Heterocyclic compounds as immunomodulators of pd-l1 interaction

Abstract

PD-L1 inhibitors having various compounds of the formula are disclosed in general and in particular in two aspects. Methods of making such PD-L1 inhibitor compounds are disclosed in general and in particular in two aspects. 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 conditions are disclosed.

Description

TECHNICAL FIELD

[0001] The present application relates generally to compounds, and more particularly to compounds that modulate the biological activity of PD-L1 protein. BACKGROUND

[0002] Programmed death ligand 1 ("PD-L1") is a protein that plays a major role in suppressing the adaptive arm of the immune system. Normally, the adaptive immune system responds to an antigen associated with immune system activation by an exogenous or endogenous danger signal. In turn, clonal expansion of antigen-specific CD8+ T cells and / or CD4+ helper cells is propagated. Binding of PD-L1 on T cells to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal that reduces the proliferation of antigen-specific T cells in the lymph node, while reducing the apoptosis of regulatory T cells (anti-inflammatory suppressor T cells).

[0003] Thus, molecules capable of modulating PD-L1 activity can be widely applied to the treatment of various disease conditions. SUMMARY

[0004] One aspect of the present application relates to compounds having the general structure of Formula (I):

[0005]

[0006] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof, wherein,

[0007] A and B are each independently selected from the group consisting of halogen, cyano, -N3, alkyl and substituted alkyl, amine, alkylamine, alkoxy;

[0008] Z1is -CR 1 = or -N=;

[0009] Z2is -CR 2 =;

[0010] Z3is -CR 3 = or -N=;

[0011] Z4is -CR 4 = or -N=,

[0012] Z5is -CR 5 =;

[0013] Z6is -CR 6 = or -N=;

[0014] R 1 and R 4each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, alkoxy;

[0015] R 2 and R 5 each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, alkoxy;

[0016] R 3 and R 6 each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, alkoxy;

[0017] Y1and Y2are independently -C(R 7 )(R 8 )-, -CR 9 =, -NR 10 -, -O- or -S-;

[0018] X1and X2are each independently -C(R 11 )(R 12 )-, -N=, -NR 13 -, -S- or -O-;

[0019] R 7 , R 8 , R 9 , R 11 and R 12 each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, alkoxy;

[0020] R 10 and R 13 each independently -H, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, alkylamine, alkoxy;

[0021] L1and L2are each an alkyl, substituted alkyl, or heteroatom chain containing m atoms between ring 3 and W1and ring 6 and W2, where m = 0, 1, 2, 3, 4, 5, or 6; when m is 0, W1or W2is directly connected to the corresponding nitrogen in ring 3 or ring 6, respectively;

[0022] W1and W2are each independently hydrogen, a five-membered heterocycle or substituted five-membered heterocycle, a six-membered heterocycle or substituted six-membered heterocycle, carboxyalkyl or substituted carboxyalkyl, cyanoalkyl or substituted cyanoalkyl, aminoalkyl or substituted aminoalkyl, hydroxyalkyl or substituted hydroxyalkyl, 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.

[0023] 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, 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.

[0024] Another aspect of the present application relates to a method for preparing a compound of Formula (I). DETAILED DESCRIPTION

[0025] Reference will 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. Aspects of the present application will be described with respect to exemplary embodiments, including methods, materials and examples, which are meant to be non-limiting and the scope of the present application is intended to encompass all equivalents, alternatives and modifications, whether generally known in the art 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 this application belongs. One skilled in the art will recognize that techniques and materials equivalent to those described herein can be used in the practice of aspects and embodiments of the present application. The aspects and embodiments of the present application described are not limited to the methods and materials described.

[0026] As used in this specification and claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound or a combination of two or more compounds.

[0027] Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. When such ranges are 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 each endpoint of a range is significant, and that the use of "about" with respect to one particular endpoint also applies to the other endpoint of the range. It will also be understood that the disclosure of a number of values and ranges for a parameter is a disclosure of each and every value and range for the parameter. For example, a disclosure of values "10" to "100" is a disclosure of each and every value and range from 10 to 100, including but not limited to 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100, as well as ranges such as 10-20, 20-40, 40-60, 60-80, 80-100, 10-50, 20-70, 30-90, 40-100, 50-100, etc.

[0028] At various places in the present specification, certain features of the compounds are disclosed in groups or ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges.

[0029] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are intended. Compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active form or as racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also exist, 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 separate isomers.

[0030] Resolution of racemic mixtures of compounds can be performed by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, binaphthyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as beta- camphor sulfonic acid. Other resolving agents suitable for fractional crystallization methods include alpha-methylbenzylamine in stereoisomerically pure form (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, TV-methyl ephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0031] Resolution of racemic mixtures can also be performed by elution over a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0032] In compounds having more than one chiral center, each chiral center in the compound can independently be (R) or (S), unless otherwise indicated.

[0033] The compounds of the present application also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and overall charge. Example prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium, or, through appropriate substitution, locked in space as one form.

[0034] The compounds of the present application can also include isotopes of all atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms in a compound of the present application can be replaced or substituted with an atomic isotope occurring in nature or not occurring in nature. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compound includes two or more deuterium atoms.

[0035] I. Definitions

[0036] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. The term is also meant to include compounds of the present application, regardless of how they are prepared, e.g., synthesized, by a biological process (e.g., metabolism or enzymatic conversion), or a combination thereof.

[0037] All compounds and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) and can also be isolated. When in solid form, the compounds and salts thereof described herein can exist in various forms and can, for example, take the form of solvates, including hydrates. The compounds can be in any solid form, such as a polymorph or solvate, and thus, unless explicitly stated otherwise, references to the compounds and salts thereof in the specification are to be understood as encompassing any solid form of the compound.

[0038] In some embodiments, the compounds of the application or salts thereof are substantially isolated. By "substantially isolated" 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 for the compound of the application.

[0039] Substantial isolation can include compositions containing 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 the compound of the application or a salt thereof.

[0040] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, appropriate for use with tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0041] As used herein, the expressions "ambient temperature" and "room temperature" are as understood in the art and generally refer to a temperature that is about the temperature of the room in which the reaction is being performed (e.g., reaction temperature), for example, a temperature from about 20 °C to about 30 °C.

[0042] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds wherein the parent compound is modified by converting at least one of its existing acid or base moieties into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral 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 the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. As used herein, the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in, inter alia, Remington's 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.

[0043] The terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0044] The phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

[0045] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting the disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology), such as reducing the severity of the disease.

[0046] The term "solvate" refers to a compound formed by the interaction of a solvent and an EPI, a metabolite, or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0047] As used in the present application, the term "substituted" or "optionally substituted" means that one or more hydrogen atoms of the group to which the term "substituted" or "optionally substituted" refers is replaced with a substituent independently selected from lower alkyl, lower aryl, lower aralkyl, lower cycloalkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroaralkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxyl ester, carboxyl, formylamino, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower formylaminoalkylaryl, lower formylaminoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxyl-, lower carbamoylaminoalkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkoxyalkyl, provided that the number of substituents is such that the normal valence of the atom to which the substituent is attached is not exceeded, and that the substituted compound is chemically stable.

[0048] The term "alkyl" refers to straight chain, branched chain, or cyclic hydrocarbon groups having only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which can optionally be substituted.

[0049] The term "aryl" refers to aryl groups having from 5 to 14 ring atoms and having at least one ring that is aromatic and has a conjugated pi-electron system, and the term includes carbocyclic aryl, heterocyclic aryl, and biaryl groups, all of which can optionally be substituted

[0050] Carbocyclic aryl is a group having 6-14 ring atoms in which the ring atoms in the aromatic ring are carbon atoms. Carbocyclic aryl includes monocyclic carbocyclic aryl groups and polycyclic or fused compounds, such as optionally substituted naphthyl.

[0051] Heterocyclic aryl or heteroaryl is a group having 5-14 ring atoms in which 1 to 4 of the ring atoms are heteroatoms in the aromatic ring, and the remaining ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryls include furyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, imidazolyl, and the like, all of which groups are optionally substituted.

[0052] The term "biaryl" denotes an aryl group having 5-14 atoms, which aryl groups contain more than one aromatic ring, including fused ring systems and aryl groups substituted with other aryl groups. Such groups can be optionally substituted. Suitable biaryls include naphthyl and biphenyl.

[0053] The terms "substituted aryl" and "substituted heteroaryl" mean aryl and heteroaryl groups substituted with 1-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.

[0054] The term "aralkyl" means an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, pyridylmethyl, and the like, and can be optionally substituted.

[0055] The term "heteroarylalkyl" means an alkylene group substituted with a heteroaryl group.

[0056] The term "alkylaryl" means an aryl group substituted with an alkyl group. "Lower alkylaryl" means such a group in which the alkyl group is lower alkyl.

[0057] The term "lower" in connection with an organic group or compound herein means 6 or fewer carbon atoms, respectively. Such groups can be straight-chained, branched, or cyclic.

[0058] The term "higher" in connection with an organic group or compound herein means 7 or more carbon atoms, respectively. Such groups can be straight-chained, branched, or cyclic.

[0059] The term "cyclic alkyl" or "cycloalkyl" means a cyclic alkyl group having 3 to 10 carbon atoms (and in one aspect 3 to 6 carbon atoms). Suitable cyclic groups include norbornyl and cyclopropyl. Such groups can be substituted.

[0060] The terms "heterocycle," "heterocyclic alkyl," or "heterocycloalkyl" refer to cyclic groups having from 3 to 10 atoms (and in one aspect from 3 to 6 carbon atoms, containing at least one heteroatom, and in another aspect from 1 to 3 heteroatoms). Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups can be attached via a nitrogen or via a carbon atom in the ring. Heterocycloalkyl groups include unsaturated rings, fused rings, and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.

[0061] The terms "aryl amino" (a) and "aralkyl amino" (b) refer to the group -NRR', where, respectively, (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.

[0062] The term "acyl" refers to -C(O)-R, where R is alkyl, heterocycloalkyl, or aryl.

[0063] The term "carboxyl ester" refers to -C(O)-OR, where R is alkyl, aryl, aralkyl, cycloalkyl, or heterocycloalkyl, all of which are optionally substituted.

[0064] The term "carboxyl" refers to -C(O)-OH.

[0065] The term "oxo" refers to =O in an alkyl or heterocycloalkyl group.

[0066] The term "amino" refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, and heterocycloalkyl, all but H being optionally substituted; and R and R' can form a cyclic ring system.

[0067] The term "formylamino" refers to -C(O)NR2, where each R is independently hydrogen or alkyl.

[0068] The term "sulfonamido" or "-sulfonamido" refers to -S(=O)2R2, where each R is independently hydrogen or alkyl.

[0069] The term "halogen" or "halo" refers to -F, -Cl, -Br, and -I.

[0070] The term "alkylaminoalkylcarboxyl" refers to the group alkyl-NR-alk-C(O)-O-, where "alk" is an alkylene group, and R is H or lower alkyl.

[0071] The term "sulphonyl" or "sulfonyl" refers to -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0072] The term "sulphonate" or "sulfonate" refers to -SO2-OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0073] The term "alkenyl" refers to an unsaturated group having from 2 to 12 atoms and containing at least one carbon-carbon double bond and includes straight chain, branched chain, and cyclic groups. The alkenyl group can optionally be substituted. Suitable alkenyl groups include allyl. A "1-alkenyl" refers to an alkenyl group where the double bond is between the first and second carbon atoms. If the 1-alkenyl group is attached to another group (e.g., the 1-alkenyl is a W substituent attached to a cyclic phosphonate), the 1-alkenyl is attached at the first carbon.

[0074] The term "alkynyl" refers to an unsaturated group having from 2 to 12 atoms and containing at least one carbon-carbon triple bond and includes straight chain, branched chain, and cyclic groups. The alkynyl group can optionally be substituted. Suitable alkynyl groups include ethynyl. A "1-alkynyl" refers to an alkynyl group where the triple bond is between the first and second carbon atoms. If the 1-alkynyl group is attached to another group (e.g., the 1-alkynyl is a W substituent attached to a cyclic phosphonate), the 1-alkynyl is attached at the first carbon.

[0075] The term "alkylene" refers to a divalent straight chain, branched chain, or cyclic saturated aliphatic radical. In one aspect, the alkylene contains up to and including 10 atoms. In another aspect, the alkylene contains up to and including 6 atoms. In another aspect, the alkylene contains up to and including 4 atoms. The alkylene can be straight chain, branched chain, or cyclic.

[0076] The term "acyloxy" refers to an ester group -O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

[0077] 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.

[0078] The term "alkylaminoalkyl" refers to the group alkyl-NR-alk-, where each "alk" is an independently selected alkylene group, and R is H or lower alkyl. A "lower alkylaminoalkyl" refers to a group where the alkyl and alkylene groups are lower alkyl and alkylene, respectively.

[0079] The term "arylaminolalkyl" refers to the group aryl-NR-alk-, where "alk" is an alkylene group, and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In a "lower arylaminolalkyl", the alkylene group is lower alkylene.

[0080] The term "alkylaminoaryl-" refers to the group alkyl-NR-aryl-, wherein "aryl" is a divalent radical and R is -H, alkyl, aralkyl or heterocycloalkyl. In "lower alkylaminoaryl", alkyl is lower alkyl.

[0081] The term "alkoxyaryl" refers to aryl substituted with alkoxy. In "lower alkoxyaryl", alkyl is lower alkyl.

[0082] The term "aryloxyalkyl" refers to alkyl substituted with aryloxy.

[0083] The term "arylalkyloxyalkyl" refers to the group aryl-alk-O-alk-, wherein "alk" is alkylene. "Lower arylalkyloxyalkyl" refers to such groups wherein alkylene is lower alkylene.

[0084] The term "alkoxy-" (alkoxy- or alkyloxy-) refers to the group alkyl-O-.

[0085] The term "alkoxyalkyl" (alkoxyalkyl or alkyloxyalkyl) refers to the group alkyl-O-alk-, wherein "alk" is alkylene. In "lower alkoxyalkyl", each alkyl and alkylene is lower alkyl and alkylene, respectively.

[0086] The term "alkylthio-" refers to the group alkyl-S-.

[0087] The term "alkylthioalkyl" refers to the group alkyl-S-alk-, wherein "alk" is alkylene. In "lower alkylthioalkyl", each alkyl and alkylene is lower alkyl and alkylene, respectively.

[0088] The term "alkoxycarbonyloxy-" refers to alkyl-O-C(O)-O-.

[0089] The term "aryloxycarbonyloxy-" refers to aryl-O-C(O)-O-.

[0090] The term "alkylthiocarbonyloxy" refers to alkyl-S-C(O)-O-.

[0091] The term "amido" refers to the group NR2-C(O)-, RC(O)-NR 1 -, NR2-S(=O)2- and RS(=O)2-NR 1 -, wherein R and R 1 include -H, alkyl, aryl, aralkyl and heterocycloalkyl

[0092] The term "formamido" refers to NR2-C(O)- and RC(O)-NR 1 -, wherein R and R 1including -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea -NR-C(O)-NR-.

[0093] The term "sulphonamido" or "sulfonamido" means NR2-S(=O)2- and RS(=O)2-NR 1 -, where R and R 1 including -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include sulfonylurea -NR-S(=O)2-NR-.

[0094] The term "carboxamidoalkylaryl" or "carboxamidoaryl" means aryl-alk-NR 1 -C(O) and ar-NR 1 -C(O)-alk-, where "ar" is aryl, "alk" is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0095] The term "sulphonamidoalkylaryl" or "sulfonamidoaryl" means aryl-alk-NR 1 -S(=O)2- and ar-NR 1 -S(=O)2-, where "ar" is aryl, "alk" is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0096] The term "hydroxyalkyl" means an alkyl group substituted with one -OH.

[0097] The term "haloalkyl" means an alkyl group substituted with halo.

[0098] The term "cyano" means -CN.

[0099] The term "nitro" means -NO2.

[0100] The term "acylalkyl" means alkyl-C(O)-alk-, where "alk" is alkylene.

[0101] The term "carbamoylamidoalkyl" means the group NR 2- C(O)-N(R)-alk-, where R is alkyl or H, and "alk" is alkylene. "Lower carbamoylamidoalkyl" means such a group where "alk" is lower alkylene

[0102] The term "heteroarylalkyl" means an alkylene group substituted with a heteroaryl group.

[0103] II. Compounds interfering with the activity of PD-L1

[0104] One aspect of the present application relates to compounds that interfere with the activity of PD-L1. In some embodiments, the compound has a general structure as shown in Formula (I):

[0105]

[0106] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof, wherein,

[0107] A and B are each independently selected from halogen, cyano, -N3, alkyl and substituted alkyl, amine, alkyl amine, alkoxy;

[0108] Z1is -CR 1 = or -N=;

[0109] Z2is -CR 2 =;

[0110] Z3is -CR 3 = or -N=;

[0111] Z4is -CR 4 = or -N=,

[0112] Z5is -CR 5 =;

[0113] Z6is -CR 6 = or -N=;

[0114] R 1 and R 4 are each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkyl amine, alkoxy;

[0115] R 2 and R 5 are each independently, each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkyl amine, alkoxy;

[0116] R 3 and R 6 are each independently, each independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkyl amine, alkoxy;

[0117] Y1and Y2are independently -C(R 7 )(R 8 )-, -CR 9 =, -NR 10 -, -O- or -S-;

[0118] X1and X2are each independently -C(R11 (R) 12 -, -N=, -NR 13 -、-S- or -O-;

[0119] R 7 R 8 R 9 R 11 and R 12 Each can be independently -H, halogen, cyano, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkynyl, aryl, amine, alkylamine, or alkoxy.

[0120] R 10 and R 13 Each of these can be independently -H, alkyl, cycloalkyl, substituted alkyl, alkenyl, alkenyl, alkynyl, aryl, alkylamine, or alkoxy.

[0121] L1 and L2 are each an alkyl, substituted alkyl, or heteroatom chain containing m atoms between ring 3 and W1 and between ring 6 and W2, where m = 0, 1, 2, 3, 4, 5, or 6; when m is 0, W1 or W2 is directly connected to the corresponding nitrogen in ring 3 or ring 6, respectively.

[0122] W1 and W2 are each independently hydrogen, a five-membered heterocycle or a substituted five-membered heterocycle, a six-membered heterocycle or a substituted six-membered heterocycle, a carboxylalkyl or a substituted carboxylalkyl, a cyanalkyl or a substituted cyanalkyl, an aminoalkyl or a substituted aminoalkyl, a hydroxyalkyl or a substituted hydroxyalkyl, 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.

[0123] The compound of formula (I) can be symmetrical about the axis DD (i.e., the left side of formula (I) is a mirror image of the right side of formula (I)) or asymmetrical (i.e., the left side of formula (I) is different from the right side of formula (I)).

[0124] Preferred core structures

[0125] In some embodiments, the compound of formula (I) comprises a core structure selected from the group consisting of formulas (II)-(XXIII):

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] In some embodiments, the compound of Formula (I) comprises the following core structure:

[0132]

[0133] In some embodiments, L1and L2are each independently selected from -CH2-,

[0134] (CH2)2– and –(CH2)3-.

[0135] In some embodiments, L1and L2are each independently selected from

[0136] –CH(CH3)-, -CH2– and –CH2-CH(CH3)–.

[0137] Side chains of type I

[0138] In some embodiments, W1and / or W2are each independently a Type I side chain. As used herein, the term “Type I side chain” refers to a structure containing (1) a five-membered heterocyclic ring having at least one nitrogen atom as a ring atom or a substituted five-membered heterocyclic ring having at least one nitrogen atom as a ring atom, or (2) a six-membered heterocyclic ring having at least one nitrogen atom as a ring atom or a substituted five-membered heterocyclic ring having at least one nitrogen atom as a ring atom, wherein linker L1or L2is directly connected to a ring atom in the five- or six-membered heterocyclic ring.

[0139] In some embodiments, W1and / or W2are each independently a heterocyclic ring. In some embodiments, W1and / or W2are each independently a five-membered heterocyclic ring having at least one nitrogen atom as a ring atom. In some embodiments, W1and / or W2are each independently a six-membered heterocyclic ring having at least one nitrogen atom as a ring atom.

[0140] In some embodiments, W1and / or W2are each independently selected from the group of Type I side chains listed below:

[0141] and

[0142] Side chains of type 2

[0143] In some embodiments, W1and / or W2are each independently a Type II side chain. As used herein, the term “Type II side chain” refers to a W1structure having the general formula:

[0144] and a W2structure having the general formula:

[0145] wherein R​14 and R 16 each independently -H, alkyl, substituted alkyl, hydroxyalkyl or substituted hydroxyalkyl, hydroxy carboxylic acid or salt or ester thereof, substituted hydroxy carboxylic acid or salt or ester thereof, carboxylic acid or salt or ester or alkyl ether, substituted carboxylic acid or salt or ester or alkyl ether, formamido or lactone; and

[0146] wherein R 15 and R 17 each independently -H, alkyl or substituted alkyl.

[0147] 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 alkyl-amino-alkyl, Q2 is -O- or -CH2-, and R 18 is -H, alkyl or substituted alkyl.

[0148] In some embodiments, R 14 or R 16 or both are independently selected from the group consisting of:

[0149] and

[0150] In some embodiments, W1or W2is each independently an amino acid.

[0151] In some embodiments, the side chain W1or W2is L-serine

[0152] In some embodiments, the side chain W1or W2is L-serine ester.

[0153] In some embodiments, both side chains W1and W2are L-serine

[0154] In some embodiments, both side chains W1and W2are L-serine ester.

[0155] Other side chains

[0156] In some embodiments, W1or W2is each independently -C(O)-ONa, -CN, -CH2OH or -CH2NH2.

[0157] Exemplary compounds

[0158] In some embodiments, the compound of formula (I) comprises the following core structure:

[0159]

[0160] In some embodiments, the compound of Formula (I) comprises the following core structure:

[0161]

[0162] In some embodiments, the compound of Formula (I) consists of two identical core structures linked together.

[0163] In some embodiments, the compound of Formula (I) consists of two identical core structures linked together.

[0164] In some embodiments, the compound of Formula (I) consists of the core structure and the core structure linked together.

[0165] In some embodiments, the side chain W1and / or W2is independently selected from the group consisting of:

[0166]

[0167] In some embodiments, the compound of Formula (I) includes only one side chain, wherein:

[0168] W1is

[0169] W2is H and L2is absent (i.e., m = 0). In other words, there is no side chain on the nitrogen atom of ring 6. In further embodiments, L1is C1-C3alkyl.

[0170] In some embodiments, the compound of Formula (I) includes a side chain that is asymmetric about the axis DD.

[0171] In some embodiments, W1is and W2is selected from Type I and Type II side chains. In further embodiments, L1and L2are each independently C1-C3alkyl.

[0172] In some embodiments, W1is and W2is selected from Type I and Type II side chains. In further embodiments, L1and L2are each independently C1-C3alkyl.

[0173] In some embodiments, W1is and W2is selected from Type I and Type II side chains. In further embodiments, L1and L2are each independently C1-C3alkyl.

[0174] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0175] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0176] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0177] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0178] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0179] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0180] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0181] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0182] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0183] In some embodiments, W1is and W2is In further embodiments, each of L1and L2is independently C1-C3alkyl.

[0184] Without limitation, certain embodiments of the compounds (or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, solvates, or tautomers thereof) disclosed herein are set forth in Table 1:

[0185] Table 1

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] The present application also includes isotopically-substituted compounds of the present disclosure. An "isotopically-substituted" compound is a compound of the present application in which one or more atoms are replaced by an atom having the same atomic number but a different atomic mass or mass number, e.g., an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., a naturally occurring atomic mass or mass number). It will be appreciated that a "radiolabeled" compound is a compound that has incorporated at least one radioactive isotope (e.g., a nuclide).

[0198] III. Uses of compounds of formula (I)

[0199] Another aspect of the present application relates to the use of a compound of Formula (I). Compounds of Formula (I) interfere with the interaction between PD-L1 and PD-1, and are therefore useful in the treatment of diseases and conditions associated with PD-1 activity and diseases and conditions associated with PD-L1.

[0200] In some embodiments, the compounds of Formula (I) promote the formation of PD-L1 dimers and, thus, inhibit the interaction between PD-L1 and PD-1. In certain embodiments, the 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 the response to vaccination. In some embodiments, the present disclosure provides a method for inhibiting a PD-1 / PD-L1 protein / protein interaction. The method includes administering to an individual or patient an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. The compounds of Formula (I) can be used alone, in combination with other agents or therapies, or as an adjuvant or neo-adjuvant for treating a disease or disorder, including cancer or infectious disease. For the uses described herein, any of the compounds of the present disclosure, including any embodiment thereof, can be used.

[0201] The compounds of the present application inhibit the PD-1 / PD-L1 protein / protein interaction, resulting in PD-1 pathway blockade. PD-1 blockade can enhance the immune response to cancer cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides in vivo treatment to an individual or patient using the compounds of any formula herein, or salts or stereoisomers thereof, thereby inhibiting the growth of cancerous tumors. The compounds of any formula as described herein, or the compounds as set forth in any claim and described herein, or salts or stereoisomers thereof, can be used to inhibit the growth of cancerous tumors. Alternatively, the compounds of any formula as described herein, or the compounds as set forth in any claim and described herein, or salts or stereoisomers thereof, can be used in conjunction 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 includes contacting tumor cells with a compound of any formula as described herein, or the compounds as set forth in any claim and described herein, or salts or stereoisomers thereof, in vitro. In another embodiment, the present disclosure provides a method for inhibiting tumor cell growth in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a compound of any formula as described herein, or the compounds as set forth in any claim and described herein, or salts or stereoisomers thereof.

[0202] In some embodiments, provided herein are methods for treating cancer. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any formula as described herein, as set forth in any claim and described herein, or salts thereof. Examples of cancer include those whose growth can be inhibited using the compounds of the present disclosure, as well as cancers that generally respond to immunotherapy.

[0203] Examples of cancers that can be treated using the compounds of the disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's Disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, soft-tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary gland cancer, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers (including cancers induced by asbestos), and combinations of said cancers. The compounds of the disclosure can also be used to treat metastatic cancer, particularly metastatic cancer that expresses PD-L1.

[0204] In some embodiments, cancers that can be treated with the compounds of the disclosure include melanoma (e.g., metastatic malignant melanoma, cutaneous melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer (e.g., invasive breast carcinoma), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer (e.g., head and neck squamous cell carcinoma), urothelial cancer (e.g., bladder cancer, non-muscle invasive bladder cancer (NMIBC)), and microsatellite instability high (MSIhlgh) cancer.

[0205] In addition, the disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the disclosure.

[0206] In some embodiments, cancers that can be treated 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., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular NHL), Hodgkin lymphoma, or multiple myeloma), and combinations of the foregoing.

[0207] In some embodiments, cancers that can be treated using the compounds of the present disclosure include, but are not limited to, cholangiocellular carcinoma, biliary duct 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, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spine cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0208] In some embodiments, diseases and indications that can be treated using the 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.

[0209] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular NHL), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0210] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0211] Exemplary lung cancers include non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0212] Exemplary gastrointestinal tract cancers include esophageal cancer (carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoid carcinoma), and colorectal cancer (e.g., colorectal adenocarcinoma).

[0213] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilm's 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma). In some embodiments, the cancer is a urological cancer (e.g., papillary renal carcinoma, testicular germ cell cancer, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, or prostate cancer).

[0214] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0215] 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 (osteocartilaginous exostosis), benign chondroma, chondroblastioma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumors.

[0216] Exemplary nervous system cancers include skull cancers (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges cancers (meningioma, meningiosarcoma, hemangiopericytoma), brain cancers (astrocytic tumors, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0217] Exemplary gynecological cancers include uterine cancers (endometrial cancer), cervical cancers (cervical cancer, pre-tumor cervical dysplasia), ovarian cancers (ovarian cancer (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulvar cancers (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancers (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tube (carcinoma).

[0218] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi’s sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, and nevus dysplastic nevus. In some embodiments, diseases and indications that can be treated 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, cholangiocarcinoma, esophageal cancer, and urothelial cancer.

[0219] The PD-1 pathway that can be blocked with the compounds of the present disclosure can also be useful in treating infections, such as viral, bacterial, fungal, and parasitic infections. In some embodiments, provided herein are methods for treating an infection. The method includes administering to a patient in need thereof a therapeutically effective amount of any of the formulae as described herein, such as the compounds set forth in any of the claims and described herein, salts thereof. Examples of viruses that cause infections that can be treated by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, D, or E virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, coronavirus, severe acute respiratory syndrome virus, ebola virus, and measles virus. In some embodiments, viruses that cause infections that can be treated by the methods of the present disclosure include, but are not limited to, hepatitis (A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, human herpesvirus 4), 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 virus, poliovirus, rabies virus, JC virus, tuberculosis, and arboviral encephalitis virus.

[0220] The present disclosure provides a method for treating a bacterial infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulae as described herein, such as the compounds set forth in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic bacteria that cause infections that can be treated by the methods of the present disclosure include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci, and gonococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.

[0221] The present disclosure provides a method for treating a fungal infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulae as described herein, such as the compounds set forth in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic fungi that cause infections that can be treated by the methods of the present disclosure include Candida (C. albicans, C. krusei, C. glabrata, C. tropicalis, etc.), Cryptococcus neoformans, Aspergillus (A. fumigatus, A. niger, etc.), Mucorales (Mucor, Absidia, Rhizopus), Sporothrix schenckii, Blastomyces dermatidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0222] The present disclosure provides a method for treating a parasitic infection. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any formula described herein, such as a compound set forth in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic parasites that cause infections that can be treated by the methods of the present disclosure include Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0223] In some embodiments, provided herein are methods for treating inflammation. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any formula described herein, such as a compound set forth in any of the claims and described herein, or a salt thereof.

[0224] In some embodiments, provided herein are methods for treating an autoimmune disease. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of any formula described herein, such as a compound set forth in any of the claims and described herein, or a salt thereof.

[0225] It is believed that the compounds of Formula (I), or any embodiments thereof, can have satisfactory pharmacological properties and promising biopharmaceutical properties, such as toxicological properties, metabolic and pharmacokinetic properties, solubility, and permeability. It will be appreciated that determining suitable biopharmaceutical properties is within the knowledge of one skilled in the art, for example, determining cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

[0226] In some embodiments, the compounds of the present application can be used to prevent or reduce the risk of any of the diseases mentioned herein; for example, to prevent or reduce the risk of a disease, condition or disorder in an individual who can be pre-diagnosed with the disease, condition or disorder but has not yet experienced or displayed the pathology or symptomatology of the disease.

[0227] In some embodiments, the present disclosure provides a method of enhancing, stimulating and / or increasing an immune response in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of any of the formulae as described herein, such as the compounds or compositions set forth in any of the claims and described herein, or a salt thereof.

[0228] Combination therapy

[0229] The compounds of the present disclosure can be combined with one or more other therapies for the treatment of a disease, such as a cancer or an infection. Examples of diseases and indications that can be treated with combination therapy include those diseases and indications as described herein.

[0230] Examples of cancers include solid tumors and non-solid tumors, such as liquid tumors, blood cancers. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors 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 (a, b, g, d, 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 RK A, 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 infection. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infection 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, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., Parsaclisib (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;For example, erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab or panitumumab, VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, axitinib, vandetanib, ramucirumab, lenvatinib, ziv-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., CCR2 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, B-Raf inhibitors-MEK inhibitors combinations (such as encorafenib plus binimetinib, dabrafenib plus trametinib, or cobimetinib plus vemurafenib), and adenosine receptor antagonists, or combinations thereof.

[0231] In some embodiments, the compounds of the present disclosure can be combined with a TLR7 agonist (e.g., imiquimod).

[0232] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as by chemotherapy, irradiation therapy, tumor-targeting therapy, adjuvant therapy, immunotherapy, or surgical intervention. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, g-CSF, and 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 virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3K6 inhibitors, and the like. These compounds can be administered in combination with one or more anticancer drugs, such as a chemotherapeutic agent. Examples of chemotherapy include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone, 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, epirubicin, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gemcitabine, gemtuzumab, goserelin, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alfa, irinotecan, irinotecan, ixabepilone, lapatinib, letrozole, leucovorin, leuprolide, levamisole, lomustine, megestrol, melphalan, mercaptopurine, methotrexate, methoxymestrol, mitomycin, mitotane, mitoxantrone, nandrolone, nelarabine, nilutamide, nofetumomab, octreotide, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa, pentostatin, pemetrexed, pentazocine, pentostatin, piposulfan, plicamycin, procarbazine, raloxifene, rituximab, sargramostim, strontium chloride, streptozocin, sunitinib, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, toremifene, trastuzumab, uracil mustard, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, and zoledronate.propionate), eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine hydrochloride, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nilutamide, nolatrexed dihydrochloride, octreotide acetate, ondansetron hydrochloride, oxaliplatin, paclitaxel, pamidronate disodium, pegaspargase, pentostatin, pilocarpine hydrochloride, porfimer sodium, procarbazine hydrochloride, quinacrine, raloxifene hydrochloride, raltitrexed, rituximab, samarium (153) lexidronam, sargramostim, strontium (89) chloride, streptozocin, sunitinib malate, suramin, tamoxifen, temozolomide, teniposide, tegafur, testolactone, thalidomide, thiamiprine, thiotepa, tioguanine, tositumomab, trastuzumab, treosulfan, trofosfamide, uracil mustard, valrubicin, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vinorelbine maleate, zoledronatephenpropionate, nelarabine, nofetumomab, oxaliplatin, paelitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, piperobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate The following are listed: maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0233] Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies to co-stimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies to PD-1 and PD-L1, or cytokine antibodies (IL-10, TGF-b, etc.). Examples of antibodies to PD-1 and / or PD-L1 that can be combined with the compounds of the present disclosure for the treatment of cancer or infections such as viral, bacterial, fungal, and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and SHR-1210.

[0234] The compounds of the present disclosure can be combined with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infections.

[0235] Exemplary immune checkpoint inhibitors include inhibitors to 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 KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0236] 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.

[0237] 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-PD1 antibody is pembrolizumab.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] The compounds of the present disclosure can also be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies.

[0244] A compound of any formula as described herein, such as set forth in any claim and described herein, or a salt thereof, can be combined with another immunogenic agent, such as a cancer cell, a purified tumor antigen (including recombinant proteins, peptides, and carbohydrate molecules), a cell, and a cell transfected with a gene encoding an immunostimulatory cytokine. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0245] A compound of any formula as described herein, such as set forth in any claim and described herein, or a salt thereof, can be used in combination with a vaccination regimen for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papilloma virus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, a compound of the present disclosure can be used in combination with tumor-specific antigens such as heat shock proteins isolated from tumor tissue itself. In some embodiments, a compound of any formula as described herein, such as set forth in any claim and described herein, or a salt thereof, can be combined with dendritic cells to activate a potent anti-tumor response.

[0246] A compound 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. A compound of the present disclosure can also be combined with macrocyclic peptides that activate the host immune response.

[0247] A compound of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0248] A compound of any formula as described herein, such as set forth in any claim and described herein, or a salt thereof, can be used in combination with a vaccine to stimulate an immune response to pathogens, toxins, and self-antigens.

[0249] When more than one pharmaceutical agent is administered to a patient, the pharmaceutical agents can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two pharmaceutical agents).

[0250] Formulations, dosage forms, and routes of administration

[0251] When used as pharmaceuticals, the compounds of the disclosure can be administered in the form of pharmaceutical compositions. Accordingly, the present disclosure provides a composition comprising a compound of any formula as described herein, a compound as set forth in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any embodiment thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration.

[0252] Parenteral administration can be in the form of a single bolus dose, or it can be, for example, by continuous perfusion pump. Pharmaceutical compositions for topical administration, as well as formulations, can 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 can be necessary or desirable.

[0253] The present application also includes pharmaceutical compositions containing, as an active ingredient, a compound of the disclosure or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the compositions of the application, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, a carrier or a 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 a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0254] In making the formulations, the active compound can be milled to provide the appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0255] The compounds of the present application can be milled using known milling procedures, such as wet milling, in order to obtain a particle size suitable for tablet formation as well as for other formulation types. Subdivided (nanoparticulate) formulations of the compounds of the present application can be prepared by methods known in the art, see, e.g., WO 2002 / 000196.

[0256] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the application can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0257] In some embodiments, the pharmaceutical composition comprises siliconized microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the siliconized microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0258] 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 the group consisting of microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyoxyl ethylene. 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 polyoxyl ethylene. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH 102 TM In some embodiments, the lactose monohydrate is Fast-flo 316 TM In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier TM ) and / or hydroxypropyl methylcellulose 2208 K100 LV (e.g., Methocel K00 LV TM). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105 TM

[0259] In some embodiments, the composition is produced using a wet granulation process. In some embodiments, the composition is produced using a dry granulation process.

[0260] The composition 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 for unitary dosing to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0261] The components used to formulate the pharmaceutical compositions have high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, typically at least Analytical grade, and more typically at least Pharmaceutical grade). Particularly for human consumption, the compositions are preferably manufactured or formulated to meet the standards defined in the Good Manufacturing Practice regulations applicable by the U.S. Food and Drug Administration. For example, suitable formulations can be sterile and / or substantially isotonic and / or fully comply with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.

[0262] The active compounds can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0263] ​The therapeutic dosage of the compounds of the present application can vary according to, for example, the particular use for which the treatment is being sought, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present application in a pharmaceutical composition can vary depending upon a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a compound of the present application can be provided in an aqueous physiological buffer at a concentration of from about 0.1 to about 10% w / v. Some typical dose ranges are from about 1 pg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dose range is from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. Dosage can depend on variables such as the type and progress of disease or condition, the overall health status of the particular patient, the relative biological efficacy of the compound selected, the formulation of the excipients, and the route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0264] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present application. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally 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 mg to about 1000 mg of the active ingredient of the present application.

[0265] The tablets or pills of the present application can be coated or otherwise compounded to provide a dosage form affording the release of a portion of a compound of the present application at a time other than on ingestion of the entire composition. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in turn compounded with a agent that delays or prevents release of the inner component for a period of time following ingestion. Various materials can be used for this purpose, including glycerol monostearate or glycerol stearate, those polymers such as ethyl cellulose, methyl cellulose, hydroxypropylmethyl-cellulose, cross-linked sodium carboxymethylcellulose and the like. Glyceryl monostearate or glyceryl stearate can be used, if desired, to coat tablets or pills.

[0266] Liquid forms in which a compound and compositions of the present application can be combined with a pharmaceutical carrier include aqueous solutions, suitably flavored suspensions, aqueous or oil suspensions, and flavored, emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0267] Compositions for inhalation or inhalation include pharmaceutically acceptable solutions and suspensions or mixtures thereof in aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, these compositions are administered via the oral or nasal route for local or systemic effects. The compositions can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizing device, or the nebulizing device can be attached to a mask plug or intermittent positive pressure ventilation machine. Solutions, suspensions, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0268] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, etc. The carrier composition of creams may be based on a combination of water with glycerin and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate, and hexadecyl stearyl alcohol). Gels may be formulated using isopropanol and water, suitably combined with other components (such as glycerin, hydroxyethyl cellulose, etc.). In some embodiments, the topical formulation contains at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of the compounds of this application. Topical formulations may be suitably packaged in, for example, 100 g tubes, which optionally include instructions for use in treating the selected indication (e.g., psoriasis or other skin conditions).

[0269] The amount of compound or composition administered to a patient will vary depending on the drug being administered, the purpose of administration (such as prevention or treatment), the patient's condition, and the method of administration. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially suppress the symptoms and complications of the disease. The effective dose will depend on the condition of the disease being treated and, by the judgment of the attending clinician, on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0270] The compositions administered to patients may be in the form of the aforementioned pharmaceutical compositions. These compositions may be sterilized using conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for use as is or lyophilized, with the lyophilized formulation combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It should be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0271] The therapeutic dosage of the compounds of the present application can vary according to, for example, the particular use for which the treatment is being applied, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present application in a pharmaceutical composition can vary depending upon a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a compound of the present application can be provided in an aqueous physiological buffer at concentrations of from about 0.1 to about 10% w / v. Some typical dose ranges are from about 1 pg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dose range is from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. Dosage can depend on variables such as the type and extent of disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, the formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0272] 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 cited throughout this application, as well as the figures and tables are hereby incorporated by reference.

[0273] Examples

[0274] Example 1

[0275] Preparation of (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (Intermediate SM1)

[0276]

[0277] 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), DMAP (0.006 g, 0.049 mmol, 0.05 equiv) in DCM (2 ml) was stirred at room temperature for 16 h, 1 N HC1 (5 ml) was added slowly, extracted with DCM, and the organics were concentrated to yield SM1 (0.170 g, 73%).

[0278] Example 2

[0279] 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)

[0280]

[0281] Steps 1 and 2

[0282] To a 500 ml round bottom flask was added 3-bromo-2-chlorophenol (12.4 g, 0.060 mol, 1.0 eq), B2Pin2 (16.4 g, 0.065 mol, 1.08 eq), KOAc (20.5 g, 0.210 mol, 3.5 eq), Pd(dppf)Cl2-DCM (4.1 g, 5.1 mmol, 0.085 eq), followed by solvent dioxane (300 ml), the final mixture was charged with N2, and stirred at 95 °C for 3 h. Then, the reaction mixture was cooled to room temperature and filtered, the filter cake was washed with dioxane (100 ml), the filtrate was used directly in the next step.

[0283] To the previous filtrate was added 3-bromo-2-chlorophenol (12.0 g, 0.059 mol, 0.99 eq), K2CO3 (24.8 g, 0.180 mol, 3.0 eq) and Pd(dppf)Cl2-DCM (2.1 g, 2.40 mmol, 0.042 eq), followed by H2O (80 ml), the final mixture was charged with N2, and stirred at 85 °C for 3.5 h. Then, the reaction mixture was cooled to room temperature and filtered, 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 x 2), the combined organic phase was decolored 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 phase was concentrated under vacuum. The residue was purified by recrystallization from DCM / PE = 1.5 / 1 to give the desired product as a light yellow solid (10.1 g, yield: 46%).

[0284] Step 3

[0285] To a stirred mixture of SM2-02 (10.1 g, 0.039 mol, 1.0 eq) in DCM (200 ml) at 0 °C was added DIPEA (19.4 g, 0.151 mol, 3.8 eq), followed by Tf20 (26.8 g, 0.095 mol, 2.4 eq) after SM2-02 was dissolved, then allowed to reach room temperature and continue stirring for 2 h. Water (100 ml) was added to induce the reaction, then separated, 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, the filtrate was concentrated in vacuum. The residue was purified by recrystallization with EtOH / H2O = 1 / 1 to give the desired product as a light yellow solid (18.3 g, yield: 89%).

[0286] Step 4

[0287] To a stirred solution of SM2-03 (14.2 g, 0.027 mol, 1.0 eq) in dioxane (80 ml) at room temperature was added B2Pin2 (27.8 g, 0.109 mol, 4.0 eq), KOAc (16 g, 0.164 mol, 6.0 eq) and Pd(dppf)Cl2DCM (3.3 g, 4.1 mmol, 0.15 eq), then charged with N2 and stirred at 85 °C for 2 h. Then cooled to room temperature, to the mixture was added EA (150 ml) and water (150 ml), 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, the filtrate was concentrated in vacuo. The residue was dissolved with EA (50 ml), then PE (300 ml) was slowly added to the solution to form a black suspension. After stirring for 30 min, filtered, the filter cake was washed with 140 ml (PE / EA = 6 / 1), 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 off-white solid.

[0288] Example 3

[0289] Preparation of 2,2'-((2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazine-7,4-diyl))dimalononitrile (Intermediate SM3)

[0290]

[0291] Step 1

[0292] A solution of 7-bromo-2H-benzo[b][l,4]oxazin-3(4H)-one (5.00 g, 21.93 mmol, 1 eq), bromoacetaldehyde diethyl acetal (5.55 g, 32.89 mmol, 1.5 eq), Cs2CO3(14.29 g, 43.86 mmol, 2.0 eq) in DMF (60 ml) was stirred at 60 °C for 16 h, 180 mL H2O was added, extracted by EA, the organic layer was collected and purified by silica gel to produce 7-bromo-4-(2,2-dimethoxyethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (5.40 g, 78%).

[0293] Step 2

[0294] A solution of compound SM2 (2.50 g, 5.26 mmol, 1 eq), 7-bromo-4-(2,2- dimethoxyethyl)-2H-benzo[b][l,4]oxazin-3(4H)-one (3.49 g, 11.04 mmol, 2.1 eq), K2CO3 (2.90 g, 21.04 mmol, 4.0 eq), Pd(dppf)Cl2 DCM (0.21 g, 0.263 mmol, 0.05 eq) in dioxane (40 ml) and H2O (8 ml) was stirred at 80 °C under N2 for 2 h, 30 mL H2O was added, extracted by EA, the organic layer was collected and purified by silica gel to yield 7,7'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(4-(2,2-dimethoxyethyl)- 2H-benzo[b][l,4]oxazin-3(4H)-one) (3.10 g, 85%)

[0295] Step 3

[0296] A solution of 7,7'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(4-(2,2-dimethoxyethyl)- 2H-benzo[b][l,4]oxazin-3(4H)-one) (3.10 g, 4.47 mmol, 1 eq) in IN HCl (aq) / dioxane (15 ml / 30 ml) was stirred at 80 °C for 1 h, 30 mL H2O was added, extracted by EA, the organic layer was washed with NaHC03 and concentrated to the title compound SM3 (2.91 g, crude).

[0297] Preparation of 3,3'-((2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazin-7,4-diyl))dimalononitrile (Intermediate SM4)

[0298]

[0299] Compound SM4 can be prepared after the same procedure as obtaining SM3 using 3-bromo-l,l-dimethoxypropane as the reactant.

[0300] Example 4

[0301] Preparation of 7,7'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(2H-benzo[b][l,4]oxazin-3(4H)- ketone) (Intermediate SM5)

[0302]

[0303] Referring to the following reaction scheme, SM2 (0.05 g, 0.11 mmol, 1 eq), 7-bromo-2H- benzo[b][l,4]oxazin-3(4H)-one (0.062 g, 0.27 mmol, 2.5 eq), Pd(dppf)Cl2(0.008 g, 0.01 mmol, 0.1 eq) and potassium carbonate (0.058 g, 0.42 mmol, 4 eq) were dissolved in dioxane / H2O (3 ml, v / v = 5: 1). The reaction was carried out at 85 °C for 2 h under N2atmosphere. 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 (DCM / MeOH = 10 / 1 elution) to yield compound SM5, 7,7'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(2H- benzo[b][l,4]oxazin-3(4H)-one) (13 mg, yield: 15.6%).

[0304] Example 5 (Preparation of reductive amination)

[0305] 5A. Preparation of l-(2-(7-(2,2'-dichloro-3'-(4-(2-((S)-3-hydroxypyrrolidin-l-yl)ethyl)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)-[l,l'-biphenyl]-3-yl)-3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)ethyl)pyrrolidine-3-carboxylic acid

[0306]

[0307] To a stirred solution of compound SM3 (0.015 g, 0.024 mmol, 1 eq), pyrrolidine-3-carboxylic acid (0.0035 g, 0.03 mmol, 1.3 eq), (S)-pyrrolidine-3-ol hydrochloride (0.004 g, 0.032 mmol, 1.3 eq) and one drop of AcOH in CH2Cl2 / MeOH (1 mL / 0.5 mL) was added sodium triacetoxyborohydride (0.051 g, 0.24 mmol, 10 eq) at room temperature. After 4 h, it was directly concentrated and 0.5 mL of H2O and 3 mL of MeOH were added, the mixture was purified by reverse phase HPLC (0.1% trifluoroacetic acid in water / acetonitrile) to afford GLC01-481 (6 mg, 31%).

[0308] 1H 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).

[0309] LCMS (ESI): for C 41 H 40 Cl2N4O7 calculated; [M+H] + : 771.23, found: 771.50

[0310] 5B. The following compounds can be prepared using different amine substrates with SM3 or SM4:

[0311]

[0312] 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).

[0313] LCMS (ESI): for C 36 H 36 Cl2N4O6 calculated; [M+H] + : 691.2, found: 691.2

[0314]

[0315] 1H 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).

[0316] LCMS (ESI): for C 42 H 42 Cl2N4O6 calculated; [M+H] + : 797.3, found: 797.3

[0317]

[0318] 1 H NMR (500 MHz, DMSO-d6) δ 7.51 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.6, 1.8 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.19 - 7.15 (m, 2H), 7.13 (d, J = 2.0 Hz, 2H), 4.73 (s, 4H), 4.36 (s, 2H), 4.31 - 4.14 (m, 6H), 3.72 - 3.64 (m, 4H), 3.12 - 2.97 (m, 4H), 2.20 - 2.08 (m, 4H).

[0319] LCMS (ESI): for C 42 H 40 Cl2N4O 10 calculated; [M+H] + : 831.22, found: 831.45

[0320]

[0321] 1H NMR (500 MHz, DMSO-d6) δ 7.48 (dt, J = 13.7, 7.5 Hz, 6 H), 7.40 (d, J = 7.4 Hz, 2 H), 7.33 (d, J = 8.3 Hz, 2 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.11 (s, 2 H), 4.69 (s, 4 H), 4.08 (s, 2 H), 4.02 (s, 2 H), 3.50 (s, 2 H), 2.63 (s, 2 H), 2.58 (d, J = 6.6 Hz, 4 H), 2.27 (s, 6 H), 2.14 - 1.92 (m, 8 H), 1.65 - 1.57 (m, 2 H).

[0322] LCMS (ESI): for C 44 H 46 Cl2N6O6 calculated; [M+H] + : 825.3, found: 825.3

[0323]

[0324] 1 H NMR (500 MHz, DMSO-d6) δ 8.18 (t, J = 5.8 Hz, 2 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.45 (d, J = 7.6 Hz, 2 H), 7.41 (d, J = 7.3 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.17 (dd, J = 8.3, 1.9 Hz, 2 H), 7.13 (s, 2 H), 4.74 (s, 4 H), 4.24 (t, J = 6.7 Hz, 4 H), 3.32 (q, J = 6.2 Hz, 5 H), 3.23 (d, J = 8.0 Hz, 4 H), 3.07 (t, J = 5.9 Hz, 4 H), 1.84 (s, 6 H).

[0325] LCMS (ESI): for C 40 H 42 Cl2N4O6 calculated; [M+H] + : 773.26, found: 773.55

[0326]

[0327] 1H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.7, 1.9 Hz, 2H), 7.41 (dd, J = 7.4, 1.8 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (dd, J = 8.4, 2.0 Hz, 2H), 7.13 (d, J = 2.0 Hz, 2H), 4.73 (s, 4H), 4.38 - 4.18 (m, 4H), 4.04 (s, 2H), 3.97 - 3.77 (m, 4H), 3.22 (t, J = 7.1 Hz, 4H), 2.53 - 2.51 (m, 2H).

[0328] LCMS (ESI): for C 38 H 36 Cl2N4O 10 calcd; [M+H] + : 779.19, found: 779.25

[0329]

[0330] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.13 (s, 2H), 4.74 (s, 4H), 4.24 (t, J = 5.8 Hz, 4H), 3.24 - 3.15 (m, 8H), 2.63 (t, J = 6.8 Hz, 4H).

[0331] LCMS (ESI): for C 38 H 36 Cl2N4O8 calcd; [M+H] + : 747.2, found: 747.2

[0332]

[0333] 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)

[0334] LCMS (ESI): for C 42 H 40 Cl2N4O8 calculated; [M+H] + : 799.2, found: 799.2

[0335]

[0336] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 1.9 Hz, 2H), 4.74 (s, 4H), 4.34 - 4.18 (m, 4H), 4.15 (s, 2H), 3.20 (d, J = 6.9 Hz, 4H), 3.13 (d, J = 12.2 Hz, 2H), 2.97 (t, J = 11.0 Hz, 2H), 2.45 (d, J = 5.4 Hz, 4H), 2.39 - 2.36 (m, 4H).

[0337] LCMS (ESI): for C 40 H 40 Cl2N4O 10 calculated; [M+H] + : 807.22, found: 807.25

[0338]

[0339] 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.48 - 7.44 (m, 2H), 7.43 - 7.38 (m, 4H), 7.19 (dd, J = 8.4, 2.0 Hz, 2H), 7.14 (d, J = 2.0 Hz, 2H), 5.42 (s, 2H), 4.75 (s, 4H), 4.34 (t, J = 7.3 Hz, 4H), 3.76 (t, J = 5.2 Hz, 4H), 3.50 - 3.40 (m, 4H), 3.33 - 3.16 (m, 4H), 2.93 (s, 6H).

[0340] LCMS (ESI): for C 38 H 40 Cl2N4O6 calculated; [M+H] + : 719.23, found: 719.52

[0341]

[0342] 1 H NMR (500 MHz, DMSO-d6) δ 7.51 (t, J = 7.6 Hz, 2H), 7.46 (dd, J = 7.6, 1.9 Hz, 2H), 7.40 (dd, J = 7.3, 1.9 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (dd, J = 8.3, 2.0 Hz, 2H), 7.13 (d, J = 2.1 Hz, 2H), 4.72 (s, 4H), 4.25 (s, 4H), 3.75 (d, J = 11.7 Hz, 2H), 3.60 (d, J = 11.6 Hz, 2H), 3.11 (d, J = 8.6 Hz, 4H), 2.65 - 2.55 (m, 4H), 1.35 (s, 6H).

[0343] LCMS (ESI): for C 40 H 40 Cl2N4O 10 calculated; [M+H] + : 807.22, found: 807.41

[0344]

[0345] 1HNMR (500 MHz, DMSO-d6) δ 7.52 - 7.44 (m, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.11 (s, 2H), 4.70 (s, 6H), 4.18 (s, 2H), 4.03 (t, J = 7.0 Hz, 4H), 2.80 (dd, J = 9.4, 6.2 Hz, 2H), 2.67 - 2.60 (m, 6H), 2.38 (dd, J = 9.9, 3.4 Hz, 2H), 2.03 - 1.91 (m, 4H), 1.53 (dd, J = 8.5, 4.2 Hz, 2H).

[0346] LCMS (ESI): for C 40 H 40 Cl2N4O6 calculated; [M+H] + : 743.2, found: 743.2

[0347]

[0348] 1 HNMR (500 MHz, DMSO-d6) δ 7.52 - 7.44 (m, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.11 (s, 2H), 4.70 (s, 5H), 4.24-4.18 (m, 3H), 4.03 (t, J = 7.0 Hz, 2H) 3.24 - 3.15 (m, 4H), 2.80 (dd, J = 9.4, 6.2 Hz, 1H), 2.67-2.60 (m, 5H) 2.38 (dd, J = 9.9, 3.4 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.53 (dd, J = 8.5, 4.2 Hz, 1H).

[0349] LCMS (ESI): for C 42 H 40 Cl2N4O 10 calculated; [M+H] + : 831.2, found: 831.2

[0350]

[0351] 1H NMR (500 MHz, DMSO-d6) δ 7.51 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.8, 1.9 Hz, 2H), 7.40 (dd, J = 7.5, 1.9 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 8.2, 2.0 Hz, 2H), 7.12 (d, J = 1.9 Hz, 2H), 5.30 (s, 2H), 4.72 (s, 4H), 4.33 - 4.29 (m, 2H), 4.20 - 4.12 (m, 4H), 4.07 - 3.87 (m, 4H), 3.59 - 3.56 (m, 2H), 3.07 - 3.02 (m, 2H), 2.88 - 2.82 (m, 2H), 2.10 - 2.03 (m, 4H).

[0352] LCMS (ESI): for C 42 H 40 Cl2N4O 10 calculated; [M+H] + : 831.21, found: 831.50

[0353]

[0354] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.7, 1.9 Hz, 2H), 7.41 (dd, J = 7.4, 1.8 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (dd, J = 8.4, 2.0 Hz, 2H), 7.13 (d, J = 2.0 Hz, 2H), 4.73 (s, 4H), 4.38 - 4.18 (m, 4H), 4.04 (s, 2H), 3.97 - 3.77 (m, 4H), 3.22 (t, J = 7.1 Hz, 4H), 2.53 - 2.51 (m, 2H).

[0355] LCMS (ESI): for C 36 H 36 Cl2N4O6 calculated; [M+H] + : 779.19, found: 779.25

[0356]

[0357] 1H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.7 Hz, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 2.1 Hz, 2H), 4.73 (s, 4H), 4.39 (s, 2H), 4.35 - 4.25 (m, 6H), 3.55 - 3.51 (m, 4H), 3.25 - 3.20 (m, 4H), 2.65 - 2.60 (m, 2H), 2.07 (d, J = 13.5 Hz, 2H).

[0358] LCMS (ESI): for C 42 H 40 Cl2N4O 10 Calculated; [M+H] + : 831.21, found: 831.45

[0359]

[0360] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 2H), 8.56 (s, 4H), 7.52 (t, J = 7.6 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.18 (dd, J = 8.2, 2.0 Hz, 2H), 7.14 (d, J = 1.9 Hz, 2H), 4.75 (s, 4H), 4.24 (t, J = 6.5 Hz, 4H), 3.23 - 3.16 (m, 4H), 3.03 - 2.97 (m, 4H), 2.27 (t, J = 7.0 Hz, 4H), 1.62 - 1.52 (m, 8H).

[0361] LCMS (ESI): for C 42 H 44 Cl2N4O8 Calculated; [M+H] + : 803.25, found: 803.51

[0362]

[0363] 1HNMR (500 MHz, DMSO-d6) δ 7.52 - 7.44 (m, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.11 (s, 2H), 4.70 (s, 4H), 4.24 - 4.18 (m, 3H), 4.03 (t, J = 7.0 Hz, 2H) 3.24 - 3.15 (m, 4H), 2.80 (dd, J = 9.4, 6.2 Hz, 1H), 2.67 - 2.60 (m, 5H) 2.38 (dd, J = 9.9, 3.4 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.53 (dd, J = 8.5, 4.2 Hz, 1H).

[0364] LCMS (ESI): for C 39 H 38 Cl2N4O7 calculated; [M+H] + : 745.2, found: 745.2

[0365]

[0366] 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), 3.65 (s, 1H), 3.40 - 3.20 (m, 11H), 3.10 (s, 1H), 2.23 (s, 4H)

[0367] LCMS (ESI): for C 39 H 38 Cl2N4O7 calculated; [M+H] + : 745.2, found: 745.2

[0368]

[0369] 1H NMR (500 MHz, DMSO-d6) δ 7.50 (t, J = 7.5 Hz, 2H), 7.47-7.44 (m, 2H), 7.41 (t, J = 7.9 Hz, 4H), 7.18 (dd, J = 8.4, 2.0 Hz, 2H), 7.12-7.09 (m, 2H), 4.67 (s, 4H), 4.08 (t, J = 6.4 Hz, 4H), 3.32 (t, J = 6.0 Hz, 2H), 3.01-2.93 (m, 4H), 2.92-2.81 (m, 4H), 2.74-2.66 (m, 2H), 1.91-1.81 (m, 4H), 1.67-1.48 (m, 6H).

[0370] LCMS (ESI): for C 44 H 44 Cl2N4O8 calculated; [M+H] + : 827.25, found: 827.50

[0371]

[0372] 1 H NMR (500 MHz, DMSO-d6) δ 7.53-7.48 (m, 1H), 7.46 (dd, J = 7.6, 1.9 Hz, 1H), 7.40 (dd, J = 7.4, 1.9 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 4.70 (s, 2H), 4.29 (dd, J = 9.2, 5.4 Hz, 1H), 4.02 (dd, J = 9.3, 2.9 Hz, 1H), 3.98 (t, J = 7.2 Hz, 2H), 3.57 (s, 1H), 2.82-2.66 (m, 4H), 2.24 (dd, J = 17.2, 3.3 Hz, 1H).

[0373] LCMS (ESI): for C 40 H 36 Cl2N4O8 calculated; [M+H] + : 771.20, found: 771.48.

[0374]

[0375] 1H NMR (500 MHz, DMSO-d6) δ 7.51 - 7.43 (m, 2 H), 7.38 (dd, J = 7.8, 1.9 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 2.1 Hz, 1 H), 4.82 (s, 1 H), 4.70 (s, 2 H), 4.01 - 3.94 (m, 2 H), 3.59 - 3.44 (s, 3 H), 2.83 - 2.64 (m, 4 H), 2.25 - 2.20 (m, 1 H).

[0376] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.22, found: 807.45.

[0377]

[0378] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 - 7.46 (m, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.40 (dd, J = 7.4, 2.1 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.16 (dd, J = 8.2, 2.0 Hz, 1 H), 7.10 (d, J = 2.1 Hz, 1 H), 4.69 (s, 2 H), 3.98 (t, J = 7.2 Hz, 2 H), 3.41 - 3.33 (m, 1 H), 2.78 - 2.66 (m, 2 H), 1.29 (d, J = 6.6 Hz, 3 H).

[0379] LCMS (ESI): for C 38 H 36 Cl2N4O8 Calculated; [M+H] + : 747.20, found: 747.41.

[0380]

[0381] 1H NMR (500 MHz, DMSO-d6) δ 7.50 (t, J = 7.5 Hz, 2H), 7.48 - 7.43 (m, 2H), 7.39 (dd, J = 7.4, 1.7 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.17 - 7.13 (m, 2H), 7.11 - 7.07 (m, 2H), 4.81 (t, J = 5.6 Hz, 2H), 4.69 (s, 4H), 4.07 (q, J = 7.1 Hz, 4H), 4.02 - 3.91 (m, 4H), 3.59 - 3.49 (m 4H), 3.32 - 3.28 (m, 2H), 2.88 - 2.78 (m, 2H), 2.72 - 2.65 (m, 2H), 1.16 (t, J = 7.1, 1.0 Hz, 6H).

[0382] LCMS (ESI): for C 42 H 44 Cl2N4O 10 Calculated; [M+H] + : 835.24, found: 835.51.

[0383]

[0384] 1 H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.46 (d, J = 6.9 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 1.9 Hz, 2H), 5.75 (s, 2H), 4.73 (s, 4H), 4.40 - 4.21 (m, 6H), 3.95 - 3.87 (m, 4H), 3.78 (s, 6H), 3.30 - 3.22 (m, 4H).

[0385] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.49.

[0386]

[0387] 1H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.45 (m, 4H), 7.40 - 7.37 (m, 4H), 7.15 (d, J = 8.0 Hz, 2H), 7.10 (s, 2H), 4.70 (s, 4H), 4.16 (m, 2H), 4.08 (m, 2H), 3.85 (m, 2H), 3.08 (d, J = 4 Hz, 2H), 3.04 (m, 2H), 2.87 (m, 2H), 1.13 (d, J = 8.0 Hz, 6H).

[0388] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.21.

[0389]

[0390] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.43 (m, 4H), 7.41 - 7.36 (m, 4H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (s, 2H), 4.71 (s, 4H), 4.15 (m, 2H), 4.09 (m, 2H), 3.87 (m, 2H), 3.10 (d, J = 4 Hz, 2H), 3.05 (m, 2H), 2.90 (m, 2H), 1.14 (d, J = 8.0 Hz, 6H).

[0391] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.21.

[0392]

[0393] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.35 (m, 10H), 7.16 (d, J = 8.0 Hz, 2H), 7.11 (s, 2H), 7.02 - 6.82 (m, 2H), 4.74 (s, 4H), 4.10 (m, 4H), 3.51 (m, 4H), 2.99 (t, J = 6 Hz, 4H), 2.87 (m, 2H), 1.78 (m, 2H), 1.67 (m, 2H).

[0394] LCMS (ESI): for C 40 H40 Cl2N4O 10 Calcd; [M+H] + : 807.21, Found: 807.21.

[0395]

[0396] 1 HNMR (500 MHz, DMSO-d6) δ 7.53 (t, J = 7.5 Hz, 2H), 7.48 (d, J = 6.9 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 1.9 Hz, 2H), 4.73 (s, 4H), 4.69 (s, 2H), 3.92 (dd, J = 6.0, 2.7 Hz, 4H), 3.72 - 3.65 (m, 4H), 3.31 - 3.29 (m, 2H), 3.08 - 2.87 (m, 4H).

[0397] LCMS (ESI): for C 38 H 36 Cl2N4O 10 Calcd; [M+H] + : 779.18, Found: 779.40.

[0398]

[0399] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.35 (m, 10H), 7.16 (d, J = 8.0 Hz, 2H), 7.11 (s, 2H), 7.02 - 6.82 (m, 2H), 4.74 (s, 4H), 4.11 (m, 4H), 3.49 (m, 4H), 3.02 (t, J = 6 Hz, 4H), 2.90 (m, 2H), 1.81 (m, 2H), 1.69 (m, 2H).

[0400] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calcd; [M+H] + : 807.21, Found: 807.21.

[0401]

[0402] 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.8, 1.8 Hz, 2H), 7.39 (dd, J = 7.5, 1.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.15 (dd, J = 8.3, 2.0 Hz, 2H), 7.09 (d, J = 2.0 Hz, 2H), 4.92 - 4.87 (m, 2H), 4.69 (s, 4H), 4.03 - 3.95 (m, 4H), 3.55 - 3.51 (m, 6H), 3.29 - 3.27 (m, 2H), 2.85 - 2.80 (m, 2H), 2.71 - 2.64 (m, 2H), 1.16 (t, J = 6.6 Hz, 12H).

[0403] LCMS (ESI): for C 44 H 48 Cl2N4O 10 Calcd; [M+H]+: 863.27, Found: 863.77

[0404]

[0405] 1 H NMR (500 MHz, DMSO-d6) δ 7.7 (s, 2H), 7.52 - 7.21 (m, 10H), 4.73 (s, 4H), 4.40 - 4.20 (m, 4H), 3.94 - 3.90 (m, 2H), 3.50 - 3.20 (m, 4H), 2.82 (d, J = 4.8 Hz, 4H), 2.87 (m, 2H).

[0406] LCMS (ESI): for C 40 H 38 Cl2N6O 10 Calcd; [M+H] + : 833.20, Found: 833.20.

[0407]

[0408] 1H NMR (500 MHz, DMSO-d6) δ 7.5 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.7, 1.8 Hz, 4H), 7.42 - 7.36 (m, 4H), 7.15 (dd, J = 8.3, 2.0 Hz, 2H), 4.70 (s, 4H), 4.14 (hept, J = 7.2, 6.7 Hz, 4H), 3.61 (dd, J = 9.6, 4.1 Hz, 2H), 3.54 (dd, J = 9.5, 6.2 Hz, 2H), 3.33 (t, J = 5.1 Hz, 2H), 3.33 (p, J = 6.0 Hz, 4H), 1.10 (s, 18H).

[0409] LCMS (ESI): for C 46 H 52 Cl2N4O 10 Calculated; [M+H] + : 891.31, found: 891.31.

[0410]

[0411] 1 H NMR (500 MHz, DMSO-d6) δ 13.07 (s, 2H), 7.52 - 7.38 (m, 10H), 7.10 (s, 2H), 4.87 (s, 4H), 4.4 - 4.3 (m, 2H), 4.22 - 4.15 (m, 4H), 4.01 - 3.95 (m, 4H), 3.87 - 3.79 (m, 4H), 3.11 - 3.04 (m, 4H).

[0412] LCMS (ESI): for C 42 H 36 Cl2N4O 10 Calculated; [M+H] + : 827.18, found: 827.18.

[0413]

[0414] 1 H NMR (500 MHz, DMSO-d6) δ 7.51 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.7, 1.9 Hz, 2H), 7.42 - 7.35 (m, 4H), 7.17 (dd, J = 8.3, 1.9 Hz, 2H), 7.11 (d, J = 2.0 Hz, 2H), 4.71 (s, 4H), 4.18 (q, J = 11.6, 9.3 Hz, 4H), 3.66 (m, 4H), 3.26 (s, 6H), 3.07 (m, 4H).

[0415] LCMS (ESI): for C 40 H 40 Cl2N4O 10 calculated; [M+H] + : 807.21, found: 807.21.

[0416]

[0417] 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), 4.01 (t, J = 7.0 Hz, 4H), 3.81 (s, 4H), 3.04 - 3.00 (m, 4H), 1.97 (t, J = 8.1 Hz, 4H).

[0418] LCMS (ESI): for C 38 H 36 Cl2N4O8 calculated; [M+H] + : 747.19, found: 747.46

[0419]

[0420] 1 H NMR (500 MHz, DMSO-d6) δ 7.51 (t, J = 7.6 Hz, 2H), 7.45 (dd, J = 7.7, 1.8 Hz, 2H), 7.40 (dd, J = 7.4, 1.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (dd, J = 8.3, 2.0 Hz, 2H), 7.13 (d, J = 1.9 Hz, 2H), 4.74 (s, 4H), 4.01 (t, J = 7.1 Hz, 4H), 3.12 (t, J = 7.0 Hz, 4H), 3.03 (t, J = 7.8 Hz, 4H), 2.61 (d, J = 7.0 Hz, 4H), 1.98 - 1.90 (m, 4H).

[0421] LCMS (ESI): for C 40 H 40 Cl2N4O8 calculated; [M+H] + : 775.22, found: 775.50

[0422]

[0423] 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), 4.01 (t, J = 7.0 Hz, 4H), 3.31 - 3.29 (m, 2H), 3.04 - 3.00 (m, 4H), 1.97 (t, J = 8.1 Hz, 4H).

[0424] LCMS (ESI): for C 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.50

[0425]

[0426] 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)

[0427] LCMS (ESI): for C 44 H 44 Cl2N4O 10 Calculated; [M+H] + : 859.24, found: 859.50

[0428]

[0429] 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 = 7.0 Hz, 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).

[0430] LCMS (ESI): for C 44 H 48 Cl2N4O 10 Calculated; [M+H] + : 863.27, found: 863.50.

[0431] Example 6

[0432] 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(propanoyl))bis(3-hydroxypropanoic acid)

[0433]

[0434] Synthesis of Intermediate 2

[0435] A solution of compound SM4 (0.515 g, 2.258 mmol, 1 eq), 1-bromopropan-2-one (0.340 g, 2.48 mmol, 1.10 eq), Cs2C03(0.960 g, 2.93 mmol, 1.30 eq) in DMF (5 ml) was stirred at room temperature for 1 h, 15 mL H20 was added slowly, the solid was collected and dried to yield the title compound 2 (0.400 g, 62%).

[0436] Synthesis of Intermediate 4

[0437] To a stirred solution of compound SM2 (0.300 g, 1.056 mmol, 1 eq), compound 3 (0.315 g, 2.024 mmol, 1.90 eq), DIEA (0.274 g, 2.124 mmol, 2.01 eq), 4A and 2 drops of AcOH in DCM (6 ml) was added NaBH(OAc)3 (1.00 g, 4.73 mmol, 4 eq) at room temperature. After 3-4 h, 10 mL H2O was added, extracted by DCM, collected the organic layer and purified by silica gel to yield the title compound 4 (0.07 g, 17%).

[0438] Synthesis of intermediate 6

[0439] A solution of compound SM2 (0.043 g, 0.09 mmol, 1 eq), compound 4 (0.07 g, 0.18 mmol, 2.0 eq), K2CO3 (0.05 g, 0.36 mmol, 4.0 eq), Pd(dppf)Cl2 DCM (0.008 g, 0.009 mmol, 0.1 eq) in dioxane (3 ml) and H2O (0.5 ml) was stirred at 80 °C for 2 h, 5 mL H2O was added, extracted by EA, collected the organic layer and purified by Pre-TLC to yield the title compound 6 (0.05 g, 66%).

[0440] Synthesis of GLC01-563

[0441] To a stirred solution of compound 6 (0.025 g, 0.030 mmol, 1 eq) in MeOH (2 mL) was added a solution of NaOH (0.020 g, 0.50 mmol, 16.6 eq) in H2O (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 afford GLC01-563 (12 mg, 50%).

[0442] 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).

[0443] LCMS (ESI): m / z 657.2 (M+H)+; 679.2 (M+Na)+. 40 H40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.43

[0444] GLC01-550 was prepared using the procedure

[0445]

[0446] 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).

[0447] LCMS (ESI): m / z 807.3 (M+H)+. 40 H 40 Cl2N4O 10 Calculated; [M+H] + : 807.21, found: 807.43

[0448] Example 7

[0449] 7A. Preparation of (2S,2'S)-2,2'-((((2,2'-dichloro-[l,l'-biphenyl]-3,3'- diyl)bis(6-fluoro-3-oxo-2,3-dihydro-4H-benzo[b][l,4]oxazine-7,4-diyl))bis(ethane- 2, 1 -diyl))bis(azanediyl))bis(3-hydroxypropanoic acid) diethyl ester and (2S,2'S)- 2,2'-((((2,2'-dichloro-[l,l'-biphenyl]-3,3'-diyl)bis(6-fluoro-3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazine-7,4-diyl))bis(ethane-2,l-diyl))bis(azanediyl))bis(3- hydroxypropanoic acid)

[0450]

[0451]

[0452] Synthesis of Intermediate 2

[0453] A solution of compound 1 (0.100 g, 0.598 mmol, 1.00 equiv), NBS (0.115 g, 0.646 mmol, 1.08 equiv), one drop of AcOH in CH3CN (1.5 ml) was stirred at 50 °C for 16 h, 5 mL of H2O was added slowly, extracted with EA, the organic was concentrated to yield title compound 2 (0.100 g, 68%).

[0454] Synthesis of intermediate 3

[0455] 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), Cs2CO3(5.00 g, 15.33 mmol, 2.51 equiv) in DMF (15 ml) was stirred at 60 °C for 16 h, 45 mL of H2O was added slowly, the solid was collected and dried in vacuum to yield compound 3 (0.65 g, 32%).

[0456] Synthesis of intermediate 5

[0457] 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), Pd(dppf)Cl2 DCM (0.030 g, 0.036 mmol, 0.06 equiv) in dioxane (3 ml) and H2O (0.5 ml) was stirred at 80 °C for 2 h, 5 mL of H2O was added, extracted by EA, the organic layer was concentrated and purified by silica gel (PE:EA = 3:1-1:1) to yield title compound 5 (0.330 g, 77%).

[0458] Synthesis of intermediate 6

[0459] 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 H2O was added, extracted by EA, the organic layer was concentrated to yield compound 6 (0.330 g, crude).

[0460] Synthesis of GLC01-589

[0461] 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), 4 A and AcOH (0.155 g, 2.59 mmol, 5.0 equiv) in DCM (7 ml) was added NaBH(OAc)3(0.500 g, 2.37 mmol, 4.5 equiv) at room temperature. After 3-4 h, 10 mL H2O was added, extracted by DCM, the organic layer was collected and purified by silica gel (DCM:MeOH = 50:1-20:1) to give GLC01-589 (0.200 g, 44%).

[0462] 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).

[0463] LCMS (ESI): for C 42 H 42 Cl2F2N4O 10 Calculated; [M+H] + : 871.22, found: 871.50

[0464] Synthesis of GLC01-554

[0465] 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 H2O (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%).

[0466] 1HNMR (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).

[0467] LCMS (ESI): for C 38 H 34 Cl2F2N4O 10 Calculated; [M+H] + : 815.16, found: 815.33

[0468] 7B. The following compounds can be prepared using different starting materials

[0469]

[0470] 1 HNMR (400 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.49 (d, J = 4 Hz, 2H), 7.43 (d, J = 4.0 Hz, 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).

[0471] LCMS (ESI): for C 38 H 34 F2Cl2N4O 10 Calculated; [M+H] + : 815.16, found: 815.16.

[0472]

[0473] 1 HNMR (400 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.49 (d, J = 4 Hz, 2H), 7.43 (d, J = 4.0 Hz, 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).

[0474] LCMS (ESI): for C 38 H 34 F2Cl2N4O10 Calculated; [M+H] + : 815.16, found: 815.16.

[0475]

[0476] 1 H NMR (500 MHz, DMSO-d6) δ 7.31 (dd, J = 8.1, 5.3 Hz, 4H), 7.21 (d, J = 7.7 Hz, 2H), 7.14 (d, J = 7.5 Hz, 2H), 7.06 (dd, J = 8.3, 1.7 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 4.82 (s, 2H), 4.68 (s, 4H), 4.07 (q, J = 7.1 Hz, 4H), 4.03 - 3.90 (m, 4H), 3.56 (hept, J = 5.1 Hz, 4H), 2.85 (dd, J = 12.3 6.8 Hz, 2H), 2.69 (dq, J = 13.3, 7.1, 6.3 Hz, 2H), 1.94 (s, 6H), 1.16 (t, J = 7.0 Hz, 6H),

[0477] LCMS (ESI): for C 44 H 50 N4O 10 Calculated; [M+H] + : 795.35, found: 795.35.

[0478]

[0479] 1 H NMR (500 MHz, DMSO-d6) δ 9.16 (s, 3H), 7.42 - 7.28 (m, 4H), 7.22 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 7.10 (dd, J = 8.2, 1.9 Hz, 2H), 7.05 (d, J = 2.0 Hz, 2H), 5.71 (s, 1H), 4.72 (s, 4H), 4.29 (hept, J = 7.5, 7.0 Hz, 4H), 4.18 (d, J = 3.4 Hz, 2H), 3.91 (d, J = 3.4 Hz, 4H), 3.25 (t, J = 7.7 Hz, 4H), 1.95 (s, 6H),

[0480] LCMS (ESI): for C 40 H 42 N4O 10 Calculated; [M+H] + : 739.29, found: 739.50.

[0481]

[0482] 1 H NMR (500 MHz, DMSO-d6) δ 7.33 (dd, J = 8.3, 5.4 Hz, 4H), 7.22 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 7.08 (dd, J = 8.2, 1.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 2H), 5.47 (s, 2H), 4.72 (s, 4H), 4.39 - 4.34 (m, 2H), 4.28 - 4.19 (m, 4H), 3.71 - 3.67 (m, 2H), 3.24 - 3.20 (m, 2H), 3.08 - 3.02 (m, 2H), 2.68 - 2.56 (m, 2H), 2.46 - 2.34 (m, 2H), 2.20 - 2.11 (m, 4H), 1.95 (s, 6H).

[0483] LCMS (ESI): for C 44 H 46 N4O 10 calculated; [M+H] + : 791.32, found: 791.58

[0484] Example 8

[0485] 8A. Preparation of (2S,2'S)-2,2'-((((2,2'-difluoro-[l,l'-biphenyl]-3,3'- diyl)bis(3-oxo-2,3-dihydro-4H-benzo[b][l,4]oxazine-7,4-diyl))bis(ethane-2,l- diyl))bis(azanediyl))bis(3-hydroxypropanoic acid) diethyl ester and (2S,2'S)-2,2'-((((2,2'-difluoro-[l,l'-biphenyl]-3,3'-diyl)bis(3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazine-7,4-diyl))bis(ethane-2,l-diyl))bis(azanediyl))bis(3- hydroxypropanoic acid)

[0486]

[0487] Synthesis of Intermediate GLC01-612-04

[0488] To a stirred solution of GLC01-612-03 (100 mg, 0.206 mmol, 1.0 eq) and SM (164 mg, 0.453 mmol, 2.2 eq) in 4 ml of 1,4-dioxane and 0.8 ml of water, K2CO3 (114 mg, 0.826 mmol, 4.0 eq) and Pd(dppf)Cl2 DCM (33 mg, 0.04 mmol, 0.2 eq) were added under an atmosphere of nitrogen at room temperature. Then, the resulting mixture was heated at 85 °C for 2 h. Water (15 ml) was added to dilute the reaction mixture, extracted with EA (3 x 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 under vacuum. The residue was purified by preparative TLC (PE / EA = 2 / 1) to afford the desired product as a light yellow solid (70 mg, yield: 52%).

[0489] Synthesis of GLC01-612

[0490] To a stirred mixture of GLC01-612-04 (50 mg) in ACN (3 ml) and water (3 ml), TFA (0.3 ml) was added at room temperature. After stirring at 80 °C for 1 h, the pH of the resulting solution was adjusted to 8-9 with aqueous K2CO3 solution, extracted with EA, washed with brine, the organic phase was concentrated under reduced pressure, the residue was used directly in the next step (43 mg, yield: 100%). The reductive amination step was performed after the above procedure.

[0491] 1 H NMR (500 MHz, DMSO) d 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).

[0492] LCMS (ESI): m / z 803.3 [M+H]+, 825.3 [M+Na]+. 42 H 44 F2N4O 10 Calculated; [M+H] + : 803.3, found: 803.3

[0493] Synthesis of GLC01-613

[0494] Hydrolysis reaction was performed after the above procedure.

[0495] 1 H NMR (500 MHz, DMSO) d 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).

[0496] LCMS (ESI): for C 38 H 36 F2N4O 10 Calculated; [M+H] + : 747.3, found: 747.3

[0497] Example 9 (preparation of homocore with different core)

[0498] 9A. Preparation of 6,6'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'- diyl)bis(l-(((S)-5-oxopyrrolidin-2-yl)methyl)-3,4-dihydroquinolin-2(lH)-one)

[0499]

[0500] Substrate A was prepared using the same procedure as SM5

[0501] A mixture of compound A (100 mg, 1 eq), Cs2CO3(253 mg, 4.0 eq), SM1 (157 mg, 3.0 eq) in DMF was stirred at 40 °C for 2 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column (DCM / MeOH = 20 / 1) to give the title compound 281 (98 mg, yield: 71%). 1HNMR (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).

[0502] LCMS (ESI): for C 40 H 36 Cl2N4O4 calculated; [M+H] + : 707.22, found: 707.43.

[0503] 9B. The following compounds can be prepared using different bromide substrates:

[0504]

[0505] 1H 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)

[0506] LCMS (ESI): for C 40 H 40 Cl2N4O2 calculated; [M+H]+: 679.25, found: 679.45

[0507]

[0508] 1H 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).

[0509] LCMS (ESI): for C 38 H 32 Cl2N4O6 calculated; [M+H] + : 711.17, found: 711.47

[0510]

[0511] 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.8, 1.8 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (dd, J = 8.6, 1.8 Hz, 2H), 7.10 (d, J = 2.1 Hz, 2H), 4.71 (s, 4H), 4.07 - 3.88 (m, 6H), 2.35 - 2.24 (m, 2H), 2.21 - 2.04 (m, 4H), 1.84 - 1.73 (m, 2H).

[0512] LCMS (ESI): for C 38 H 32 Cl2N4O6 calculated; [M+H] + : 711.17, found: 711.50

[0513]

[0514] 1H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.8, 1.8 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.34 (s, 2H), 7.10 (s, 2H), 4.71 (s, 4H), 4.07 - 3.88 (m, 6H), 2.35 - 2.24 (m, 2H), 2.21 - 2.04 (m, 4H), 1.84 - 1.73 (m, 2H).

[0515] LCMS (ESI): for C 38 H 34 Cl2N6O6 calculated; [M+H] + : 741.19, found: 741.50

[0516]

[0517] 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.93 (t, J = 1.7 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 8.7, 2.1 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 3.9 Hz, 2H), 7.49 (dd, J = 5.6, 3.8 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.27 - 4.20 (m, 1H), 4.11 - 4.03 (m, 1H), 2.42 - 2.30 (m, 1H), 2.24 - 2.16 (m, 1H), 2.03 - 1.95 (m, 1H), 1.891 - 1.84 (m, 1H).

[0518] LCMS (ESI): for C 38 H 30 Cl2N6O4 calculated; [M+H] + : 705.18, found: 705.52.

[0519]

[0520] 1HNMR (500 MHz, DMSO-d6) δ 8.29 (s, 2H), 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), 4.41 (dd, J = 14.0, 8.6 Hz, 2H), 4.23 (dd, J = 13.8, 5.3 Hz, 2H), 4.09 - 4.02 (m, 2H), 2.60 - 2.54 (m, 2H), 2.41 - 2.32 (m, 3H), 2.25 - 2.06 (m, 5H), 1.92 - 1.84 (m, 2H).

[0521] LCMS (ESI): for C 38 H 34 Cl2N6O4 calculated; [M+H] + : 709.20, found: 709.44

[0522]

[0523] 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 2H), 7.86 (s, 2H), 7.58 - 7.53 (m, 6H), 7.46 (dd, J = 5.9, 3.6 Hz, 2H), 4.21 - 4.15 (m, 2H), 4.05 (dd, J = 13.2, 6.6 Hz, 2H), 4.01 - 3.96 (m, 2H), 2.20 (q, J = 10.8 Hz, 4H), 2.08 (dd, J = 11.3, 3.9 Hz, 4H), 1.53 (s, 6H), 1.48 (s, 6H).

[0524] LCMS (ESI): for C 42 H 40 Cl2N4O6 calculated; [M+H] + : 767.24, found: 767.50

[0525]

[0526] 1H NMR (400 MHz, DMSO-d6) δ 7.79 - 7.71 (m, 2H), 7.55 - 7.49 (m, 2H), 7.48 - 7.41 (m, 4H), 7.38 (td, J=7.2, 1.7 Hz, 2H), 7.06 (d, J=2.6 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 4.73 (s, 4H), 4.04 - 3.88 (m, 6H), 2.33 - 1.94 (m, 6H), 1.78 (d, J=13.0 Hz, 2H).

[0527] LCMS (ESI): for C 38 H 30 Cl4N4O6 calculated; [M+H] + : 779.10, found: 779.41.

[0528]

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.62 (d, J=8 Hz, 2H), 7.56 - 7.49 (m, 6H), 7.45 (s, 2H), 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).

[0530] LCMS (ESI): for C 36 H 26 F4Cl2N6O6 calculated; [M+H] + : 785.12, found: 785.12.

[0531]

[0532] 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 2H), 7.86 (s, 2H), 7.58 - 7.53 (m, 6H), 7.46 (dd, J=5.9, 3.6 Hz, 2H), 4.21 - 4.15 (m, 2H), 4.05 (dd, J=13.2, 6.6 Hz, 2H), 4.01 - 3.96 (m, 2H), 2.20 (q, J=10.8 Hz, 4H), 2.08 (dd, J=11.3, 3.9 Hz, 4H), 1.53 (s, 6H), 1.48 (s, 6H).

[0533] LCMS (ESI): for C 40 H38 Cl2N6O6calculated; [M+H] + : 769.23, found: 769.50.

[0534]

[0535] 1 HNMR (500 MHz, DMSO-d6) δ 7.76 (s, 2H), 7.53 (t, J = 7.4 Hz, 3H), 7.48 - 7.42 (m, 4H), 7.31 (t, J = 10.8 Hz, 2H), 7.05 (d, J = 6.9 Hz, 2H), 4.70 (s, 4H), 4.05 - 3.87 (m, 6H), 2.33 - 2.23 (m, 2H), 2.20 - 2.04 (m, 4H), 1.77 (dd, J = 13.6, 7.7 Hz, 2H).

[0536] LCMS (ESI): for C 38 H 30 Cl2F2N4O6calculated; [M+H] + : 747.15, found: 747.10

[0537]

[0538] 1 H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J = 2.9 Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.46 (d, J = 7.1 Hz, 4H), 7.19 (d, J = 8.6 Hz, 2H), 7.04 (t, J = 7.8 Hz, 2H), 4.81 (d, J = 14.7 Hz, 4H), 4.08 - 4.01 (m, 2H), 3.93 (d, J = 12.0 Hz, 4H), 2.34 - 2.23 (m, 2H), 2.21 - 2.04 (m, 4H), 1.77 (dd, J = 13.2, 8.2 Hz, 2H).

[0539] LCMS (ESI): for C 38 H 30 Cl2F2N4O6calculated; [M+H] + : 747.15, found: 747.11

[0540]

[0541] 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 2H), 7.51 (dt, J = 14.3, 7.2 Hz, 4H), 7.42 (d, J = 7.0 Hz, 2H), 7.15 (d, J = 14.0 Hz, 2H), 7.04 (s, 2H), 4.74 - 4.67 (m, 4H), 4.10 (dd, J = 14.3, 7.5 Hz, 2H), 3.98 - 3.85 (m, 4H), 2.19 (t, J = 9.6 Hz, 2H), 2.15 - 2.06 (m, 4H), 1.70 (dd, J = 16.5, 7.0 Hz, 2H).

[0542] LCMS (ESI): for C 38 H 30 Cl2F2N4O6 calculated; [M+H] + : 747.15, found: 747.15

[0543]

[0544] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.92 (s, 2H), 7.81 (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).

[0545] LCMS (ESI): for C 36 H 30 Cl2N6O6 calculated; [M+H] + : 713.16, found: 713.16.

[0546]

[0547] 1H 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), 4.41 (dd, J = 14.0, 8.6 Hz, 2H), 4.23 (dd, J = 13.8, 5.3 Hz, 2H), 4.09 - 4.02 (m, 2H), 3.50 (s, 6H), 2.60 - 2.54 (m, 2H), 2.41 - 2.32 (m, 3H), 2.25 - 2.06 (m, 5H), 1.92 - 1.84 (m, 2H).

[0548] LCMS (ESI): for C 40 H 38 Cl2N6O4 calculated; [M+H] + : 737.23, found: 737.52

[0549]

[0550] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (s, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.6, 1.7 Hz, 2H), 7.42 (dd, J = 7.4, 1.9 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.19 (d, J = 2.1 Hz, 2H), 5.53 (s, 4H), 3.99 - 3.88 (m, 2H), 3.78 (d, J = 5.6 Hz, 4H), 2.32 - 2.24 (m, 2H), 2.23 - 2.09 (m, 4H), 1.90 - 1.80 (m, 2H).

[0551] LCMS (ESI): for C 36 H 32 Cl2N4O8S2 calculated; [M+H] + : 783.10, found: 783.42

[0552]

[0553] 1H NMR (500 MHz, DMSO-de) δ 7.50 (t, J = 7.5 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.32 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H), 7.07 (dt, J = 8.3, 1.6 Hz, 1H), 5.38 (s, 1H), 3.91 - 3.74 (m, 2H), 3.68 - 3.50 (m, 3H), 2.48 - 2.32 (m, 2H), 2.15 - 1.93 (m, 4H).

[0554] LCMS (ESI): for C 40 H 38 Cl2N6O4 calculated; [M+H] + : 737.24, found: 737.57.

[0555]

[0556] 1 H NMR (500 MHz, DMSO-de) δ 7.78 - 7.73 (m, 2H), 7.58 (dd, J = 7.7, 1.9 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43 (dd, J = 7.4, 1.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 4.91 (d, J = 1.4 Hz, 2H), 4.06 - 4.01 (m, 1H), 3.96 - 3.90 (m, 2H), 2.37 - 2.24 (m, 2H), 2.16 - 2.05 (m, 2H).

[0557] LCMS (ESI): for C 36 H 30 Cl2N6O6 calculated; [M+H] + : 713.17, found: 713.48.

[0558]

[0559] 1 H NMR (400 MHz, DMSO-de) 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).

[0560] LCMS (ESI): for C 34 H 28C12N8O6calc; [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.55 (br s, 1H), 7.52-7.45 (m, 2H), 7.41-7.36 (m, 2H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 4.73 (s, 2H), 4.11-3.98 (m, 2H), 3.34-3.28 (m, 1H), 3.06-2.99 (m, 1H), 2.83-2.74 (m, 1H), 2.30-2.22 (m, 1H), 2.02-1.95 (m, 1H).

[0561] Example 10 (preparation of different core)

[0562] 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

[0563]

[0564] A mixture of compound SM5 (100 mg, 1 eq), Cs2C03(251 mg, 4.0 eq), bromoacetonitrile (69 mg, 3.0 eq) in DMF was stirred at 40 °C for 2 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column (DCM / MeOH = 20 / 1) to give title compound 397 (92 mg, yield: 67.6%).

[0565] 1H NMR (500 MHz, DMSO-d6) δ 7.55 (br s, 1H), 7.52-7.45 (m, 2H), 7.41-7.36 (m, 2H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 4.73 (s, 2H), 4.11-3.98 (m, 2H), 3.34-3.28 (m, 1H), 3.06-2.99 (m, 1H), 2.83-2.74 (m, 1H), 2.30-2.22 (m, 1H), 2.02-1.95 (m, 1H).

[0566] LCMS (ESI): Calcd for C32H20Cl2N4O4; [M+H]+: 595.09, found: 595.40.

[0567] 10B. In the following procedure, compounds can be prepared from different bromide side chains

[0568]

[0569] 1H NMR (500 MHz, DMSO-d6) δ 7.55 (br s, 1H), 7.52-7.45 (m, 2H), 7.41-7.36 (m, 2H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 4.73 (s, 2H), 4.11-3.98 (m, 2H), 3.34-3.28 (m, 1H), 3.06-2.99 (m, 1H), 2.83-2.74 (m, 1H), 2.30-2.22 (m, 1H), 2.02-1.95 (m, 1H).

[0570] LCMS (ESI): Calculated for C38H32Cl2N4O6; [M+H]+: 711.18, found: 711.47.

[0571]

[0572] 1H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.44 (dd, J = 7.7, 1.8 Hz, 1H), 7.39 (dd, J = 7.4, 1.7 Hz, 1H), 7.12 - 7.08 (m, 3H), 4.67 (s, 2H), 4.49 (t, J = 6.0 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H).

[0573] LCMS (ESI): Calculated for C36H28Cl2N8O4; [M+H]+: 707.17, found: 707.43.

[0574]

[0575] 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).

[0576] LCMS (ESI): Calculated for C38H30Cl2N6O4; [M+H]+: 705.18, found: 705.42.

[0577]

[0578] 1H NMR (500 MHz, DMSO-d6) δ 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.7, 1.9 Hz, 2H), 7.42 - 7.36 (m, 4H), 7.15 (dd, J = 8.2, 2.0 Hz, 2H), 7.09 (d, J = 2.0 Hz, 2H), 4.93 (t, J = 5.7 Hz, 2H), 4.69 (s, 4H), 4.00 (t, J = 6.1 Hz, 4H), 3.65 - 3.59 (m, 4H).

[0579] LCMS (ESI): Calculated for C32H26Cl2N2O6; [M+H]+: 605.12, found: 605.50

[0580]

[0581] 1H NMR (500 MHz, DMSO-d6) δ 7.52 - 7.45 (m, 2H), 7.41 - 7.37 (m, 2H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 4.68 (s, 2H), 4.06 (t, J = 6.5 Hz, 2H), 3.43 (dd, J = 9.0, 6.8 Hz, 2H), 3.31 (t, J = 6.5 Hz, 2H), 3.17 (dd, J = 8.9, 6.8 Hz, 2H).

[0582] LCMS (ESI): Calculated for C38H34Cl2N6O6; [M+H]+: 741.20, found: 741.50.

[0583]

[0584] 1H NMR (500 MHz, DMSO-d6) δ 7.48 (t, J = 7.6 Hz, 1H), 7.43 (dd, J = 7.6, 1.9 Hz, 1H), 7.35 (dd, J = 7.4, 1.8 Hz, 1H), 7.07 (dd, J = 8.3, 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.65 (s, 2H), 4.16 (s, 2H).

[0585] LCMS (ESI): Calculated for C32H22Cl2N2O8; [M+H]+: 633.08, found: 633.37.

[0586]

[0587] 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 2H), 8.74 (d, J = 2.1 Hz, 2H), 8.28 (d, J = 2.3 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 (dd, J = 7.7, 1.9 Hz, 2H), 7.44 - 7.39 (m, 4H), 7.16 (dd, J = 8.3, 2.0 Hz, 2H), 7.12 (d, J = 2.0 Hz, 2H), 4.67 (s, 4H), 4.23 (t, J = 7.3 Hz, 4H), 3.01 (t, J = 7.3 Hz, 4H).

[0588] LCMS (ESI): Calculated for C44H30CI2N6O4; [M+H]+: 777.17, found: 777.45

[0589]

[0590] 1H 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), 4.75 (s, 4H), 3.75 - 3.67 (m, 4H), 3.24 - 3.17 (m, 4H), 3.08 - 3.02 (m, 4H), 2.34 - 2.16 (m, 4H), 1.97 - 2.01 (m, 4H).

[0591] LCMS (ESI): Calculated for C40H36CI2N4O6; [M+H]+: 739.20, found: 739.50

[0592]

[0593] 1H NMR (500 MHz, DMSO-d6) δ 7.54-7.48 (m, 2H), 7.46 (dd, J = 7.6, 1.9 Hz, 1H), 7.40 (dd, J = 7.4, 1.9 Hz, 1H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 4.59 (s, 2H), 4.52 (d, J = 13.1 Hz, 1H), 4.39 (t, J = 12.3 Hz, 1H), 3.92 (d, J = 13.5 Hz, 1H), 3.25-3.13 (m, 1H), 2.70-2.53 (m, 2H), 2.42-2.27 (m, 1H), 2.04 (s, 3H), 1.86-1.71 (m, 2H).

[0594] LCMS (ESI): Calculated for C42H40Cl2N4O6; [M+H]+: 767.24, found: 767.56.

[0595]

[0596] 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.31 (m, 4H), 7.25 (dd, J = 8.3, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 5.36 (s, 2H), 4.77 (s, 2H).

[0597] LCMS (ESI): Calculated for C32H22Cl2N10O4; [M+H]+: 681.13, found: 681.41.

[0598]

[0599] 1H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.46 (dd, J = 7.7, 1.9 Hz, 1H), 7.42-7.38 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 4.72 (d, J = 3.3 Hz, 2H), 4.41 (t, J = 7.9 Hz, 1H), 4.20-4.08 (m, 3H), 4.02-3.94 (m, 1H).

[0600] LCMS (ESI): Calculated for C36H28Cl2N4O8; [M+H]+: 715.14, found: 715.42.

[0601]

[0602] 1H NMR (500 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 7.8, 1.8 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (dd, J = 8.6, 1.8 Hz, 2H), 7.10 (d, J = 2.1 Hz, 2H), 7.09 (d, J = 5.4, 2.8 Hz, 2H), 6.96 (d, J = 2.7 Hz, 2H), 4.74 (s, 4H),

[0603] LCMS (ESI): Calcd. for C36H26Cl2N6O4; [M+H]+: 677.14, Found: 677.43

[0604]

[0605] 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.29 (q, J = 2.4 Hz, 1H), 7.47 (dq, J = 7.7, 4.2 Hz, 1H), 7.42 (dt, J = 7.5, 2.4 Hz, 1H), 7.37 (dt, J = 7.6, 2.3 Hz, 1H), 7.13 (d, J = 4.1 Hz, 1H), 7.05 (d, J = 4.2 Hz, 2H), 5.27 (d, J = 4.2 Hz, 2H), 4.91 (d, J = 4.2 Hz, 2H).

[0606] LCMS (ESI): Calcd. for C42H26Cl2N6O4; [M+H]+: 749.15, Found: 749.44.

[0607] Example 11 (Same Core Different Sides)

[0608] 11A. Preparation of 7,7'-(2,2'-dichloro-[l,l'-biphenyl]-3,3'- diyl)bis(4-(((S)-pyrrolidin-2-yl)methyl)-2H-benzo[b][l,4]oxazin-3(4H)- one)

[0609]

[0610] 1.

[0611] To a stirred solution of 411-01 (500 mg, 2.49 mmol, 1.0 eq) in DCM (5 ml) was added TosCI (567 mg, 2.98 mmol, 1.2 eq) and TEA (502 mg, 4.97 mmol, 2.0 eq), followed by DMAP (30 mg, 0.249 mmol, 0.1 eq) at room temperature and stirred for 4 h. To the reaction was added water and DCM and separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum. The residue was used directly in the next step (950 mg, yield: 107%).

[0612] 2.

[0613] To a stirred solution of SM4 (117 mg, 0.51 mmol, 1.0 eq) in DMF (2 ml) was added 411-02 (219 mg, 0.62 mmol, 1.2 eq) and CS2CO3 (337 mg, 1.03 mmol, 2.0 eq) at ambient temperature. The resulting mixture was then stirred at 70 °C overnight. The reaction was quenched with water, extracted with EA. The combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (PE / EA = 4 / 1) to afford the desired product as a light yellow oil (105 mg, yield: 50%).

[0614] 3.

[0615] To a solution of 411-03 (105 mg, 0.26 mmol, 2.2 eq) and SM2 (55 mg, 0.12 mmol, 1.0 eq) in dioxane (2.5 ml) and H2O (0.5 ml) was added Pd(dppf)CI2DCM (19 mg, 0.024 mmol, 0.2 eq), K2CO3 (64 mg, 0.48 mmol, 4.0 eq) under N2atmosphere. The final mixture was then stirred at 80 °C for 2 h. Cooled to room temperature, water was added and extracted twice with EA, the combined organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to afford the desired product as a white solid (50 mg, yield: 49%).

[0616] 4.

[0617] To a stirred solution of 411-03 (50 mg, 0.056 mmol, 1.0 eq) in MeOH (1 ml), HC1 in dioxane (1 ml, 4 M) was added and then the solution was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed by reduced pressure and dried under lyophilization to get the desired product (36 mg, yield: 95%).

[0618] 1H 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).

[0619] LCMS (ESI): for C 38 H 36 Cl2N4O4 (free form) calculated; [M+H]+: 683.2, found: 683.2

[0620] 11B. The following compounds can also be prepared:

[0621]

[0622] 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 4H), 7.51 (t, J = 7.5 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.40 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.13 (s, 2H), 4.73 (d, J = 12.0 Hz, 4H), 4.08 (ddd, J = 41.2, 14.4, 7.4 Hz, 4H), 3.32 - 3.23 (m, 4H), 3.15 - 3.05 (m, 2H), 2.98 - 2.89 (m, 2H), 2.66 (dd, J = 15.2, 7.7 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.69 (dq, J = 16.8, 8.4 Hz, 2H).

[0623] LCMS (ESI): for C 38 H 36 C l2N4O4 (free form) calculated; [M+H]+: 683.2, found: 683.2

[0624]

[0625] 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 2H), 9.63 (s, 2H), 7.54 - 7.45 (m, 6H), 7.41 (d, J = 7.3 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.14 (s, 2H), 4.81 - 4.72 (m, 4H), 4.45 (dd, J = 15.2, 7.8 Hz, 2H), 4.28 (dd, J = 15.2, 4.7 Hz, 2H), 4.07 (s, 2H), 3.84 (dd, J = 24.5, 11.5 Hz, 2H), 3.73 - 3.54 (m, 4H), 2.92 (d, J = 14.7 Hz, 2H).

[0626] LCMS (ESI): for C 38 H 32 C l2 F4N4O4 (free form) calculated; [M+H]+: 755.2, found: 755.2

[0627]

[0628] 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 4H), 7.51 (t, J = 7.5 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.40 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.13 (s, 2H), 4.74 (s, 4H), 4.08 (ddd, J = 41.0, 14.5, 7.4 Hz, 4H), 3.31 - 3.22 (m, 4H), 3.11 (dd, J = 11.9, 5.8 Hz, 2H), 2.94 (td, J = 13.5, 6.5 Hz, 2H), 2.66 (dd, J = 15.2, 7.6 Hz, 2H), 2.04 (dt, J = 12.6, 6.4 Hz, 2H), 1.69 (dq, J = 16.7, 8.3 Hz, 2H).

[0629] LCMS (ESI): for C 38 H 36 C l2 N4O4 (free form) calculated; [M+H]+: 683.2, found: 683.2

[0630]

[0631] 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 2H), 8.51 (d, J = 9.4 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.47 - 7.40 (m, 6H), 7.16 (d, J = 8.5 Hz, 2H), 7.14 (s, 2H), 4.77 (s, 4H), 4.42 (dd, J = 15.4, 8.2 Hz, 2H), 4.19 (dd, J = 15.0, 4.3 Hz, 2H), 3.75 (s, 2H), 3.51 (s, 2H), 2.21 (d, J = 8.5 Hz, 2H), 2.14 - 2.06 (m, 2H), 1.83 (dd, J = 13.9, 8.4 Hz, 2H), 1.67 - 1.59 (m, 2H), 1.33 (d, J = 6.4 Hz, 6H).

[0632] LCMS (ESI): for C 40 H 40 Cl2N4O4 (free form) calculated; [M+H]+: 711.2, found: 711.2

[0633]

[0634] 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.87 (s, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.47 (d, J = 7.4 Hz, 2H), 7.43 - 7.38 (m, 4H), 7.19 (d, J = 8.3 Hz, 2H), 7.15 (s, 2H), 4.77 (dd, J = 31.2, 15.1 Hz, 4H), 4.39 - 4.30 (m, 2H), 4.03 (s, 2H), 3.91 (d, J = 14.2 Hz, 2H), 3.48 (s, 2H), 1.95 (d, J = 10.9 Hz, 2H), 1.73 (dd, J = 18.0, 10.2 Hz, 2H), 1.62 (dd, J = 18.2, 9.8 Hz, 6H), 1.33 (d, J = 8.7 Hz, 2H), 1.23 (s, 2H).

[0635] LCMS (ESI): for C 42 H 40 Cl2N4O4 (free form) calculated; [M+H]+: 735.2, found: 735.2

[0636]

[0637] 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 2H), 9.03 (s, 2H), 7.53 - 7.46 (m, 6H), 7.41 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 9.3 Hz, 2H), 7.14 (s, 2H), 4.78 (d, J = 15.5 Hz, 4H), 4.41 - 4.30 (m, 4H), 3.94 (s, 2H), 3.22 (s, 2H), 3.11 - 3.05 (m, 2H), 2.02 - 1.92 (m, 4H), 0.74 - 0.61 (m, 8H).

[0638] LCMS (ESI): for C 42 H 40 Cl2N4O4 (free form) calculated; [M+H]+: 735.2, found: 735.2

[0639]

[0640] 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 6H), 7.74 (d, J = 8.4 Hz, 2H), 7.54 - 7.45 (m, 4H), 7.40 (d, J = 7.3 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 7.11 (s, 2H), 4.72 (dd, J = 39.8, 15.0 Hz, 4H), 4.45 (s, 2H), 4.27 - 4.19 (m, 2H), 3.95 (d, J = 4.6 Hz, 2H), 3.80 (d, J = 9.3 Hz, 2H), 3.68 - 3.56 (m, 4H), 2.11 (d, J = 5.7 Hz, 4H), 1.97 - 1.89 (m, 2H), 1.83 (s, 4H), 1.00 (d, J = 6.8 Hz, 6H), 0.91 (d, J = 6.7 Hz, 6H).

[0641] LCMS (ESI): for C 48 H 54 Cl2N6O6 (free form) calculated; [M+H]+: 881.4, found: 881.4

[0642]

[0643] 1H NMR (500 MHz, DMSO-d6) δ 7.73 (d, J = 8.4 Hz, 2H), 7.53 - 7.44 (m, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 7.09 (s, 2H), 4.72 (m, 4H), 4.44 (s, 2H), 4.27 - 4.19 (m, 2H), 3.95 (d, J = 4.6 Hz, 2H), 3.80 (d, J = 9.3 Hz, 2H), 3.70 (s, 6H), 3.68 - 3.56 (m, 4H), 2.11 (d, J = 5.7 Hz, 4H), 1.97 - 1.89 (m, 2H), 1.83 (s, 4H), 1.00 (d, J = 6.8 Hz, 6H), 0.91 (d, J = 6.7 Hz, 6H).

[0644] LCMS (ESI): for C 52 H 58 Cl2N6O 10 Calculated; [M+H]+: 997.4, found: 997.4

[0645] 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 2H), 8.84 (s, 2H), 7.53 - 7.44 (m, 6H), 7.41 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.14 (s, 2H), 5.32 (s, 2H), 4.76 (t, J = 10.6 Hz, 4H), 4.35 (ddd, J = 20.6, 17.7, 8.9 Hz, 8H), 3.91 (d, J = 5.5 Hz, 2H), 3.00 - 2.93 (m, 2H), 2.09 (dd, J = 12.9, 5.0 Hz, 2H), 1.87 (td, J = 12.8, 4.7 Hz, 2H).

[0646] LCMS (ESI): for C 38 H 36 Cl2N4O6(free form) Calculated; [M+H]+: 715.2, found: 715.2

[0647]

[0648] 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).

[0649] LCMS (ESI): for C 42 H 40 C12N4O6 calculated; [M+H]+: 767.2, found: 767.2

[0650]

[0651] 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).

[0652] LCMS (ESI): for C 38 H 36 C12N4O4 calculated; [M+H]+: 683.22, found: 683.49.

[0653]

[0654] 1H NMR (500 MHz, DMSO-de) δ 9.07 (br s, 1H), 8.81 (br s, 1H), 7.52 (m, 1H), 7.48-7.44 (m, 2H), 7.41 (dd, J = 7.5, 1.8 Hz, 1H), 7.18-7.10 (m, 2H), 4.77 (s, 2H), 4.35-4.01 (m, 2H), 3.30-3.31 (m, 2H), 2.84 (s, 1H), 2.02-1.91 (m, 2H), 1.73-1.61 (m, 2H), 1.56-1.42 (m, 2H).

[0655] LCMS (ESI): for C 40 H 40 Cl2N4O4 calculated; [M+H]+: 711.25, found: 711.43

[0656]

[0657] 1H NMR (500 MHz, DMSO-de) δ 9.74 (s, 1H), 9.40 (s, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 2.2 Hz, 2H), 4.36-4.25 (m, 1H), 4.16-4.04 (m, 2H), 3.91-3.74 (m, 2H), 3.69-3.53 (m, 2H), 3.32-3.26 (m, 2H).

[0658] LCMS (ESI): for C 38 H 36 Cl2N4O6 calculated; [M+H]+: 715.21, found: 715.39.

[0659]

[0660] 1H NMR (400 MHz, DMSO-de) 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).

[0661] LCMS (ESI): for C 32 H 28 Cl2N4O4 calculated; [M+H]+: 603.15, found: 603.15.

[0662] Example 12 (asymmetric, asymmetric)

[0663] (S)-7-(2,2'-Dichloro-3'-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)-[l,l'- biphenyl]-3-yl)-4-((5-oxopyrrolidin-2-yl)methyl)-2H-benzo[b][l,4]oxazin-3(4H)-one

[0664]

[0665] SM5 (20.0 mg, 1 eq), SM1 (10.4 mg, 1 eq) and cesium carbonate (25 mg, 2 eq) were dissolved in DMF (1 ml). The reaction was carried out at 40 °C for 2 h. 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 (DCM / MeOH = 20 / 1) to produce the title compound 429 (11 mg, yield: 46.3%). 1 H NMR (500 MHz, DMSO-d6) d 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): for C 33 H 25 Cl2N3O5 calculated; [M+H] + : 614.13, found: 614.41

[0666] In the following procedure, the compound named 385 was obtained by the same procedure.

[0667]

[0668] 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): m / z 629.14 [M+H] calculated for C 33 H 26 Cl2N4O5 calculated; [M+H] + : 629.14, found: 629.44

[0669] Example 13

[0670] 13A. Preparation of (2-(7-(2,2'-dichloro-3'-(3-oxo-4-(((S)-pyrrolidin-2-yl)methyl)-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)-[l,l'-biphenyl]-3-yl)-3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)ethyl)-L-serine

[0671]

[0672] (a) To prepare compound 1A-1, compound 1A-2 (0.35 g, 1.54 mmol, 1.0 eq), cesium carbonate (0.75 g, 2.30 mmol, 1.5 eq) were dissolved in DMF (10 ml). The reaction was carried out at 60 °C for 5 h. After cooling, 10 ml of water and 10 ml of EA (ethyl acetate) were added for extraction, and the organic phase was washed with water and purified on silica gel, eluted with PE / EA (v / v, 8: 1) to produce compound 1A, i.e., (S)-tert-butyl 2-((7-bromo-3-oxo-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-yl)methyl)pyrrolidine-l-carboxylate (0.35 g, yield: 55.5%)

[0673]

[0674] (b) With reference to the following reaction scheme, compound 1B (25 mg) was dissolved in dioxane (0.5 ml), then 1 N HC1 solution (0.5 ml) was added dropwise, the temperature was raised to 85 °C, and the reaction was carried out for 0.5 h. The pH of the reaction solution was adjusted to 7 to 8 by adding a saturated Na2CO3 solution, and 10 ml of EA was added for extraction. The organic phase was concentrated to produce 1B (25 mg, yield: 107.0%).

[0675]

[0676] (c) With reference to the following reaction scheme, compound 1C (25 mg, 0.09 mmol, 1 eq), 1D (29 mg, 0.19 mmol, 2 eq), TEA (19 mg, 0.19 mmol), and one drop of AcOH were dissolved in DCM (3 ml), and the resulting mixture was allowed to stir at room temperature for 1 h. Then, NaBH(OAc)3 (37 mg, 0.45 mmol, 5 eq) was added, and the reaction was carried out for 1 h. Then, 10 ml of H2O and 10 ml of DCM were added for extraction. The organic phase was concentrated to produce 1C (25 mg, yield: 72%).

[0677]

[0678] (d) With reference to the following reaction scheme, compound 1F (0.05 g, 0.11 mmol, 1 eq), 1A (0.043 g, 0.11 mmol, 1 eq), 1E (0.04 g, 0.11 mmol, 1 eq), Pd(dppf)Cl2 (0.008 g, 0.01 mmol, 0.1 eq), and potassium carbonate (0.058 g, 0.42 mmol, 4 eq) were dissolved in dioxane / H2O (3 ml, v / v = 5:1). The reaction was carried out under an N2 atmosphere at 85 °C for 2 h. 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 produce compound 1G, i.e., (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-carboxylic acid tert-butyl ester, 0.017 g, yield: 20%.

[0679] LCMS (ESI): m / z 1000.9 (M+H)+for C 44 H 46C12H8N4O9calculated; [M+H]+: 845.26, found: 845.26.

[0680]

[0681] (e) With reference to the following reaction scheme, 1 N HC1 (1 mL) was added to a solution of compound 1G (17 mg, 0.02 mmol) in dioxane (1 mL) and then stirred at room temperature for 3 h. Then, Na2C03(aq) was added to the reaction mixture to neutralize the unreacted HC1. The reaction mixture was extracted with EA and water. The organic phase was concentrated and purified by preparative HPLC to yield 1F (10 mg, yield: 67%).

[0682]

[0683] (f) With reference to the following reaction scheme, 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) and then stirred at room temperature for 1 h. Then, HC1 (1 M) was added to the reaction mixture to neutralize the unreacted NaOH. The reaction mixture was purified by preparative HPLC to yield the title compound 1 (7.4 mg, yield: 75.5%).

[0684] 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).

[0685] LCMS (ESI): m / z 845.26 (M+H)+. 40 H 36 C12N4O8calculated; [M+H]+: 731.21, found: 731.21. +

[0686]

[0687] 13B. The following compounds were prepared using the same procedure

[0688] ​

[0689] 1 H 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), 4.19 (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)

[0690] LCMS (ESI): for C 39 H 39 Cl2N5O5 calculated; [M+H] + : 728.23, found: 728.23.

[0691]

[0692] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.44 (s, 1H), 7.53-7.49 (m, 2H), 7.47-7.43 (m, 2H), 7.42-7.33 (m, 4H), 7.21-7.12 (m, 3H), 7.10 (s, 1H), 5.54, (s, 1H), 4.75 (s, 2H), 4.71 (s, 2H), 4.46-4.40 (m, 2H), 4.34-4.28 (m, 2H), 4.06-3.89 (m, 3H), 3.78-3.66 (m, 2H), 3.44-3.40 (m, 2H), 3.27-3.03 (m, 2H), 2.32-2.20 (m, 2H), 2.18-2.08 (m, 2H), 2.02-1.91 (m, 2H), 1.75-1.86 (m, 2H).

[0693] LCMS (ESI): for C 39 H 38 Cl2N4O5 calculated; [M+H] + : 713.22, found: 713.22.

[0694]

[0695] 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.51-7.37 (m, 7H), 7.17-6.97 (m, 5H), 4.71 (s, 2H), 4.62 (s, 2H), 4.15 (t, J = 4.0 Hz, 2H), 3.70-3.62 (m, 3H), 3.05-2.99 (m, 2H).

[0696] LCMS (ESI): for C 33 H 27 Cl2N3O7 calculated; [M+H] + : 648.12, found: 648.12.

[0697]

[0698] 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.53-7.48 (m, 2H), 7.47-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.18 (d, J = 4.0 Hz, 1H), 7.15-7.12 (m, 2H), 7.10 (s, 1H), 4.75 (s, 2H), 4.71 (s, 2H), 4.22 (t, J = 4.0 Hz, 2H), 4.05-4.00 (m, 1H), 3.96-3.93 (m, 2H), 3.69-3.58 (m, 1H), 3.29 (t, J = 4.0 Hz, 2H), 3.27-3.25 (m, 3H), 2.16-2.06 (m, 2H), 2.30-2.28 (m, 2H), 2.12-2.02 (m, 2H).

[0699] LCMS (ESI): for C 40 H 36 Cl2N4O8 calculated; [M+H] + : 771.19, found: 771.19.

[0700]

[0701] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.14 (t, J = 4.0 Hz, 1H), 7.78 (s, 1H), 7.53-7.48 (m, 2H), 7.47-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.18 (d, J = 4.0 Hz, 1H), 7.15-7.12 (m, 2H), 7.10 (s, 1H), 4.75 (s, 2H), 4.71 (s, 2H), 4.24 (t, J = 4.0 Hz, 2H), 4.04-4.00 (m, 1H), 3.97-3.92 (m, 2H), 3.32-3.30 (t, J = 4.0 Hz, 2H), 3.25-3.21 (m, 2H), 3.08-3.04 (m, 2H), 2.31-2.26 (m, 2H), 2.17-2.07 (m, 2H), 1.85 (s, 3H).

[0702] LCMS (ESI): for C 39 H 37 Cl2N5O6 calculated; [M+H] + : 742.21, found: 742.21.

[0703]

[0704] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.53-7.49 (m, 2H), 7.47-7.43 (m, 2H), 7.42-7.33 (m, 4H), 7.21-7.12 (m, 3H), 7.10 (s, 1H), 5.54, (s, 1H), 4.75 (s, 2H), 4.71 (s, 2H), 4.46-4.40 (m, 2H), 4.34-4.28 (m, 2H), 3.89-4.06 (m, 3H), 3.78-3.66 (m, 2H), 3.27-3.03 (m, 2H), 2.32-2.20 (m, 2H), 2.18-2.08 (m, 2H), 2.02-1.91 (m, 2H), 1.75-1.86 (m, 2H).

[0705] LCMS (ESI): for C 39 H 36 Cl2N4O6 calculated; [M+H] + : 727.20, found: 727.20.

[0706]

[0707] 1 H NMR (500 MHz, DMSO-d6) δ 7.76 (br s, 1H), 7.55 (br s, 1H), 7.53-7.47 (m, 2H), 7.48-7.44 (m, 2H), 7.42-7.36 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 7.18-7.13 (m, 2H), 7.11 (dd, J = 6.9, 2.0 Hz, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 4.09-3.90 (m, 5H), 3.34-3.29 (m, 1H), 3.06-3.01 (m, 1H), 2.82-2.75 (m, 1H), 2.30-2.23 (m, 2H), 2.18-2.05 (m, 2H), 2.02-1.96 (m, 1H), 1.83-1.74 (m, 1H). LCMS (ESI): m / z 711.18 [M+H] at 10 min. Calculated for C39H39N5O6: 711.18, found: 711.51. 38 H 32 Cl2N4O6 + : 711.18, found: 711.51.

[0708]

[0709] 1 H NMR (500 MHz, DMSO-d6) δ 7.76 (br s, 1H), 7.55 (br s, 1H), 7.53-7.47 (m, 2H), 7.48-7.44 (m, 2H), 7.42-7.36 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 7.18-7.13 (m, 2H), 7.11 (dd, J = 6.9, 2.0 Hz, 2H), 4.73 (s, 2H), 4.71 (s, 2H), 4.09-3.90 (m, 5H), 3.34-3.29 (m, 1H), 3.06-3.01 (m, 1H), 2.82-2.75 (m, 1H), 2.30-2.23 (m, 2H), 2.18-2.05 (m, 2H), 2.02-1.96 (m, 1H), 1.83-1.74 (m, 1H). LCMS (ESI): m / z 711.18 [M+H] at 10 min. Calculated for C39H39N5O6: 711.18, found: 711.51.

[0710] LCMS (ESI): m / z 697.20 [M+H] at 10 min. Calculated for C38H37N5O5: 697.20, found: 697.47. 38 H 34 Cl2N4O5 + : 697.20, found: 697.47.

[0711] Example 14

[0712] PD-1 / PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Binding Assay

[0713] The assay was performed in a standard black 384-well polystyrene plate with a final volume of 20 μL. The inhibitors were first serially diluted in DMSO, then added to the plate wells, followed by the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assay was performed in PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA at 25 °C. Recombinant human PD-L1 protein (19-238) with a histidine tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with a Fe tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). The PD-L1 protein and PD-1 protein 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 min. After the incubation, 10 μL of HTRF detection buffer supplemented with europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) and anti-His apocytochrome (PerkinElmer-AD0059H) conjugated anti-His antibody specific for Fe was added. After centrifugation, the plate was incubated at 25 °C for 60 min, followed by reading on a PHERAstar FS plate reader (ratio 665 nm / 620 nm). The final concentrations in the assay were 3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG, and 20 nM anti-His apocytochrome. IC50values were determined by fitting a curve of percent control activity versus log of inhibitor concentration. 50 assay.

[0714] Table 1

[0715]

[0716]

[0717] Example 15

[0718] PD-L1 internalization

[0719] 1. Experimental protocol

[0720] Day 1. Cell seeding: PD-L1 / CHO-K1 cells were trypsinized in flasks, then the cell number was counted and diluted to 1 x 105cells / ml. Cells were seeded into 6-well plates (Corning, 3516) at 2 mL / well. The plates were incubated at 37 °C in a 5% CO2incubator for 24 hours.

[0721] ​Day 2. Prepare compounds and treat cells: Dilute GLC01-258 from 15 mM to 0.5 mM by using DMSO, dilute 15 mM compound from 15 mM to 15 nM by DMSO, then dilute the compound 500-fold by using assay buffer. Prepare 0.2% DMSO in assay buffer for vehicle control and low control. Remove plates, aspirate media and discard. Add 2 mL of diluted compound, vehicle control and low control to the corresponding wells. Then incubate the plates for 17 hours at 37°C in a 5% CO2 incubator.

[0722] Day 3. Prepare samples for FACS: After 17 hours of incubation, discard media and wash by PBS. Digest cells in each well by trypsin. Centrifuge and discard supernatant, then wash cells twice by DPBS (without Ca 2+ , Mg 2+ ). Dilute antibody (PE conjugated mouse anti-human CD274) 10-fold by DPBS, then add staining solution to compound treated samples and vehicle control samples. Low control only add DPBS without antibody. Incubate plates for 20 minutes at room temperature and protected from light. After 20 minutes, wash samples twice by DPBS. Then centrifuge and discard supernatant. Resuspend cells by 300 uL DPBS, and transfer samples to 5 mL polystyrene round-bottom tubes (Falcon, cat# 352054), then test by BD FACSCanto. Test samples by BD FACSCanto.

[0723] 2. Data analysis

[0724] Set PD-L1 signal of vehicle control to 100% and PD-L1 signal of low control to 0%. Then calculate PD-L1 signal of compound treated samples

[0725] 0% PD-L1 signal: low control without staining by anti-CD274

[0726] 100% PD-L1 signal: vehicle control stained by anti-CD274

[0727] % activation of PD-L1 internalization = 1 - PD-L1 signal of compound.

[0728] Table 2

[0729]

[0730]

[0731] Example 16

[0732] PD-L1 dimerization

[0733] Compounds were tested in biochemical protein-protein interaction assays to determine if the compounds could specifically dimerize the extracellular domain of PD-L1.

[0734] (1) Dilute cpd sequentially in DMSO at a 1:3 ratio, 10+0 replicates per column (reference dilution plate map)

[0735] (2) Transfer 0.2 μΐ, of cpd solution per row using Echo into 384 assay plate, containing 2 replicates per column (reference assay plate map).

[0736] (3) Add 20 μΐ, of prepared mixture solution including PDL1-Eu and PDL1-A2 to the assay plate, centrifuge at 1000 rpm for 1 min.

[0737] (4) Incubate at 25 °C for 120 min.

[0738] (5) Read fluorescence signal on Envision 2104 plate reader.

[0739] (6) Read ratio (665 nm / 615 nm) signal on Envision.

[0740] (7) Analyze raw data using Equation (V. Data Analysis)

[0741] Table 3

[0742]

[0743] Example 17

[0744] PDL1 Jurkat-NFAT reporter assay

[0745] a. Preparation of Hep3B-OS8-hPDL1

[0746] 1. Hep3B-OS8-hPDL1 cells were cultured in 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and 100 μg / mL G418 and hygromycin B were added to the medium.

[0747] 2. Resuspend the cells with RPMI 1640 medium containing 10% FBS, and adjust the cell density to 1.25E5 cells / mL.

[0748] 3. Seed the cells into 96-well flat bottom plates (1.25E4 cells / 100 μΐ, / well).

[0749] b. Preparation of compound solutions

[0750] 4. Remove media from pre-plated Hep3B-OS8-PDL1 cells. Wash once with 200 pL assay media.

[0751] 5. Prepare compound dilutions in RPMI 1640 media containing 10% FBS according to the layout.

[0752] 6. Add 50 pL of compound to each well at 9 concentrations (3 pM, 1 pM, 0.3 pM, 0.1 pM, 0.03 pM, 0.01 pM, 0.003 pM, 0.001 pM, and 0.0003 pM). Keytruda will be part of the positive control at a concentration of 5 pg / mL.

[0753] 7. Incubate for 20-30 min at 37 °C, 5% CO2.

[0754] c. Preparation of Jurkat-NFAT-PD1

[0755] 8. Jurkat-NFAT-PD1 cells were cultured in 1640 media supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and to this media was added 1000 pg / mL hygromycin B and 0.3 pg / mL puromycin.

[0756] 9. On the second day of the assay, resuspend the cells in RPMI 1640 media containing 10% FBS and adjust the cell density to 2.5E5 cells / mL.

[0757] 10. Seed the cells onto a 96-well flat bottom plate (1.25E4 cells / 50 pL / well).

[0758] 11. Incubate the assay plate in a humidified incubator at 37 °C, 5% CO2 for 6 hours.

[0759] 12. Equilibrate the cells in culture at room temperature for 5-10 min.

[0760] 13. Add an equal volume (100 pL / well) of ONE-Glo Luciferase Assay System to each well and wait at least 3 min for complete cell lysis and measure in luminometer. TM

[0761] Table 4

[0762] Compound ID Jurkat-NFATEC 50 (nm) 465 0.3 529 111.1

[0763] Example 18

[0764] a. Hep3B-OS8-hPDL1 and T cell co-culture assay​

[0765] Tumor preparation

[0766] 1. Hep3B-OS8-hPDL1 cells were cultured in 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and 100 pg / mL G418 and hygromycin B were added to the medium.

[0767] 2. Harvest Hep3B-OS8-hPDL1 cells and treat with 10 pg / mL mitomycin C for 1.5 h at 37 °C, then wash the cells thoroughly with PBS four times.

[0768] 3. Resuspend the cells with RPMI 1640 medium containing 10% FBS, and adjust the cell density to 5E5 cells / mL.

[0769] 4. Seed the cells onto a 96-well flat-bottom plate (2.5E4 cells / 50 pL / well).

[0770] b. CD3+ T cell isolation (30 mL blood)

[0771] 5. Dilute the human blood sample from a single donor with the same volume of sterile PBS, for example, add 25 mL of sterile PBS to 25 mL of fresh whole blood and mix thoroughly by gently shaking.

[0772] 6. Transfer 15 mL of Lymphoprep medium into a new 50 mL centrifuge tube.

[0773] 7. Add the diluted blood sample onto the surface of the Ficoll medium as gently as possible to ensure a clear demarcation line between the two liquids, and the volume ratio between Ficoll and diluted blood (30 mL) is 1:2.

[0774] 8. Gently move the tube to utilize acceleration (5) and minimal deceleration (0) settings at 1000 x g for 25 min at 20 °C during centrifugation.

[0775] 9. After centrifugation, four interfaces can be observed, from top to bottom, plasma layer, mononuclear cell layer, Ficoll medium layer and RBC layer, and move the tube as gently as possible to keep the four interfaces separated. Carefully aspirate the second layer of mononuclear cells and transfer to another new sterile centrifuge tube, and if unavoidable, aspirate a specific volume of plasma instead of Ficoll medium.

[0776] 10. Add three times the volume of PBMC with sterile PBS in the tube containing PBMC.

[0777] 11. Wash the cells twice with 5-10 mL PBS, then count the cells using a hemocytometer. Centrifuge at 350 x g for 10 min at 20 °C. Use the acceleration (5) and deceleration (5) settings during centrifugation.

[0778] 12. Resuspend the cells in the recommended medium and adjust the density of the PBMC to a final concentration of 5E7 cells / mL.

[0779] 13. Isolate CD3+ T cells using the EasySep™ Human T Cell Isolation Kit (STEMCELL Technologies Cat. No. 17951) and seed the cells into a 96-well flat bottom plate (5E4 cells / 100 μL / well).

[0780] c. Preparation of compound solutions

[0781] 14. Prepare compound dilutions in RPMI 1640 medium containing 10% FBS according to the layout. 15. Add 50 μL volume of compound to each well {7 concentrations (0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM and 30 μM) for 3 compounds (GLC01-258, GLC01-269, GLC01-465) and the same concentration (1 μM) for 6 compounds (GLC01-411, GLC01-292, GLC01-445, GLC01-475, GLC01-470 and GLC01-468)}.

[0782] 16. Nab-paclitaxel will be part of the positive control at a concentration of 5 μg / mL.

[0783] 17. Incubate for 72 hours at 37 °C, 5% CO2.

[0784] 18. Collect the supernatant by centrifugation and measure IFN-γ by ELISA.

[0785] Table 5

[0786] Compound ID Tumor and T cell EC 50 (nm) 465 1.2 529 324.9 533 6.032 554 5.1

[0787] Example 19

[0788] Mouse PK study

[0789] (1) Weigh the compound and dissolve in 1 mg / mL of 5% solutol in saline vehicle, shake well and sonicate to form a clear colorless solution. After overnight fasting, a group of 3 mice is given the solution orally at a dose of 10 mg / kg.

[0790] (2) Blood was collected from the submandibular vein and anticoagulated with sodium heparin. After collection, the blood was placed on ice and the plasma was isolated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2°C-8°C) within 1 hour. Blood sampling time points were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours.

[0791] (3) The samples were stored in a refrigerator at -20°C. To the plasma sample (40 μΐ^) was added 160 μΐ^ of ice-cold acetonitrile containing an internal standard, vortexed for 3 minutes, and centrifuged at 11,000 rpm for 5 minutes. 100 μΐ^ of supernatant was added to 100 μΐ^ of water, and 5 μΐ^ of supernatant was injected into the LC / MS / MS instrument to detect the compound (if the compound is an ester, then the acid is detected).

[0792] The data is in Table 6:

[0793] Table 6

[0794]

[0795]

[0796] While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present application compositions and methods should not be limited by any of the above described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents.

[0797] The above description is intended to teach a person skilled in the art how to make and use the application. It is not intended to be exhaustive or to be necessary to limit the application to the precise form disclosed. Many modifications and variations are possible in light of this teaching. It is intended that the scope of the application be limited not with this detailed description, but rather by the claims appended hereto. Unless otherwise claimed, the claims are intended to cover any and all modifications and variations.

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer thereof, the core structure of the compound consists of a core structure selected from the group consisting of the following formulae: wherein L1and L2are each an alkyl or heteroatom chain containing m carbon atoms between ring 3 and W1and between ring 6 and W2, wherein m = 0, 1, 2, 3, 4, 5, or 6; when m is 0, W1or W2is directly connected to the corresponding nitrogen in ring 3 or ring 6, respectively; W1is W2is hydrogen, Type I side chain, Type II side chain, L-serine, or L-serine ester; wherein the Type I side chain is one of the following: Type I side chain, Type II side chain, L-serine, or L-serine ester; wherein the Type II side chain of W2has the following general formula: - C(O)ONa, -CN, -CH2OH, and -CH2NH2; wherein Type II side chains of W1 have the following general formula: L1and L2are each an alkyl containing m carbon atoms, wherein m = 0, 1, 2, 3, 4, 5, or 6; when m is 0, W1or W2is directly connected to the corresponding nitrogen in ring 3 or ring 6, respectively. wherein R 14 is one of the following: wherein R 15 independently -H or alkyl, wherein R 16 is one of the following: wherein R 17 independently -H or alkyl.

2. The compound of claim 1, wherein, L1and L2are each independently C1-C3alkyl.

3. The compound of claim 1, wherein, 4. The compound of any one of claims 1-3, wherein, W2is H and L2is absent. W1 is and 5. The compound of any one of claims 1-3, wherein, 6. The compound of any one of claims 1-3, wherein, W1 is and W2 is Type I or Type II side chain.

7. The compound of any one of claims 1-3, wherein, W1 is and W2 is Type I or Type II side chain.

8. The compound of any one of claims 1-3, wherein, W1 is and W2 is Type I or Type II side chain.

9. The compound of any one of claims 1-3, wherein, W1 is and W2 is Type I or Type II side chain. the compound is selected from the group consisting of: W1 is and W2 is 10. A compound, wherein, the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer thereof.

11. The compound of claim 10, wherein, the compound is or a pharmaceutically acceptable salt, stereoisomer thereof.

12. The compound according to any one of claims 1 to 3, wherein, 13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer thereof.

14. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for treating a disease or condition associated with the interaction between PD-L1 and PD-1. the disease is cancer.

15. Use according to claim 14, wherein, ​

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