein is -H, alkyl, or substituted alkyl.

21. W １ teeth 【Chemical 27】 and W ２ teeth 【Chemical 28】 The compound according to any one of claims 1 to 5,

22. A compound selected from the group consisting of: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】

23. The compound 【Chemistry 30】 2. The compound of claim 1, wherein:

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof.

25. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof, or a pharmaceutical composition according to claim 24, in the preparation of a medicament for treating a disease or condition associated with the interaction between PD-L1 and PD-1.

26. 26. The use according to claim 25, wherein the disease is cancer.

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