Heterocyclic immunomodulators as PDL1 checkpoint inhibitors

Abstract

The present disclosure describes pyridinone-containing inhibitors of PD-L1, pharmaceutical compositions containing these compounds, chemical processes for preparing these compounds, and their use in the treatment of infectious diseases and cancer. Formula (I): [Formula 1] TIFF2022535879000052.tif30170

Description

[Background technology]

[0001] Programmed death-ligand 1 (PD-L1) is a 40-kDa immune checkpoint protein encoded in humans by the CD274 gene. Upon binding to its receptor PD-1, expressed on activated B cells, T cells, and myeloid cells, PD-L1 initiates signaling pathways that lead to downregulation of T-cell proliferation and activation, promoting tumor cell escape from T-cell-mediated immune surveillance and thereby contributing to cancer severity and progression. PD-L1 expression is highly expressed in a wide variety of solid tumors (e.g., breast, lung, colon, ovarian, melanoma, bladder, liver, salivary gland, stomach, glioma, thyroid, thymic epithelium, head and neck) (Brown JA et al., 2003. J. Immunol. 170:1257-66; Dong H et al., 2002. Nat. Med. 8:793-800; Hamanishi J, et al., 2007. Proc. Natl. Acad. Sci. USA 104:3360-65; Strome SE et al., 2003. Cancer Res. 63:6501-5; Inman BA et al., 2007. Cancer 109:1499-505; Konishi J et al., 2004. Clin. Cancer Res. 10:5094-100; Nakanishi J et al., 2007. Proc. Natl. Acad. Sci. USA 104:3360-65; al._2007.Cancer Immunol. Immunother._56:1173-82), and the protein has emerged as an attractive target for the development of anti-cancer therapeutics. Expression of PD-L1 is further involved in evading immune responses involved in infectious diseases (e.g., chronic viral infections including HBV and HIV). Therefore, PD-L1 also serves as a therapeutic target for the treatment of various infectious diseases. Summary of the Invention

[0002] The therapeutic efficacy of PD-L1 agonists (and PD-1 antagonists) has been verified in clinical trials. However, response rates remain low. For example, Opdivo® (nivolumab) treatment achieved a 26% overall response rate (ORR) across 27 clinical trials analyzed (Tie Y et al., 2016 Int. J. Cancer. 140:948-58). Therefore, there is a need in the art for effective treatments for PD-L1-associated diseases.

[0003] The present disclosure relates to general and preferred embodiments as defined in the independent and dependent claims appended hereto, respectively, which are incorporated herein by reference. In particular, the present disclosure relates to compounds of formula (I): [ka] (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof) (In the formula, R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO2R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y , O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring optionally substituted with one or more substituents selected from the group consisting of: O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently H, halogen, C1~4 C substituted with alkyl and one or more F 1~4 alkyl; R 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 heteroalkyl; C 1~6 Alkyl and C 1~6 Each heteroalkyl optionally is C 1~4 Alkyl, OH, OCH3, -CO2H, -CO2C 1~4 Alkyl, C 3~6 substituted with one or more substituents selected from heterocycle, aryl, and heteroaryl; C 3~6 The heterocycle is optionally substituted with one or more substituents selected from oxo, OH, and COH; However, R 8 and R 9 are not both H; or R 8 and R 9 Combine them together and make C 1~6 C optionally substituted with one or more substituents selected from alkyl, oxo, OH and COH 3~6 Forming a heterocyclic ring; R 10 H, CN, halogens, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y , SO2-C 1~6 selected from alkyl, aryl, and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; X is N or CR 12 and; R 12 are H, F, Cl, CN, C(=O)NR x R y aryl and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; and R x and R y are independently H and C 1~6 alkyl).

[0004] In embodiments, the compound of formula (I) is a compound selected from those species described or exemplified in the detailed description below.

[0005] The present disclosure is also directed to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0006] The present disclosure is also directed to a pharmaceutical combination comprising a first compound and a second compound as a combined preparation for simultaneous, separate, or sequential use in the prevention or treatment of an infection or cancer in a mammal in need thereof, wherein the first compound is different from the second compound. The pharmaceutical combination may comprise a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical combination may further comprise another ingredient active against the infection or cancer.

[0007] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use as a pharmaceutical.

[0008] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in the prevention or treatment of an infectious disease, more particularly a bacterial, viral, or fungal infectious disease, more particularly a viral infectious disease, in a subject in need thereof.

[0009] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in the prevention or treatment of HBV infection or an HBV infection-induced disease in a subject in need thereof.

[0010] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in the prevention or treatment of chronic hepatitis B in a subject in need thereof.

[0011] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in the treatment of cancer, and more particularly for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof.

[0012] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use in a method for enhancing, stimulating, modulating, or increasing an immune response in a subject in need thereof.

[0013] The present disclosure is also directed to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier for use as an immune checkpoint inhibitor, more particularly as a PDL1 checkpoint inhibitor.

[0014] The present disclosure is also directed to processes for the preparation of compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein are compounds of formula (I) useful in inhibiting PD-L1: [ka] (including stereoisomers or tautomeric forms thereof, or pharmaceutically acceptable salts thereof) are provided.

[0016] definition Listed below are definitions of various terms used to describe this disclosure. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0017] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the applicable art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0018] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, the use of the terms "including" and other forms such as "include," "includes," and "included" is not limiting.

[0019] As used in this specification and claims, the term "comprising" can include "consisting of" and "consisting essentially of" embodiments. The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified ingredients / steps, and permit the presence of other ingredients / steps. However, such statements should also be construed as describing compositions or processes as "consisting of" and "consisting essentially of" the listed compounds, i.e., permitting the presence of only the specified compounds, along with any pharmaceutically acceptable carriers, and excluding other compounds.

[0020] All ranges disclosed herein are inclusive of the recited endpoints and are individually combinable (e.g., the range "50 mg to 300 mg" includes the endpoints 50 mg and 300 mg, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values, but are not precise enough to include values ​​that approximate those ranges and / or values.

[0021] As used herein, approximating terms may be applied to modify any quantitative expression that can be varied without resulting in a change in the basic function to which it relates. Thus, values ​​modified with terms such as "substantially" may not, in some cases, be limited to the exact value specified. In at least some instances, approximating terms may correspond to the precision of an instrument for measuring the value.

[0022] The term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which may also be structurally depicted by the symbol " / "), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any one of the above examples in light of the knowledge of one of ordinary skill in the art and the teachings provided herein. As used herein, the term C 1~4 Alkyl refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain. 1~6 Alkyl refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain.

[0023] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense and refer to alkyl groups attached to the remainder of the molecule via an O atom, an amino group, or an S atom, respectively.

[0024] The term "heteroalkyl" refers to a stable straight or branched chain consisting of the specified number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S. The heteroatom may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.

[0025] The term "haloalkyl" is used in its conventional sense and refers to an alkyl group, as defined herein, that is substituted with one or more halo substituents.

[0026] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocycle having 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriately bonded moieties: [ka]

[0027] The terms "heterocycle" and "heterocycloalkyl" refer to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic ring system having 3 to 12 ring members and containing carbon atoms and 1 to 5 heteroatoms independently selected from the group consisting of N, O, and S. The terms "heterocycle" and "heterocycloalkyl" include cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Examples of heterocycle and heterocycloalkyl groups include, but are not limited to, epoxydyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, and benzo-1,4-dioxane. Unless otherwise specified, the heterocycle or heterocycloalkyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0028] Monocyclic, bicyclic or tricyclic aromatic carbocycle refers to an aromatic ring system consisting of one, two or three rings, said ring system being composed exclusively of carbon atoms; the term aromatic is well known to those skilled in the art and designates a cyclically bonded system of 4n+2 electrons (Hückel's rule) having 6, 10, 14 etc. π electrons.

[0029] Particular examples of mono-, bi- or tricyclic aromatic carbocycles are phenyl, naphthyl, anthracenyl.

[0030] The term "phenyl" refers to the following moiety: [ka]

[0031] Unless otherwise specified, the term "aryl" refers to a polyunsaturated, usually aromatic hydrocarbon group which may be a single ring or multiple fused or covalently linked rings (up to three rings). Examples of aryl groups include phenyl, naphthyl, and anthracenyl.

[0032] The term "heteroaryl" refers to a monocyclic or bicyclic ring system having 5 to 10 ring members and containing carbon atoms and 1 to 5 heteroatoms independently selected from the group consisting of N, O, and S. The term heteroaryl includes 5- or 6-membered aromatic rings, where the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of a 5-membered ring, the heteroaryl ring preferably contains one nitrogen, oxygen, or sulfur member plus up to three additional nitrogen atoms. In the case of a 6-membered ring, the heteroaryl ring preferably contains 1 to 3 nitrogen atoms. When a 6-membered ring has three nitrogen atoms, up to two nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, and quinazolinyl. Unless otherwise specified, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0033] Those of ordinary skill in the art will recognize that the species of heteroaryl groups listed or exemplified above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0034] The term "cyano" refers to the group --CN.

[0035] The term "halo" or "halogen" refers to chloro, fluoro, bromo, or iodo.

[0036] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group does not bear any substituents.

[0037] The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that substitution occurs at any valency-allowed position on the system. If a particular moiety or group is not explicitly stated as being optionally substituted or substituted with any particular substituent, it is understood that such moiety or group is intended to be unsubstituted.

[0038] The terms "para," "meta," and "ortho" have their art-understood meanings. Thus, for example, a fully substituted phenyl group has substituents at both "ortho" (o) positions adjacent to the point of attachment of the phenyl ring, both "meta" (m) positions, and one "para" (p) position across from the point of attachment. To clarify the location of substituents on the phenyl ring in more detail, the two different ortho positions are designated ortho and ortho', and the two different meta positions are designated as follows: [ka] The meta and meta' positions are designated as such, as exemplified by:

[0039] When referring to substituents on a pyridyl group, the terms "para," "meta," and "ortho" refer to the orientation of the substituent relative to the point of attachment of the pyridyl ring. For example, in the structure: [ka] is X in the ortho position 1 Substituent, X in meta position 2 Substituent, and X in the para position 3 It is described as a substituted 3-pyridyl.

[0040] In order to provide a more concise explanation, some quantitative expressions provided herein are not modified with the term "about." Whether or not the term "about" is explicitly used, it should be understood that any quantity provided herein is intended to refer to an actual predetermined value, and also to an approximation to such a predetermined value that would be reasonably inferred based on the knowledge of a person skilled in the art, including equivalents and approximations resulting from experimental and / or measurement conditions for such a predetermined value. When a yield is given as a percentage, such a yield represents the mass of a given entity relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Unless otherwise indicated, concentrations given as percentages refer to mass ratios.

[0041] The terms "buffered" solution or "buffer" solution are used interchangeably herein according to their standard meaning. Buffers are used to control the pH of a medium, and their selection, use, and function are known to those skilled in the art. See, for example, G.D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry, p. 261, 5, which describes, inter alia, buffer solutions and how the concentrations of buffer components relate to the pH of the buffer. th ed. (2005). For example, a buffer solution can be obtained by adding MgSO4 and NaHCO3 to a solution in a ratio of 10:1 (w / w) to maintain the pH of the solution at about 7.5.

[0042] Any formula provided herein is intended to represent a compound having the structure depicted by the structural formula, as well as certain variations or forms. In particular, compounds of any formula provided herein may have asymmetric centers and therefore may exist in different enantiomeric forms. All optical isomers of compounds of the general formula and mixtures thereof are considered to be included within the scope of the formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, a given structure may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomeric forms.

[0043] It should further be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers."

[0044] Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, referred to as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0045] "Tautomers" refer to compounds that are interchangeable forms of a particular compound's structure and differ in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shift of a π electron and one atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are also formed by treatment with acid or base.

[0046] Tautomeric forms can be important for achieving maximum chemical reactivity and biological activity of a compound of interest.

[0047] The compounds of the present disclosure may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0048] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, or else their racemates. Methods for determining the stereochemistry and separation of stereoisomers are well known in the art.

[0049] Certain examples contain chemical structures that are depicted as absolute enantiomers but are intended to represent enantiopure substances of unknown configuration. In these cases, (R*) or (S*) or (*R) or (*S) are used in the name to indicate that the absolute stereochemistry of the corresponding stereocenter is unknown. Thus, compounds designated (R*) or (*R) refer to enantiopure compounds with either the (R) or (S) absolute configuration. When the absolute stereochemistry is established, these structures are named using (R) and (S).

[0050] symbol [ka] are used to denote the same spatial arrangement in chemical structures shown herein. [ka] are used to denote the same spatial arrangement in chemical structures shown herein.

[0051] Furthermore, any formula provided herein is intended to refer to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly recited. A given compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), may be obtained as a solvate. Solvates include those formed from the interaction or complexation of a compound of the present disclosure with one or more solvents, either in solution or in solid or crystalline form. In some embodiments, the solvent is water, and the solvate is a hydrate. Furthermore, a given crystalline form of a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), may be obtained as a co-crystal. In certain embodiments of the present disclosure, the compound of Formula (I) was obtained in crystalline form. In other embodiments, the crystalline form of the compound of Formula (I) was cubic in nature. In other embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) was obtained in crystalline form. In yet other embodiments, the compound of formula (I) is obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form. In other embodiments, the compound of formula (I) converts between one or more crystalline and / or polymorphic forms in solution.

[0052] Reference to a compound herein refers to any one of (a) the actual recited form of such compound, and (b) any of the forms of such compound in the medium considered at the time the compound is named. For example, reference to a compound such as R-COOH herein refers to, for example, R-COOH (s) , R-COOH (sol)and R-COO - (sol) In this example, R-COOH (s) refers to a solid compound as it may be in, for example, a tablet or some other solid pharmaceutical composition or formulation; R—COOH (sol) refers to the undissociated form of the compound in the solvent; R-COO - (sol) refers to the dissociated form of a compound in an aqueous environment, whether such dissociated form is derived from R-COOH, derived from a salt thereof, or becomes R-COOH upon dissociation in the medium under consideration. - refers to the dissociated form of a compound in a solvent, regardless of whether it originates from any other entity that results in the dissociated form of the compound in the solvent. As another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to the exposure of such entity to one or more forms of one or more compounds R-COOH that are present in the medium in which such exposure occurs. As yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" refers to (a) reacting such entity in one or more chemically significant forms of such entity that are present in the medium in which such reaction occurs with (b) one or more chemically significant forms of the compound R-COOH that are present in the medium in which such reaction occurs. In this context, if such entity is in, for example, an aqueous environment, the compound R-COOH is present in such same medium, and therefore the entity is reacted with the compound R-COOH. (aq) and / or R-COO - (aq)where the subscript "(aq)" denotes "aqueous" according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been selected in these naming examples; this selection is not intended to be limiting and is merely illustrative. It is understood that similar examples can be provided by other functional groups, including, but not limited to, hydroxyl, basic nitrogen members such as those found in amines, and any other groups that interact or transform according to known methods in a medium containing the present compounds. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerization, solvolysis including hydrolysis, solvation including hydration, protonation, and deprotonation. These interactions and transformations in a given medium are known by those skilled in the art, and therefore no further examples related thereto are provided herein.

[0053] In another example, zwitterionic compounds are encompassed herein by reference to compounds known to form zwitterions, even if they are not explicitly named in their zwitterionic form. Terms such as zwitterion and their synonyms, zwitterionic compounds, are well-known and are standard IUPAC-approved names that are part of a standard set of defined scientific names. In this context, the name "zwitterion" has been assigned the identifier CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) Dictionary of Molecular Entities. As is commonly known, zwitterions or zwitterionic compounds are naturally occurring compounds with formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salt." Other sources refer to these compounds as "zwitterions," although the latter term is considered a misnomer by still other sources. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula HNCHCOOH, which forms a zwitterion in some media (in this case, a neutral medium). + H3NCH2COO -Zwitterions, zwitterionic compounds, inner salts, and zwitterions in the known, well-established meaning of these terms are included within the scope of the present disclosure, as they would be understood by a person skilled in the art in each case. Since it is not necessary to name each and every embodiment that would be recognized by a person skilled in the art, structures of zwitterionic compounds related to the compounds of the present disclosure are not explicitly provided herein. However, they are part of the embodiments of the present disclosure. These interactions and transformations in a given medium that result in various forms of a given compound are known to those skilled in the art, and therefore further examples related thereto are not provided herein.

[0054] Any formula provided herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted by the formula provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 125 Such isotopically labeled compounds may be useful in metabolism studies, including drug or substrate tissue distribution assays (preferably 14 C), chemical reaction rate studies (e.g., using deuterium (i.e., D or 2 H); or tritium (i.e., T or 3 H))) are useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) or in radiation treatment of patients. 18 F or11 C labeled compounds are particularly preferred for PET or SPECT studies. 2 Substitution with heavier isotopes of 1,2,3,4,5,6,7,8,8,9,9,9,10,11,12,13,14,15,16,17,18,19,19,19,19,10,11,12,13,14,15,16,17,18,19,19,19,19,20,21,22,23,24,25,26,27,28,29,29,29,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,49,50,51,52,53,54,55,56,57,58,59,59,60,61,62,63,64,59,50,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,71,71,72,74,79,71,72,73,74,75,76,77,78,79,71,71,72,73,74,75,76,77,79 ...

[0055] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a particular variable is not intended to dictate the same selection of species for that variable appearing elsewhere. In other words, when a variable appears more than once, the selection of species from a particular list is independent of the selection of species for the same variable elsewhere in the formula, unless otherwise specifically indicated.

[0056] In accordance with the above interpretive considerations regarding designation and nomenclature, any explicit reference herein to a set is chemically significant and, unless otherwise indicated, means an independent reference to any embodiment of such set and to any and all possible embodiments of the explicitly mentioned subset of that set.

[0057] As a first example of the terminology of the substituent, the substituent S 1 example is one of S1 and S2, and the substituent S 2 example If S is one of S3 and S4, then these assignments are 1 example is S1 and S 2 example is S3;S 1 example is S1 and S 2 example is S4;S 1example is S2 and S 2 example is S3;S 1 example is S2 and S 2 example is S4; and equivalents of each one of such options. 1 example is one of S1 and S2, and S 2 example is one of S3 and S4" is used for brevity and is in no way limiting. The first example above of substituent terminology written in general terms is intended to illustrate the various substituent designations described herein. The above conventions provided herein for substituents are intended to be illustrative of the various substituent designations described herein, where applicable. 1 , R 2 , R 3 , R 4 , R 5 , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 9 , G 10 , G 11 , n, L, R, T, Q, W, X, Y, and Z, as well as any other generic substituent symbols used herein.

[0058] Furthermore, when more than one designation is given for any member or substituent, embodiments of the present disclosure include the various groupings that may be made from the recited designations and their equivalents, taken independently. As a second example regarding substituent terminology, the substituent S example is described as one of S1, S2, and S3, this enumeration is example is S1;S example is S2;S example is S3;S exampleis one of S1 and S2; S example is one of S1 and S3; S example is one of S2 and S3; S example is one of S1, S2 and S3; and S example refers to an embodiment of the present disclosure that is any equivalent of each one of these options. example is one of S1, S2, and S3" is used herein for brevity and in no way to be limiting. The second example above of substituent terminology written in general terms is intended to illustrate the various substituent designations described herein. The above conventions provided herein for substituents are applicable to R, where applicable. 1 , R 2 , R 3 , R 4 , R 5 , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , G 9 , G 10 , G 11 , n, L, R, T, Q, W, X, Y, and Z, as well as any other generic substituent symbols used herein.

[0059] The term "C" i~j " (where j>i), when applied to a group of substituents herein, is meant to refer to an embodiment of the present disclosure in which any and all number of carbon members from i to j, inclusive, are independently realized. For example, the term C 1~4 refers independently to embodiments having one carbon member (C1), two carbon members (C2), three carbon members (C3), and four carbon members (C4).

[0060] Term C n~mAlkyl refers to an aliphatic chain, whether straight or branched, with a total of N carbon members in the chain, where n≦N≦m, where m>n. Any di-substituent referred to herein is meant to encompass various attachment possibilities when more than one such possibility is permitted. For example, reference to a di-substituent -AB-, where A≠B, herein refers to such a di-substituent with A attached to the first substituent member and B attached to the second substituent member, and also refers to such a di-substituent with A attached to the second substituent member and B attached to the first substituent member.

[0061] The present disclosure also includes pharmaceutically acceptable salts of compounds of formula (I), preferably those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.

[0062] The term "pharmaceutically acceptable" means approved or approvable by the federal or state government, or by corresponding agencies in countries other than the United States, or in the United States Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, and more particularly in humans.

[0063] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or free base of a compound represented by Formula (I) that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. See generally G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J. Med. Chem., 2007, 50:6665-72; S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic response. The compounds of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore react with a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0064] The present disclosure also relates to pharmaceutically acceptable prodrugs of compounds of formula (I) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that produces the compound in vivo after administration to a subject through a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug brought to physiological pH is converted to a compound of formula (I)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject. Specific techniques for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0065] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I), which may also be used in the methods of the present disclosure. "Pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or a salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, for example, Bertolini, et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

[0066] The term "stabilizer," as used herein, refers to a polymer that can chemically inhibit or prevent the degradation of a compound of Formula I. Stabilizers are added to formulations of a compound to improve the chemical and physical stability of the compound.

[0067] The term "tablet," as used herein, refers to an orally administrable, single-dose solid dosage form that can be produced by compressing a drug substance or a pharmaceutically acceptable salt thereof with suitable excipients (e.g., fillers, disintegrants, lubricants, glidants, and / or surfactants) by conventional tableting processes. Tablets can be produced using conventional granulation methods, such as wet or dry granulation with optional milling of the granules followed by compression and optional coating. Tablets can also be produced by spray drying.

[0068] As used herein, the term "capsule" refers to a solid dosage form in which a drug is enclosed within either a hard or soft soluble container or "shell," which may be formed from gelatin, starch, and / or other suitable materials.

[0069] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. That result can be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0070] The terms "combination," "therapeutic combination," "pharmaceutical combination," or "combination product," as used herein, refer to a loose combination or kit of parts of combined administration, where two or more therapeutic agents can be administered independently, either simultaneously or separately within a time interval, particularly where the time interval allows the combination partners to exhibit a cooperative, e.g., synergistic, effect.

[0071] The term "modulator" includes both inhibitors and activators, where "inhibitor" refers to a compound that reduces, prevents, inactivates, desensitizes, or downregulates the activity and / or downstream signaling of an immune checkpoint inhibitor. For example, inhibition of at least 5%, 10%, 20%, 30%, 40% or more of activity, e.g., of PD-L1 activity, is encompassed by the term. Thus, inhibition need not be 100%.

[0072] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient having an HBV infection, a symptom of an HBV infection, or the likelihood of developing an HBV infection, with the intent of curing, curing, alleviating, alleviating, altering, correcting, ameliorating, improving, or affecting the HBV infection, the symptoms of an HBV infection, or the likelihood of developing an HBV infection. Such treatments may be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0073] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease, where the onset of a disorder or disease has not occurred, or the absence of further onset of a disorder or disease, where there has already been onset of a disorder or disease. Additionally, the ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0074] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cows, pigs, dogs, cats, and murines. Preferably, the patient, subject, or individual is human.

[0075] In the treatment methods according to the present disclosure, an effective amount of a pharmaceutical agent according to the present disclosure is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. An "effective amount" refers to an amount or dose sufficient to generally provide the desired therapeutic or prophylactic benefit in patients in need of such treatment for the specified disease, disorder, or condition. An effective amount or dose of a compound of the present disclosure can be determined by conventional methods, such as, for example, modeling, dose escalation studies, or clinical trials, and by taking into account conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous treatment or ongoing therapy, the subject's health status and response to the drug, and the judgment of the treating physician. Exemplary doses range from about 0.001 to about 200 mg of compound per kg of subject body weight per day, e.g., about 0.05 to 100 mg / kg / day, or about 1 to 35 mg / kg / day, in single or divided dose units (e.g., BID, TID, QID).

[0076] Exemplary compound dosages are from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the disclosed compound used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.

[0077] Once improvement of the patient's disease, disorder, or condition occurs, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced symptomatically to a level at which the desired therapeutic or preventive effect is maintained. Of course, once the symptoms have been alleviated to an appropriate level, treatment can be discontinued. However, the patient may require intermittent treatment for a long period of time if symptoms recur.

[0078] Compounds of the Disclosure In one aspect, provided herein is a compound of formula (I): [ka] (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof) R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO2R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y , O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring optionally substituted with one or more substituents selected from the group consisting of: O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently H, halogen, C 1~4 C substituted with alkyl and one or more F 1~4 alkyl; R 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 heteroalkyl; C 1~6 Alkyl and C 1~6 Each heteroalkyl optionally is C 1~4 Alkyl, OH, OCH3, -CO2H, -CO2C 1~4 Alkyl, C 3~6 substituted with one or more substituents selected from heterocycle, aryl, and heteroaryl; C 3~6The heterocycle is optionally substituted with one or more substituents selected from oxo, OH, and COH; However, R 8 and R 9 are not both H; or R 8 and R 9 Combine them together and make C 1~6 C optionally substituted with one or more substituents selected from alkyl, oxo, OH and COH 3~6 Forming a heterocyclic ring; R 10 H, CN, halogens, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y , SO2-C 1~6 selected from alkyl, aryl, and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; X is N or CR 12 and; R 12are H, F, Cl, CN, C(=O)NR x R y aryl and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; and R x and R y are independently H and C 1~6 alkyl).

[0079] In one embodiment, R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO2R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y and rings optionally substituted with one or more substituents selected from:

[0080] In one embodiment, R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO2R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y , O-(6- to 10-membered aryl), O-(5- to 10-membered heteroaryl), 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycle optionally substituted with one or more substituents selected from O-(6- to 10-membered aryl), O-(5- to 10-membered heteroaryl), 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycle, and 5- to 10-membered cycloalkyl.

[0081] In one embodiment, R 1 is an optionally substituted monocyclic or bicyclic ring. In another embodiment, R 1 is an optionally substituted bicyclic ring. In yet another embodiment, R 1 is an optionally substituted bicyclic ring, wherein the two rings of the bicycle are fused or covalently linked to each other. 1 is an optionally substituted bicyclic ring, wherein the two rings of the bicycle are fused.

[0082] In one embodiment, R 1 is an optionally substituted monocyclic or bicyclic aryl, heteroaryl, or heterocyclic group. 1 is an optionally substituted bicyclic aryl, heteroaryl, or heterocyclic group. 1 is an optionally substituted bicyclic aryl, heteroaryl, or heterocyclic group, wherein the two rings of the bicycle are fused or covalently linked to each other. 1 is an optionally substituted bicyclic aryl, heteroaryl, or heterocyclic group, wherein the two rings of the bicycle are fused.

[0083] In one embodiment, R 1 is an optionally substituted ring, and the ring optionally contains one or more heteroatoms. 1 is an optionally substituted ring, the ring optionally containing one or more heteroatoms each independently selected from O, S, and N. In yet another embodiment, R 1 is an optionally substituted ring, the ring optionally containing one or more oxygen atoms.

[0084] In one embodiment, R 1 is an optionally substituted saturated ring. In another embodiment, R 1 is an optionally substituted unsaturated ring. In yet another embodiment, R 1 is an optionally substituted ring that is a combination of saturated and unsaturated.

[0085] In some embodiments, R 1 is the following ring: [ka] is selected from.

[0086] In some embodiments, R 1 is the formula (g-1): [ka] is.

[0087] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently H and C 1~4 alkyl.

[0088] In some embodiments, R 2, R 3 , R 4 , R 5 , R 7 and R 11 are independently H and C 1~4 alkyl.

[0089] In some embodiments, R 6 is C 1~4 It is alkyl or Cl.

[0090] In some embodiments, R 6 is Cl, and R 2 , R 3 , R 4 , R 5 , R 7 and R 11 is H.

[0091] In some embodiments, R 8 is H and R 9 is C substituted with OH and CO2H 1~6 It is alkyl.

[0092] In some embodiments, R 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 heteroalkyl; C 1~6 Alkyl and C 1~6 Each heteroalkyl optionally is C 1~4 Alkyl, OH, OCH3, -CO2H, -CO2C 1~4 It is substituted with 1, 2, or 3 substituents selected from alkyl, aryl, and heteroaryl.

[0093] In some embodiments, R 8 and R 9 C replaced with OH and CO2H 3~6 In some embodiments, C 3~6 The heterocycle is pyrrolidine.

[0094] In some embodiments, R 10 is selected from H and CN.

[0095] In some embodiments, R 12 is selected from H, Cl, and CN.

[0096] In some embodiments, R 10 is CN and X is N.

[0097] In some embodiments, R 10 is H and X is N.

[0098] Another embodiment of the present disclosure provides an IC of 5 μM or less. 50 The compound of formula (I) has the formula: IC 50 may be measured using any means found suitable by one of skill in the art, such as all or some of the means described in Example 2 below.

[0099] A further embodiment of the present disclosure is a compound selected from the group consisting of the following compounds, stereoisomers or tautomeric forms thereof, or pharmaceutically acceptable salts thereof:

[0100] [Table 1]

[0101] [Table 2]

[0102] A further embodiment of the present disclosure is a compound selected from the group consisting of the following compounds, stereoisomers or tautomeric forms thereof, or pharmaceutically acceptable salts thereof:

[0103] [Table 3]

[0104] Pharmaceutical Composition In another aspect, provided herein are (A) A compound of formula (I): [ka] (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof) R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO2R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y , O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring optionally substituted with one or more substituents selected from the group consisting of: O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently H, halogen, C 1~4 C substituted with alkyl and one or more F 1~4 alkyl; R 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 heteroalkyl, C 1~6 Alkyl and C 1~6 Each heteroalkyl optionally is C 1~4 Alkyl, OH, OCH3, -CO2H, -CO2C 1~4 Alkyl, C 3~6 substituted with one or more substituents selected from heterocycle, aryl, and heteroaryl; C 3~6 The heterocycle is optionally substituted with one or more substituents selected from oxo, OH, and COH; However, R 8 and R 9 are not both H; or R 8 and R 9 Combine them together and make C 1~6 C optionally substituted with one or more substituents selected from alkyl, oxo, OH and COH 3~6 Forming a heterocyclic ring; R 10 H, CN, halogens, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y , SO2-C 1~6 selected from alkyl, aryl, and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; X is N or CR 12 and; R 12 are H, F, Cl, CN, C(=O)NR x R y aryl and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-COH, C 1~6 Alkyl-CO2-C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH2, C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl)2, C(=O)NR x R y and SO2-C 1~6 substituted with one or more substituents selected from alkyl; and R x and R y are independently H and C 1~6 alkyl); and (B) at least one pharmaceutically acceptable carrier A pharmaceutical composition comprising:

[0105] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound provided herein and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Many methods of administering a compound exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0106] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound provided herein within or to a patient's body so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound provided herein, and not harmful to the patient. Some examples of materials which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0107] As used herein, "pharmaceutically acceptable carriers" also include any coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds provided herein and are physiologically acceptable to patients. Supplementary active compounds may also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may also include pharmaceutically acceptable salts of the compounds provided herein. Other additional ingredients that may be included in the pharmaceutical compositions provided herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0108] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically acceptable, and otherwise biologically suitable substance for administration to a subject, e.g., an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug, and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0109] Pharmaceutical composition delivery forms containing one or more dosage units of an active agent can be prepared using suitable pharmaceutical excipients and compounding techniques known or available to those skilled in the art. The compositions can be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0110] The formulations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid formulations or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration or oral administration.

[0111] For oral administration, the compounds of the present disclosure may be provided in tablet or capsule form, or as a liquid, emulsion, or suspension. To prepare an oral composition, the compounds may be formulated to produce a dose of, for example, about 0.05 to about 100 mg / kg per day, about 0.05 to about 35 mg / kg per day, or about 0.1 to about 10 mg / kg per day. For example, a total daily dose of about 5 mg to 5 g per day may be achieved by administering the compound once, twice, three times, or four times daily.

[0112] Oral tablets may contain a compound according to the present disclosure mixed with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Typical liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable tablet disintegrating agents. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0113] Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, the compound of the present disclosure can be mixed with solid, semi-solid or liquid diluents.Soft gelatin capsules can be prepared by mixing the compound of the present disclosure with water, oil such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol.

[0114] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be freeze-dried or provided as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring agents or coloring agents.

[0115] The active agents of the present disclosure can also be administered parenterally. For example, compositions can be formulated for rectal administration as suppositories. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the present disclosure can be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in single-dose forms, such as ampoules or disposable injection devices, in multi-dose forms, such as vials from which the appropriate dose can be withdrawn, or in solid forms or preconcentrates that can be used to prepare injectable formulations. Specific infusion doses can range from about 1 to 1000 μg / kg / min of the compound, mixed with a pharmaceutical carrier, over a period ranging from a few minutes to several days.

[0116] For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug in the vehicle. Another mode of administration of the compounds of the present disclosure may utilize a patch formulation to affect transdermal delivery.

[0117] Alternatively, the compounds of the present disclosure may be administered in the methods of the present disclosure by inhalation, via the nasal or oral routes, for example, in a spray formulation also containing a suitable carrier.

[0118] Combination medicines and kits In another aspect, provided herein is a pharmaceutical combination comprising a first compound and a second compound as a combined preparation for simultaneous, separate, or sequential use in the prevention or treatment of an infection or cancer in a subject in need thereof, wherein the first compound is different from the second compound. In one embodiment, the first compound is a compound of Formula (I) (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof). In another embodiment, the first compound is a pharmaceutical composition comprising (A) a compound of Formula (I) (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof), and (B) at least one pharmaceutically acceptable carrier. In yet another embodiment, the second compound is an ingredient active against said infection or cancer.

[0119] In one embodiment, the pharmaceutical combination is for use in the prevention or treatment of an infection. In another embodiment, the infection is a bacterial, viral, or fungal infection. In yet another embodiment, the infection is a viral infection. In yet another embodiment, the infection is a chronic or asymptomatic viral infection. In another embodiment, the infection is a chronic viral infection.

[0120] By way of non-limiting example, infections caused by the following viruses may be treated or prevented by the pharmaceutical combination of the present disclosure: hepatitis viruses (more specifically, hepatitis A, hepatitis B (HBV), hepatitis C, and hepatitis D), human immunodeficiency virus (HIV), herpes viruses, papilloma viruses, and influenza. Preferably, the viral infection to be treated or prevented is HBV, HIV, or HBV and HIV.

[0121] HBV infections that may be treated according to the methods of the present disclosure include infections with HBV genotypes A, B, C, and / or D. However, in one embodiment, the disclosed methods may treat any genotype of HBV ("pan-genotypic treatment"). HBV genotyping may be performed using methods known in the art, for example, INNO-LIPA® HBV Genotyping, Innogenetics NV, Ghent, Belgium.

[0122] In certain embodiments, the second compound is an HBV inhibitor or an HIV inhibitor. In another embodiment, the second compound is an HBV inhibitor. In an exemplary embodiment, the second compound is an active ingredient known or found to be effective in treating a condition or disorder involving HBV infection, such as another PD-L1 inhibitor or a compound active against a specific condition or disorder involving HBV infection, or another target associated with HBV infection itself. Combinations may serve to increase efficacy (e.g., by including in the combination a compound that enhances the potency or efficacy of an active agent according to the present disclosure), reduce one or more side effects, or reduce the required dosage of an active agent according to the present disclosure. In further embodiments, the methods provided herein allow for the administration of at least one additional therapeutic agent at a lower dose or frequency than would be required to achieve similar results in prophylactically treating HBV infection in an individual in need thereof, compared to administering the at least one additional therapeutic agent alone.

[0123] Such compounds include HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV These include, but are not limited to, E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and any other agent or combination thereof that affects the HBV life cycle and / or affects the outcome of HBV infection.

[0124] In some embodiments, the pharmaceutical combination is for use in the prevention or treatment of cancer. By way of non-limiting example, cancers that may be prevented or treated by the disclosed methods include melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and hematological tumors.

[0125] In certain embodiments, the second compound is an anti-cancer agent selected from the group consisting of a chemotherapeutic agent, a cytotoxic agent, a radiotherapeutic agent, an anti-neoplastic agent, and an anti-proliferative agent.

[0126] With respect to any combination therapy described herein, synergy can be achieved, for example, with Sigmoid-E max The drug-drug combination effect can be calculated using a suitable method, such as the concentration-effect curve (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6:429-453), the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each of the above-mentioned equations can be applied to experimental data to generate a corresponding graph to help evaluate the effect of drug combinations. The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

[0127] Uses of the Compounds of the Disclosure The present disclosure also provides therapeutic and prophylactic methods comprising administering to a subject having a PD-L1-associated disease (e.g., an infectious disease or cancer) a compound of Formula (I) (including a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising (A) a compound of Formula (I) (including a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof), and (B) at least one pharmaceutically acceptable carrier.

[0128] In certain aspects, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use as a pharmaceutical.

[0129] In another aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in preventing or treating an infectious disease in a subject in need thereof. The infectious diseases that can be prevented and / or treated by the compounds and pharmaceutical compositions of the present disclosure are caused by infectious pathogens, including, but not limited to, bacteria, fungi, or viruses. Thus, in an embodiment of this aspect of the present disclosure, the compound or pharmaceutical composition is useful in preventing or treating a bacterial, viral, or fungal infectious disease. Preferably, the compound or pharmaceutical composition is useful in treating a viral infectious disease.

[0130] By way of non-limiting example, viral diseases or infections that may be treated by the compounds and pharmaceutical compositions of the present disclosure include hepatitis viruses (e.g., hepatitis A, hepatitis B (HBV), hepatitis C, hepatitis D), influenza, chickenpox, adenovirus, herpes viruses (e.g., herpes simplex type I (HSV-1), herpes simplex type II (HSV-II)), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, hantavirus, coxsackievirus, mumps virus, measles virus, rubella virus, poliovirus, smallpox, Epstein-Barr virus, human immunodeficiency virus (HIV), and the etiological agents of viral diseases such as viral meningitis, encephalitis, dengue fever, or smallpox.

[0131] Exemplary viral diseases or infections that may be treated by the compounds and pharmaceutical compositions of the present disclosure include hepatitis viruses (e.g., hepatitis A, hepatitis B (HBV), hepatitis C, hepatitis D), influenza, herpes viruses (e.g., herpes simplex type I (HSV-1), herpes simplex type II (HSV-II)), papillomavirus, or human immunodeficiency virus (HIV). In preferred embodiments, the viral disease or infection to be treated is HBV or HIV.

[0132] In another aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in preventing or treating HIV infection, HBV infection, HIV-induced disease, or HBV-induced disease in a subject in need thereof. In a preferred embodiment, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in preventing or treating HBV infection or HBV-induced disease in a subject in need thereof.

[0133] The present disclosure also provides methods for treating, preventing, and reducing the severity of chronic viral infections in a subject. In one aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in preventing or treating chronic viral infections. Non-limiting exemplary chronic viral infections include HIV and chronic hepatitis B. In a preferred embodiment, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in preventing or treating chronic hepatitis B in a subject in need thereof.

[0134] In certain embodiments, the present disclosure relates to a method of treating a chronic viral infection, more specifically an HBV and / or HIV infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0135] In another embodiment, the present disclosure relates to a method of reducing viral load associated with a chronic viral infection, more specifically HBV and / or HIV infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0136] In yet another embodiment, the present disclosure relates to a method for reducing recurrence of a chronic viral infection, more specifically HBV and / or HIV infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0137] In yet another embodiment, the present disclosure relates to a method for reducing the adverse physiological effects of a chronic viral infection, more specifically HBV and / or HIV infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0138] In certain embodiments, the present disclosure relates to a method for inducing remission of liver damage resulting from HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0139] In certain embodiments, the present disclosure relates to a method of treating an asymptomatic viral infection, more specifically an asymptomatic HBV and / or HIV infection, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0140] In embodiments of the above uses and methods, treating or preventing a viral infection further comprises administering to the subject at least one additional therapeutic agent. Exemplary additional therapeutic agents include HBV polymerase inhibitors, nucleic acid analogs, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly modulators, reverse transcriptase inhibitors, TLR agonists, small interfering RNAs, antisense oligonucleotides, nucleic acid polymers, and combinations thereof.

[0141] In embodiments of the above uses and methods, the subject has HIV infection or chronic HBV infection. In some embodiments, the subject is a chronically HBV infected subject with or without evidence of underlying liver inflammation.

[0142] The efficacy of treating an infectious disease may be demonstrated by a reduction in the presence of the infectious pathogen, for example, as demonstrated by an inability to culture the pathogen from the subject sample. The efficacy of treating an infectious disease may be demonstrated by a reduction in the presence of the infectious pathogen, for example, as demonstrated by a reduction in proteins, nucleic acids, or carbohydrates present in the infectious pathogen. The efficacy of treatment may be demonstrated by the presence of an immune response, for example, as demonstrated by the presence of antibodies or immune cells targeted against the infectious pathogen. The efficacy of treating an infectious disease may be demonstrated by a reduction in the presence of the infectious pathogen, for example, as demonstrated by a reduction in one or more signs or symptoms of infection, such as fever, pain, nausea, vomiting, abnormal blood chemistry, or weight loss. The specific signs or symptoms will depend on the specific pathogen. The efficacy of treating an infectious disease may be demonstrated by the development of antibodies or immune cells targeting the pathogen.

[0143] In another aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in treating cancer in a subject in need thereof. In particular, the compound or pharmaceutical composition may be useful in inhibiting the growth, proliferation, or metastasis of cancer cells in a subject. Cancer refers to any of a variety of malignant tumors characterized by the proliferation of undifferentiated cells that tend to infiltrate surrounding tissues and metastasize to new sites in the body, and also refers to pathological conditions characterized by the growth of such malignant tumors. By way of non-limiting example, the cancer may be prostate cancer, lung cancer, breast cancer, colorectal cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, bone cancer, esophageal cancer, liver cancer, stomach cancer, brain tumor, skin melanoma, and / or leukemia.

[0144] In some embodiments, the cancer may be a solid tumor. In another embodiment, the cancer may be a hematological cancer. In yet another embodiment, the cancer is a solid tumor selected from the group consisting of squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial carcinoma, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor (MPNST).

[0145] In one embodiment, the cancer is a solid tumor selected from non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma, colorectal cancer, or prostate cancer. In another embodiment, the cancer can be non-small cell lung cancer (NSCLC). In yet another embodiment, the cancer can be hepatocellular carcinoma. In yet another embodiment, the cancer can be melanoma. In one embodiment, the cancer can be ovarian cancer. In another embodiment, the cancer can be breast cancer. In yet another embodiment, the cancer can be pancreatic cancer. In yet another embodiment, the cancer can be renal cell carcinoma. In one embodiment, the cancer can be colorectal cancer. In another embodiment, the cancer can be prostate cancer.

[0146] In certain embodiments, the cancer is selected from melanoma; metastatic non-small cell lung cancer; squamous non-small cell lung cancer; non-squamous non-small cell lung cancer; squamous cell carcinoma of the head and neck; renal cell carcinoma; Hodgkin's lymphoma; cutaneous squamous cell carcinoma; hepatocellular carcinoma; pancreatic cancer; urothelial carcinoma; metastatic Merkel cell carcinoma; colorectal cancer; castration-resistant prostate cancer; ovarian cancer; gastric cancer; carcinoma of the esophagus, gastrointestinal tract, and breast; and hematological tumors.

[0147] In embodiments of the above uses and methods, treating or preventing cancer further comprises administering to the subject at least one additional therapeutic agent. Exemplary additional therapeutic agents include chemotherapeutic agents, cytotoxic agents, radiotherapeutic agents, antineoplastic agents, antiproliferative agents, and combinations thereof.

[0148] Efficacy in treating cancer may be demonstrated by a stabilization or reduction in tumor burden of the primary tumor, a metastatic tumor, or a stabilization or reduction in tumor burden as demonstrated by a delay or prevention of tumor metastasis.

[0149] In another aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use in a method for enhancing, stimulating, modulating, or increasing an immune response in a subject in need thereof. Under certain circumstances, it may be desirable to induce or enhance an immune response in a patient to treat immune disorders or cancer. Immune disorders that can be treated or prevented by the disclosed methods include, but are not limited to, bacterial infections, fungal infections, viral infections, and cancer. In certain embodiments, the enhancement, stimulation, modulation, or increase in the immune response can be the result of T cell activation by a compound or pharmaceutical composition of the present disclosure. In another embodiment, the compound or pharmaceutical composition can be used to inhibit or reduce downregulatory activity associated with PD-L1 (i.e., downregulation of T cell proliferation and activation).

[0150] In another aspect, the present disclosure relates to a compound or pharmaceutical composition of the present disclosure for use as an immune checkpoint inhibitor. In particular, the compound or pharmaceutical composition is useful as a PD-L1 checkpoint inhibitor. The effectiveness of the compound of the present disclosure as a PD-L1 inhibitor can be demonstrated, for example, by the biological assays disclosed herein.

[0151] Preparation method Certain aspects of the present disclosure relate to processes for the preparation of compounds of Formula (I), as described herein.

[0152] In certain embodiments, the process comprises reacting a compound of formula (II) [ka] of Amines of formula (III) [ka] and The method comprises at least a step of reacting in the presence of sodium cyanoborohydride, wherein R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined herein. [Example]

[0153] The following examples are for illustrative purposes only and are not intended to limit the disclosure to the materials, conditions, or process parameters described therein.

[0154] Example 1: Preparation of compounds of the present disclosure Scheme 1. Synthesis of Compound 7 [ka]

[0155] Synthesis of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(hydroxymethyl)pyridin-2(1H)-one [ka] To a solution of 3-(hydroxymethyl)pyridin-2(1H)-one (5 g, 39.960 mmol) in 1,4-dioxane (50 mL) was added 6-iodo-2,3-dihydrobenzo[b][1,4]dioxine (12.566 g, 47.952 mmol), CuI (765 mg, 3.996 mmol), KPO (16.964 g, 79.920 mmol), and N,N'-dimethylethylenediamine (929 mg, 7.992 mmol) under a N atmosphere. The resulting mixture was maintained under nitrogen and stirred at 110 °C overnight. After cooling to room temperature, the reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-15% CHOH / CHCl) to give the title compound as a white solid (4.4 g, 42%). LC / MS: 14 H 13 Calculated mass of NO4: 259.08, measured: 260.15 [M+H]+.

[0156] Synthesis of 3-(chloromethyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2(1H)-one [ka] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(hydroxymethyl)pyridin-2(1H)-one (2 g, 7.714 mmol) in CHCl (20 mL) was added SOCl (1.836 g, 15.429 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel chromatography (0-15% CHOH / CHCl) to give the title compound (2 g, 93%) as a white solid. LC / MS: C 14 H 12 Calculated mass of NO3: 277.05, measured: 278.00 [M+H]+.

[0157] Synthesis of 2,4-dihydroxy-5-methylbenzaldehyde [ka] To a solution of 4-methylbenzene-1,3-diol (5.0 g, 40.278 mmol) and DMF (4.6 mL, 2.0 equiv.) in CH3CN (70 mL) was added phosphoryl trichloride (6.3 mL, 1.2 equiv.) at 0 °C. The reaction was stirred at room temperature for 3 h, and the solid was isolated by filtration. The yellow solid was washed with chilled CH3CN (10 mL), and HO (30 mL) was added. The resulting mixture was stirred at 50 °C for 30 min, cooled to room temperature, and filtered to give 2,4-dihydroxy-5-methylbenzaldehyde as a white solid (4 g, 64%). LC / MS: mass calculated for C8H8O3: 152.05, found: 153.10 [M+H]+.

[0158] Synthesis of 4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxy-5-methylbenzaldehyde [ka] To a solution of 3-(chloromethyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2(1H)-one (4 g, 14.404 mmol) in DMF (40 mL) was added 2,4-dihydroxy-5-methylbenzaldehyde (2.411 g, 15.844 mmol), NaHCO (1.815 g, 21.606 mmol), and NaI (1.08 g, 7.202 mmol). The mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, the solids were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The crude material was purified by silica gel chromatography (0-15% CHOH / CHCl) to give the title compound as a white solid (3.5 g, 62%). LC / MS: 22 H19 Calculated mass of NO6: 393.12, measured: 394.10 [M+H]+.

[0159] Synthesis of 3-((5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formyl-4-methylphenoxy)methyl)benzonitrile [ka] To a solution of 4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxy-5-methylbenzaldehyde (3.5 g, 8.897 mmol) in DMF (35 mL) was added 3-(bromomethyl)benzonitrile (2.093 g, 10.68 mmol) and CsCO (4.348 g, 13.346 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was then quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–15% CHOH / CHCl) to afford the title compound (3.0 g, 66%) as a white solid. LC / MS:C 30 H 24 Calculated mass of N2O6: 508.16, Found: 509.10 [M+H]+.

[0160] Synthesis of (2-((3-cyanobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzyl)-D-serine [ka] To a mixture of 3-((5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formyl-4-methylphenoxy)methyl)benzonitrile (508 mg, 1 mmol), D-serine (105 mg, 0.999 mmol), and sodium cyanoborohydride (63 mg, 1.003 mmol), acetic acid (5 mL) and DMF (15 mL), respectively, were added. The mixture was then kept under nitrogen and stirred at 80° C. for 3 hours. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give 400 mg of crude product, which was purified by preparative HPLC using the following conditions: XBridge Prep OBD C18, 30 x 150 mm, 5 μm, Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 40% B to 75% B in 9 min; 220 nm; Rt: 8.99 min. After lyophilization, the title compound was obtained as a white solid (340 mg, 56%). LC / MS: Mass calculated 597.21, Found C 33 H 31 N3O8:598.20[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.99(d,J=1.8Hz,1H),7.89(dt,J=8.0,1.4Hz,1H),7.81(dt,J=7.8,1.4Hz,1H),7. 65-7.55(m,3H),7.19(s,1H),7.01-6.94(m,2H),6.91-6.84(m,2H),6.35(t,J=6.8 Hz,1H),5.29-5.17(m,2H),4.98(s,2H),4.30(s,4H),3.95-4.08(m,2H),3.75(dd, J=11.3,4.5Hz,1H),3.64(dd,J=11.3,6.8Hz,1H),3.19-3.13(m,1H),2.15(s,3H).

[0161] Synthesis of (2R,4R)-1-(2-((3-cyanobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzyl)-4-hydroxypyrrolidine-2-carboxylic acid [ka] The title compound was prepared according to the procedure for preparing 7. The crude material was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) followed by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 m; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 75% B in 9 min; 220 nm; Rt: 8.99 min. After lyophilization, the title compound was obtained as a white solid (232.3 mg, 37%). LC / MS: Calculated mass 623.23, Found C 35 H 33 N3O8:624.3[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.95(d,J=2.0Hz,1H),7.91-7.84(m,1H),7.81(dt,J=7.8,1.4Hz,1H),7.66-7.55(m,3H),7.16(s,1H),6 .98(dd,J=5.5,3.0Hz,2H),6.91-6.84(m,2H),6.35(t,J=6.8Hz,1H),5.30-5.18(m,2H),4.97(s,2H),4.3 0(s,4H),4.20(s,1H),4.06(d,J=13.0Hz,1H),3.91(d,J=12.9Hz,1H),3.48(dd,J=10.0,4.5Hz,1H),2.99 (d,J=10.9Hz,1H),2.84(dd,J=10.9,4.6Hz,1H),2.34-2.26(m,1H),2.14(s,3H),1.90(d,J=13.2Hz,1H).

[0162] Synthesis of (R)-2-((2-((3-cyanobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzyl)amino)-3-hydroxy-2-methylpropanoic acid [ka] The title compound was prepared according to the procedure for preparing compound 7 and purified by reverse phase C18 column (0-60% HO (0.5% TFA) / ACN) to give the title compound as a white solid (140 mg, 29%). LC / MS: C 34 H 33 Calculated mass of N3O8: 611.23, found: 612.3 [M+H]+. 1 H NMR(300MHz,DMSO-d6)δ 7.96(s,1H),7.89(d,J=8.2Hz,1H),7.79(d,J=7.7Hz,1H),7.65-7.52(m,3H),7.24(s,1H),7.01-6.92(m,2H),6.91-6.78(m,2H),6.34(t ,J=6.8Hz,1H),5.22(s,2H),4.98(s,2H),4.29(s,4H),4.01(s,2H),3.67(d,J=11.4Hz,2H),3.63-3.48(m,2H),2.15(s,3H),1.28(s,3H).

[0163] Synthesis of (2-((3-cyanobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzyl)-L-serine [ka] The title compound was prepared according to the procedure for preparing compound 7 and purified on a reverse-phase C18 column (0-60% HO (0.5% TFA) / ACN) to give the title compound as a white solid (140 mg, 29%). LC / MS: Calculated mass 597.21, found C 33H 31 N3O8:598.2[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.99(d,J=1.8Hz,1H),7.89(dt,J=8.0,1.4Hz,1H),7.81(dt,J=7.8,1.4Hz,1H),7. 65-7.55(m,3H),7.19(s,1H),7.01-6.94(m,2H),6.91-6.84(m,2H),6.35(t,J=6.8 Hz,1H),5.29-5.17(m,2H),4.98(s,2H),4.30(s,4H),3.95-4.08(m,2H),3.75(dd, J=11.3,4.5Hz,1H),3.64(dd,J=11.3,6.8Hz,1H),3.19-3.13(m,1H),2.15(s,3H).

[0164] Synthesis of 2-((3-chlorobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzaldehyde [ka] Compound 100 was made using a procedure similar to that for preparing compound 5.

[0165] Synthesis of (2-((3-chlorobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methylbenzyl)-D-serine [ka] To a mixture of 3-((5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formyl-4-methylphenoxy)methyl)benzonitrile (480 mg, 0.927 mmol) and D-serine (389.5 mg, 3.707 mmol) in DMF (5 mL) was added acetic acid (5.5 mg, 0.093 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, NaCNBH (204 mg, 3.244 mmol) was added, and the mixture was heated at 80° C. for 3 hours. Then, the mixture was cooled to room temperature. The mixture was added dropwise to water at 0° C. and the resulting crude was purified by reverse phase C18 column (0-60% HO (0.5% TFA) / ACN) to give the title compound as a white solid (46.7 mg, 8%). LC / MS: C 32 H 31 Calculated mass for ClN2O8: 607.18, found: 607.2 [M+H]+. 1 H NMR(300MHz,DMSO-d6)δ 7.64-7.55(m,3H),7.52-7.43(m,1H),7.43-7.30(m,2H),7.24(s,1H),7.02-6.92(m,2H),6.91-6.81(m,2H),6.34 (t,J=6.8Hz,1H),5.24-5.09(m,2H),4.98(s,2H),4.29(s,4H),3.95-4.10(m,2H),3.83-3.60(m,3H),2.13(s,3H).

[0166] Synthesis of 4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methyl-2-(pyridin-3-ylmethoxy)benzaldehyde [ka] To a solution of 4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxy-5-methylbenzaldehyde (500 mg, 1.271 mmol, 1.0 equiv) in DMF (5 mL) was added 3-(bromomethyl)pyridine (262 mg, 1.525 mmol), CsCO (621 mg, 1.907 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was added dropwise to 40 mL of ice water, and the suspension was filtered and washed with DMF to give the title compound (500 mg, 81%) as a white solid. LC / MS: C 28 H 24 Calculated mass of N2O6: 484.5, measured: 485.3 [M+H]+.

[0167] Synthesis of (4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methyl-2-(pyridin-3-ylmethoxy)benzyl)-D-serine [ka] To a mixture of 4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-5-methyl-2-(pyridin-3-ylmethoxy)benzaldehyde (500 mg, 1.032 mmol, 1 equiv.) and D-serine (433.8 mg, 4.128 mmol, 4 equiv.) in DMF (5 mL) was added acetic acid (6 mg, 0.103 mmol), and the mixture was stirred at room temperature for 30 min. NaCNBH (227 mg, 3.612 mmol) was then added, and the mixture was heated at 80 °C for 3 h. The reaction was then cooled to room temperature and subsequently added dropwise to water at 0 °C. The resulting solid was purified by reverse phase C18 column (0-60% HO (0.5% TFA) / CH3CN) to give the title compound as a white solid (159 mg, 33%). LC / MS: C 31 H 31 Calculated mass of N3O8: 573.21, Found: 574.3 [M+H]+.1 H NMR (300 MHz, DMSO-d6) δ 8.71(d,J=2.2Hz,1H),8.54(dd,J=4.8,1.6Hz,1H),8.03-7.93(m,1H),7.62(dt, J=6.7,3.0Hz,2H),7.41(dd,J=7.8,4.8Hz,1H),7.18(s,1H),7.02-6.93(m,2H), 6.93-6.84(m,2H),6.35(t,J=6.8Hz,1H),5.29-5.14(m,2H),4.99(s,2H),4.30( s,4H),4.02-3.97(m,2H),3.78-3.58(m,3H),3.16(d,J=6.0Hz,2H),2.15(s,3H).

[0168] Synthesis of 5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxybenzaldehyde [ka] To a solution of 3-(chloromethyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2(1H)-one (500 mg, 1.800 mmol, 1.0 equiv) in DMF (5 mL) was added 5-chloro-2,4-dihydroxybenzaldehyde (373 mg, 2.161 mmol, 1.2 equiv), NaCO (227 mg, 2.701 mmol), and NaI (135 mg, 0.90 mmol). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the mixture was added dropwise to 40 mL of ice water. The suspension was filtered and washed with CH3OH to give 5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxybenzaldehyde as a white solid (500 mg, 67%). LC / MS: C 21 H 16 Calculated mass of CINO6: 413.81, measured mass: 414.1 [M+H]+.

[0169] Synthesis of 3-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formylphenoxy)methyl)benzonitrile [ka] To a solution of 5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxybenzaldehyde (500 mg, 1.208 mmol) in DMF (5 mL) was added 3-(bromomethyl)benzonitrile (284 mg, 1.450 mmol), CsCO (590.5 mg, 1.812 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature overnight. The resulting mixture was added dropwise to ice water (40 mL), and the suspension was filtered and washed with CHOH to give the title compound as a white solid (400 mg, 63%). LC / MS: C 29 H 21 Calculated mass of ClN2O6: 528.94, found: 529.3 [M+H]+.

[0170] Synthesis of (5-chloro-2-((3-cyanobenzyl)oxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)benzyl)-D-serine [ka] To a mixture of 3-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formylphenoxy)methyl)benzonitrile (400 mg, 0.756 mmol) and D-serine (318 mg, 3.025 mmol) in DMF (5 mL) was added acetic acid (4.5 mg, 0.076 mmol) and the mixture was stirred at room temperature for 30 minutes. Then, NaCNBH (166 mg, 2.65 mmol) was added and the mixture was heated to 80° C. for 3 hours. The reaction was cooled to room temperature and the mixture was added dropwise to water at 0° C. The crude material was purified by reverse-phase column chromatography (C18 column, 0-60% H2O (0.5% TFA) / CH3CN) to give the title compound as a white solid (159 mg, 33%). LC / MS: C 32 H 28 Calculated mass for ClN3O8: 617.16, found: 618.2 [M+H]+. 1 H NMR(300MHz,DMSO-d6)δ 7.95(d,J=1.7Hz,1H),7.90-7.77(m,2H),7.77-7.54(m,3H),7.50(s,1H),7.05(s,1H),6.97(dd,J=5.5,3.1Hz,2H),6.87(dd,J=8.6,2 .5Hz,1H),6.36(t,J=6.8Hz,1H),5.33-5.17(m,2H),5.05(s,2H),4.28(s,4H),3.96(s,2H),3.60-3.76(m,4H),3.18(t,J=5.4Hz,1H).

[0171] Synthesis of (S)-3-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)phenoxy)methyl)benzonitrile [ka] To a mixture of 3-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formylphenoxy)methyl)benzonitrile (400 mg, 0.756 mmol, 1 equiv.) and (S)-5-aminomethyl-pyrrolidin-2-one (345 mg, 3.025 mmol, 4 equiv.) in DMF (5 ml), acetic acid (4.5 mg, 0.076 mmol) was added and the mixture was stirred at room temperature for 30 minutes. NaCNBH3 (166 mg, 2.65 mmol) was then added and the mixture was heated at 80°C for 3 hours. The reaction was then cooled to room temperature. The mixture was added dropwise to water at 0°C. The precipitate was filtered and purified by reverse-phase column chromatography (C18 column, 0-60% HO (0.5% TFA) / CH3CN). After lyophilization, the title compound was obtained as a white solid (78.2 mg, 13% yield). LC / MS: C 34 H 31 Calculated mass for ClN4O6: 627.086, found: 627.20 [M+H]+. 1H NMR(300MHz,DMSO-d6)d(ppm):8.47-8.89(m,2H),7.93(s,1H),7.74-7.91(m,2H),7.41-7.74(m,5H),7.21(s,1H),6.91-6.99(m,2H),6.31- 6.42(m,1H),5.27(s,2H),5.09(s,2H),4.29(s,4H),4.17(s,2H),3.75 -3.91(m,1H),2.83-3.09(m,2H),2.05-2.21(m,3H),1.68-1.79(m,1H)

[0172] The following compounds were synthesized using a procedure similar to that for the preparation of compound 202:

[0173] [Table 4]

[0174] The following compounds were prepared using procedures similar to those described in the preparation of compound 10.

[0175] [Table 5]

[0176] Synthesis of 5-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile [ka] To a solution of 5-(chloromethyl)nicotinonitrile (350 mg, 2.3 mmol) in DMF (4 mL) was added 5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxybenzaldehyde (790 mg, 1.9 mmol), cesium carbonate (935 mg, 2.9 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was added dropwise to 30 mL of ice water. The suspension was filtered and washed with MeOH to give the title compound as a white solid (340 mg, 34.5% yield). LC / MS: C 28 H 20 Calculated mass for ClN3O6: 529.928, found: 530.40 [M+H]+.

[0177] Synthesis of (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)benzyl)-D-serine [ka] To a mixture of 5-((4-chloro-5-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (300 mg, 0.57 mmol) and D-serine (240 mg, 2.3 mmol) in DMF (4 mL) was added acetic acid (3.4 mg, 0.057 mmol), and the mixture was stirred at room temperature for 30 minutes. Next, NaCNBH (125 mg, 2 mmol) was added, and the mixture was heated to 80 °C for 3 hours. The reaction was cooled to room temperature, and the mixture was added dropwise to water at 0 °C. The precipitate was filtered and purified by reverse-phase column chromatography (C18 column, 0–60% HO (0.5% TFA) / CH3CN) to give the title compound (54 mg, 15%) as a white solid. LC / MS:C 31 H 27 Calculated mass for ClN4O8: 618.021, found: 619.10 [M+H]+. 1 H NMR(300MHz,DMSO-d6)d(ppm):9.01-9.05(m,1H),8.96-8.99(m,1H),8.39-8.46(m,1H),7.65-7.71(m,2H),7.59(s,1H),7.12(s,1H),6.91-7. 01(m,2H),6.82-6.91(m,1H),6.38(t,J=6.9Hz,1H),5.51-6.62(m,1H), 5.30(s,2H),5.11(s,2H),4.14-4.55(m,6H),3.91(s,1H),3.85(s,2H).

[0178] Synthesis of 2-((5-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)benzaldehyde [ka] To a mixture of (5-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanol [1646287-85-5] (180 mg, 1 mmol), 5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-2-hydroxybenzaldehyde (422, 1 mmol) and triphenylphosphine (400 mg, 1.5 mmol) in DCM (4 ml) was added diisopropyl azodicarboxylate (310 mg, 1.5 mmol) at 0° C. under N. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase C18 column (0-60% HO (0.5% TFA) / ACN) to give the title compound as a white solid (150 mg, 26% yield). LC / MS: C 29 H 22 Calculated mass for ClN5O6: 571.968, found: 572.25 [M+H]+.

[0179] Synthesis of ((2-((5-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)benzyl)-D-serine [ka] To a mixture of 2-((5-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)-5-chloro-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)methoxy)benzaldehyde (150 mg, 0.26 mmol) and D-serine (110 mg, 1 mmol) in DMF (4 ml) was added acetic acid (1.6 mg, 0.026 mmol) and the mixture was stirred at room temperature for 30 minutes. NaCNBH (60 mg, 0.9 mmol) was then added and the mixture was heated at 80° C. for 3 hours. The reaction was then cooled to room temperature. The mixture was added dropwise to water at 0° C. The precipitate was filtered and subsequently purified by reverse phase column chromatography (C18 column, 0-60% HO (0.5% TFA / CH3CN)). After lyophilization, the title compound was obtained as a white solid (28.6 mg, 16% yield). LC / MS: C 32 H 29 Calculated mass for ClN6O8: 660.17, found: 661.15 [M+H]+. 1 H NMR(300MHz,DMSO-d6)d(ppm):9.41(s,1H),9.15-9.21(m,1H),8.72-8.76 (m,1H),8.60-8.66(m,1H),8.00(s,1H),7.58-7.68(m,2H),7.54(s,1H),7. 12(s,1H),6.91-7.01(m,2H),6.83-6.91(m,1H),6.34(t,J=6.8Hz,1H),5. 33(s,2H),5.08(s,2H),4.26(s,4H),3.89-4.08(m,3H),3.03-3.13(m,2H).

[0180] Example 2: PD-1 / PD-L1 Biochemical Protein-Protein Interactions Compounds were tested in a protein-protein interaction assay to determine whether they could specifically block the interaction between the extracellular domains of PD-1 and PD-L1. Binding of protein pairs is measured using a bead-based amplified luminescent proximity homogeneous assay (ALPHA) platform. Binding of each protein pair brings donor and acceptor beads into close proximity, resulting in an increase in the ALPHA signal. Assays are performed in 50 mM Tris (pH 7.4), 0.0015% Triton-X-100, and 0.1% BSA. Final protein concentrations in the assay were 5 nM (His-tagged PD-L1), 5 nM (biotinylated PD-1), 10 μg / ml ALPHA assay acceptor beads, and 10 μg / ml ALPHA assay donor beads. Binding was measured after a 2-hour assay reaction time at 25°C. Specificity of binding was determined by testing compounds in the assay with a His-tagged, biotinylated, irrelevant protein. The final protein concentration used in the assay was 5 nM, 10 μg / ml ALPHA assay acceptor beads, and 10 μg / ml ALPHA assay donor beads. Binding was measured after a 2-hour assay reaction time at 25°C. IC 50 Values ​​were calculated from fits of dose-response curves to a four-parameter equation.

[0181] Specificity of binding was determined by testing compounds in the assay with a His-tagged and biotinylated irrelevant protein (ErB3 / her3). The final protein concentration used in the assay was 5 nM, 10 μg / mL ALPHA assay acceptor beads, and 10 μg / mL ALPHA assay donor beads. Binding was measured after a 2-hour assay reaction time at 25°C. IC 50 Values ​​were calculated from fits of dose-response curves to a four-parameter equation. Compounds were determined to have an EC 50 It is specific if it shows >25 μM or a stimulation index of >3 compared to the PD-1 / PD-L1 interaction.

[0182] [Table 6]

[0183] [Table 7]

[0184] Example 3: PD-1 / PD-L1 NFAT reporter assay Compounds were tested in a functional coculture reporter assay in which TCR-mediated NFAT activity was inhibited by PD-1 binding to PD-L1. Blocking the PD-1 / PD-L1 interaction impaired PD-1-mediated dampening of TCR signaling and significantly increased NFAT-mediated transcription of luciferase. CHO cells expressing surface-bound anti-CD3 antibody and PD-L1 (artificial antigen-presenting cells, aAPC-PD-L1) were mixed with Jurkat cells overexpressing PD-1 and expressing a luciferase construct under NFAT control in RPMU assay medium containing 1% FBS and immediately plated onto plates containing compound. The cocultures were then incubated at 37°C and 5% CO2 for 20 hours. Luciferase activity was assessed by adding Bio-Glo reagent and measuring luminescence on a plate reader. Data are reported as the minimum effective concentration (LEC). LEC values ​​are calculated from fitting a dose-response curve to the mean value of the cell controls plus three times the standard deviation.

[0185] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the foregoing and accompanying figures. Such modifications are intended to be included within the scope of the appended claims.

[0186] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims. The present invention includes the following embodiments. [Claim 1] Compounds of formula (I) [ka] (including its stereoisomers or tautomeric forms, or pharmaceutically acceptable salts thereof) (In the formula, R 1 are halogens, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Heteroalkyl, NR x R y , N.R. x C(=O)R y , N.R. x CO 2 R y , N.R. x C(=O)NR x R y , OC(=O)NR x R y , O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring optionally substituted with one or more substituents selected from the group consisting of: O-(6-10 membered aryl), O-(5-10 membered heteroaryl), and a ring; R 2 、R 3 、R 4 、R 5 、R 6 、R7 and R 11 are independently H, halogen, C 1~4 C substituted with alkyl and one or more F 1~4 alkyl; R 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 heteroalkyl; C 1~6 Alkyl and C 1~6 Each heteroalkyl optionally is C 1~4 Alkyl, OH, OCH 3 , -CO 2 H, -CO 2 C 1~4 Alkyl, C 3~6 substituted with one or more substituents selected from heterocycle, aryl and heteroaryl; C 3~6 The heterocycle optionally includes oxo, OH, and CO 2 substituted with one or more substituents selected from H; However, R 8 and R 9 are not both H; or R 8 and R 9 Combine them together and make C 1~6 Alkyl, oxo, OH and CO 2 C optionally substituted with one or more substituents selected from H 3~6 Forming a heterocyclic ring; R 10 H, CN, halogens, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-CO 2 H, C 1~6 Alkyl-CO 2 -C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH 2 、C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C1~6 Alkyl-C(O)N(C 1~6 alkyl) 2 , C(=O)NR x R y , SO 2 -C 1~6 selected from alkyl, aryl, and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-CO 2 H, C 1~6 Alkyl-CO 2 -C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH 2 、C 1~6 Alkyl-CO-NHC 1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl) 2 , C(=O)NR x R y and SO 2 -C 1~6 substituted with one or more substituents selected from alkyl; X is N or CR 12 and; R 12 are H, F, Cl, CN, C(=O)NR x R y aryl and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Alkyl-CO 2 H, C 1~6 Alkyl-CO 2 -C 1~6 Alkyl, C 1~6 Alkyl-C(O)NH 2 、C 1~6 Alkyl-CO-NHC1~6 Alkyl, C 1~6 Alkyl-C(O)N(C 1~6 alkyl) 2 , C(=O)NR x R y and SO 2 -C 1~6 substituted with one or more substituents selected from alkyl; and R x and R y are independently H and C 1~6 alkyl). [Claim 2] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 11 but independently, H and C 1~4 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ... [Claim 3] R 6 But C 1~4 2. The compound of claim 1, wherein the aryl group is alkyl or Cl. [Claim 4] R 6 is Cl and R 2 、R 3 、R 4 、R 5 、R 7 and R 11 2. The compound of claim 1, wherein [Claim 5] R 1 But, equation (g-1)

change

Claims

1. Compounds of formula (I) 【Chemistry 1】 , a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof (In the formula, R １ is represented by the formula (g-1) 【Chemistry 2】 and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R １１ are independently H, halogen, C １～４ C substituted with alkyl and one or more F １～４ alkyl; R ８ is H and C １～６ alkyl, C １～６ Alkyl is —CO ２ substituted with H and optionally OH, or substituted with pyrrolidinyl, which is substituted with one or more oxo; R ９ is H and C １～６ alkyl; However, R ８ and R ９ are not both H; or R ８ and R ９ Combine them together and CO ２ forming pyrrolidinyl substituted with H and optionally OH; R １０ is H, CN, halogen, C １～６ Alkyl, OC １～６ Alkyl, C １～６ Alkyl-CO ２ H, C １～６ Alkyl-CO ２ -C １～６ Alkyl, C １～６ Alkyl-C(O)NH ２ , C １～６ Alkyl-CO-NHC １～６ Alkyl, C １～６ Alkyl-C(O)N(C １～６ alkyl) ２ , C(═O)NR ｘ R ｙ , S.O. ２ -C １～６ selected from alkyl, aryl, and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C １～６ Alkyl, OC １～６ Alkyl, C １～６ Alkyl-CO ２ H, C １～６ Alkyl-CO ２ -C １～６ Alkyl, C １～６ Alkyl-C(O)NH ２ , C １～６ Alkyl-CO-NHC １～６ Alkyl, C １～６ Alkyl-C(O)N(C １～６ alkyl) ２ , C(═O)NR ｘ R ｙ and SO ２ -C １～６ substituted with one or more substituents selected from alkyl; X is N or CR １２ and R １２ is H, F, Cl, CN, C(=O)NR ｘ R ｙ aryl and heteroaryl; Aryl and heteroaryl are optionally substituted with CN, halogen, C １～６ Alkyl, OC １～６ Alkyl, C １～６ Alkyl-CO ２ H, C １～６ Alkyl-CO ２ -C １～６ Alkyl, C １～６ Alkyl-C(O)NH ２ , C １～６ Alkyl-CO-NHC １～６ Alkyl, C １～６ Alkyl-C(O)N(C １～６ alkyl) ２ , C(═O)NR ｘ R ｙ and SO ２ -C １～６ substituted with one or more substituents selected from alkyl; and R ｘ and R ｙ are independently H and C １～６ alkyl).

2. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R １１ independently H and C １～４ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

3. R ６ But C １～４ The compound of claim 1 , wherein the aryl group is alkyl or Cl.

4. R ６ is Cl, and R ２ , R ３ , R ４ , R ５ , R ７ and R １１ The compound of claim 1 , wherein is H.

5. R ８ is H and R ９ OH and CO ２ C substituted with H １～６ The compound of any one of claims 1 to 4, which is alkyl.

6. R ８ and R ９ are combined to form OH and CO ２ The compound according to any one of claims 1 to 4, which forms a pyrrolidinyl substituted with H.

7. R １０ The compound of any one of claims 1 to 6, wherein is CN and X is N.

8. R １０ The compound of any one of claims 1 to 6, wherein is H and X is N.

9. The compound, Table 1 Table 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

10. The compound is Table 3 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 10, and further comprising at least one pharmaceutically acceptable carrier.

12. 11. A pharmaceutical combination comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an infection or cancer in a mammal in need thereof, wherein said first compound is different from said second compound, said first compound being a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and said second compound being an active ingredient against said infection or cancer.

13. the second compound is selected from the group consisting of an HBV combination drug, an HBV vaccine, an HBV DNA polymerase inhibitor, an immunomodulator, a toll-like receptor (TLR) modulator, an interferon alpha receptor ligand, a hyaluronidase inhibitor, a hepatitis B surface antigen (HBsAg) inhibitor, a cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitor, a cyclophilin inhibitor, an HBV viral entry inhibitor, an antisense oligonucleotide targeting viral mRNA, a short interfering RNA (siRNA) and a ddRNAi endonuclease modulator, a ribonucleotide reductase inhibitor, an HBV 13. The pharmaceutical combination of claim 12, wherein the HBV inhibitor is selected from the group consisting of an E antigen inhibitor, a covalently closed circular DNA (cccDNA) inhibitor, a farnesoid X receptor agonist, an HBV antibody, a CCR2 chemokine antagonist, a thymosin agonist, a cytokine, a nucleoprotein modulator, a retinoic acid-inducible gene 1 stimulator, a NOD2 stimulator, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a recombinant thymosin alpha-1, a Bruton's tyrosine kinase (BTK) inhibitor, a KDM inhibitor, an HBV replication inhibitor, an arginase inhibitor, and other HBV drugs.

14. 13. The pharmaceutical combination of claim 12, wherein the second compound is an anti-cancer agent selected from the group consisting of chemotherapeutic agents, cytotoxic agents, radiotherapeutic agents, antineoplastic agents, and anti-proliferative agents.

15. A pharmaceutical composition according to claim 11 or a pharmaceutical combination according to any one of claims 12 to 14 for use as a medicament.

16. The pharmaceutical composition of claim 11 or the pharmaceutical combination of any one of claims 12 to 14 for use in the prevention or treatment of an infectious disease in a subject in need thereof.

17. The pharmaceutical composition according to claim 11 or the pharmaceutical combination according to any one of claims 12 to 14 for use in the treatment of cancer.

18. The pharmaceutical composition according to claim 11 or the combination drug according to any one of claims 12 to 14, which is used as an immune checkpoint inhibitor.

19. Compound of formula (II) 【Transformation 3】 with an amine of formula (III) 【Chemistry 4】 in the presence of sodium cyanoborohydride, １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ A process for the preparation of compounds of formula (I) according to any one of claims 1 to 10, wherein and X are as defined in claim 1.

20. The pharmaceutical composition according to claim 11 or the pharmaceutical combination according to any one of claims 12 to 14 for use in the prevention or treatment of a bacterial, viral or fungal infectious disease.

21. The pharmaceutical composition according to claim 11 or the combination pharmaceutical according to any one of claims 12 to 14 for use in the prevention or treatment of a viral infectious disease.

22. The pharmaceutical composition of claim 11 or the pharmaceutical combination of any one of claims 12 to 14 for inhibiting the growth, proliferation or metastasis of cancer cells in a subject in need thereof.

23. The pharmaceutical composition according to claim 11 or the combination drug according to any one of claims 12 to 14, which is used as a PDL1 checkpoint inhibitor.

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