Compounds and methods for producing PD1 / PD-L1 inhibitors

Abstract

The present invention relates generally to the field of pharmaceutical compounds, in particular to compounds of formula (I) that act as inhibitors of PD1 / PD-L1 interaction.The present invention further relates to methods of preparation of compounds of formula (I).The present invention also relates to compositions of compounds of formula (I). JPEG2024516194000140.jpg36170

Description

[Technical Field]

[0001] This application claims the interests of Indian Provisional Patent Application No. 202141018688, filed on 22 April 2021, the specification of which is incorporated herein by reference in its entirety for all purposes.

[0002] Field of the present invention The present invention generally relates to the field of pharmaceutical compounds, particularly compounds of formula (I) that act as inhibitors of PD1 / PD-L1 interaction. The present invention further relates to compounds of formula (I): [ka] Regarding the method of preparation. [Background technology]

[0003] background Programmed cell death protein 1 (PD-1) is a cell surface protein that plays a crucial role in regulating the immune system in the human body. PD-1 provides a response to human cells by downregulating the immune system through suppressing the inflammatory activity of T cells and by promoting self-tolerance. Therefore, PD-1 prevents autoimmune diseases, but also prevents the immune system from killing cancer cells. PD-1 has two ligands, PD-L1 (programmed cell death ligand 1) and PD-L2 (programmed cell death ligand 2), which are members of the B7 family. Various pieces of evidence suggest that PD-1 and its ligands negatively regulate the immune response. PD-L1 has been found to be highly expressed in several cancers, and therefore, the role of PD-1 in cancer immune evasion is well established.

[0004] In cancer, PD-L1 is expressed on the surface of tumor cells in various solid malignancies, such as squamous cell carcinoma of the head and neck, melanoma, and cancers of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colon, liver, pancreas, and kidney (Topalian SL et al., Curr. Opin. Immunol., 2012, 24(2):207~212; Wang X et al., Oncotargets and Therapy, 2016, 9:5023~5039). In hepatocellular carcinoma, melanoma, and breast cancer, PD-L1 was positively correlated with poor prognosis (Muenst S. et al., Breast Cancer Res. Treat., 2014, 146(1): 15~24; Leung J. et al., Immune Network, 2014, 14(6): 265~276; Wang Q. et al., Medicine (Baltimore), 2017, 96(18): e6369). In contrast, normal human tissues express very little PD-L1 protein on the cell surface, suggesting that PD-L1 could be a selective target for antitumor therapy (Chen L. et al., J. Clin. Invest., 2015, 125(9): 3384~3391).

[0005] The PD-1 / PD-L1 molecular pathway is one of the main mechanisms of immune evasion in cancer. Activation of the PD-1 / PD-L1 pathway induces apoptosis of activated T cells, promotes T cell energy and exhaustion, enhances the function of regulatory T cells, and inhibits T cell proliferation. Therefore, disrupting this pathway restores the proliferation and cytotoxicity of CTLs, inhibits the function of regulatory T cells (Tregs), and reduces T cell apoptosis.

[0006] Interference with the PD-1 / PD-L1 pathway by therapeutic antibodies has been shown to prevent inhibitory signaling from cancer cells and induce an immune response against target / cancer cells in CTLs. Several PD-1-targeted cancer immunotherapies have been developed and approved for several malignancies. However, there is still a need for potent and selective small molecule inhibitors of the PD-1 / PD-L1 interaction pathway.

[0007] Common drug-related side effects of both anti-PD-1 and anti-PD-1 antibodies include diarrhea, pneumonia, rash, itching, kidney infection, and hormonal imbalance. Immune-related side effects, such as dermatitis, colitis, hepatitis, vitiligo, and thyroiditis, have also been reported. The long residence time of monoclonal antibodies (mAbs) can contribute to these AEs, but this can be partially avoided with small molecule inhibitors. In addition, studies using smaller, cell-membrane-permeable biologics and DNA aptamers have shown that they exhibit antibody-mimicking function and are more advantageous than antibodies in terms of chemosynthetic properties, low immunogenicity, and efficient tissue permeability (Lai WY et al., Mol. Therapy - Nucl. Acids, 2016, 5: e397). Therefore, small molecule inhibitors can offer increased oral bioavailability, increased bioefficiency, and a shortened half-life for more controllable treatment, particularly in cases of autoimmune and other adverse events. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Patent Application Publication No. 2019 / 175897 [Non-patent literature]

[0009] [Non-Patent Document 1] Topalian SL et al., Curr. Opin. Immunol., 2012, 24(2):207~212 [Non-Patent Document 2] Wang X et al., Oncotargets and Therapy, 2016, 9:5023~5039 [Non-Patent Document 3] Muenst S. et al., Breast Cancer Res. Treat., 2014, 146(1): 15-24. [Non-Patent Document 4] Leung J. et al., Immune Network, 2014, 14(6):265~276. [Non-Patent Document 5] Wang Q. et al., Medicine (Baltimore), 2017, 96(18): e6369. [Non-Patent Document 6] Chen L. et al., J. Clin. Invest., 2015, 125(9):3384~3391 [Non-Patent Document 7] Lai WY et al., Mol. Therapy - Nucl. Acids, 2016, 5: e397 [Overview of the project] [Problems that the invention aims to solve]

[0010] As discussed, PD-1 / PD-L1 inhibitors have great utility in upregulating the immune system to effectively fight cancer. Therefore, it is necessary to identify the chemical components that promote this inhibition, particularly small molecule inhibitors. Thus, the identification and development of novel PD-1 / PD-L1 inhibitor compounds that treat cancer and other diseases or conditions related to PD-1 / PD-L1 activation will open up new opportunities in the field of cancer treatment. [Means for solving the problem]

[0011] Summary of the present invention In aspects of the present invention, the compound of formula (I): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, X is selected from O or NR', Ring A is C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C2~20 heterocyclyl or -C(O)NR4-C 2~20 selected from heterocyclyl, where C 6~10 aryl, C 3~10 cycloalkyl, C 7~16 alkylaryl, C 2~10 heteroaryl, C 2~20 heterocyclyl, -CO-C 2~20 heterocyclyl or -C(O)NR4-C 2~20 heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxy, C 1~10 alkyl, C 1~10 alkoxy, C 1~10 haloalkyl, C 2~10 alkylalkoxy, -CH2-NR a C(O)R b 、-CR a R b -OR c 、-CR a R b -NR c R d or -CH2-NHC(O)NR a R b and is substituted with one or more groups selected from here, where R a 、R b 、R c and R d are independently selected from hydrogen, halogen, C 1~10 alkyl, -C(O)R", C 3~10 cycloalkyl, C 1~10 haloalkyl or C 1~10 alkoxy, R' is selected from hydrogen or C 1~10 alkyl, R1 is selected from hydrogen, cyano or C 1~10 alkyl, R2 is selected from hydrogen, C 1~10 alkyl, C 6~10 aryl, C 3~10 cycloalkyl, C 1~10 haloalkyl, C 7~16 alkylaryl, C 2~10 heteroaryl, C 3~20 alkylheteroaryl, C 2~20Heterocyclyl or C 3~20 Selected from alkyl heterocyclyl, where C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Alkyl heterocyclyls can be optionally halogenated, cyano, hydroxy, -C(O)NH2, or C 1~10 Alkyl or C 6~10 Substituted by one or more groups selected from aryl groups, R3 is halogen, C 6~10 Aryl or C 2~10 Selected from heteroaryls, where C 6~10 Aryl or C 2~10 Heteroaryls can be optionally halogenated, haloalkyl, cyano, hydroxy, amino, or C. 1~10 Alkyl, OR, C 6~10 Ariel, C 2~20 Heterocyclyl or C 2~10 Substituted with one or more groups selected from heteroaryls, Here, R'' represents hydrogen, halogen, and C. 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~10 Selected from alkyl groups, m is 1 to 5, n is 0 to 5, and l is 1 to 5. However, the compound of formula (I) is [ka] isn't it] To provide.

[0012] In another aspect of the present invention, (a) a step of reacting a compound of formula (Ia) with compound A in the presence of a reducing agent and a solvent to obtain a compound of formula (I): [ka] The present invention provides methods for preparing compounds of formula (I), including those of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts.

[0013] In yet another aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, in optionally combination with one or more other pharmaceutical compositions.

[0014] Another aspect of the present invention provides a method for treating and / or preventing a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or pharmaceutical composition disclosed herein to a subject suffering from a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer.

[0015] In another aspect of the present invention, a compound or pharmaceutical composition of formula (I) disclosed herein is provided for use in the manufacture of a pharmaceutical for inhibiting the PD-1 / PD-L1 enzyme in cells.

[0016] In yet another aspect of the present invention, a compound of formula (I) or pharmaceutical composition of the present invention is provided for use in the treatment and / or prevention of a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer, including administration to a subject suffering from a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer.

[0017] Another aspect of the present invention provides the use of a compound or pharmaceutical composition of formula (I), in conjunction with other clinically relevant cytotoxic or non-cytotoxic agents, for the treatment or prevention of disease, proliferative disorders, or cancer.

[0018] In a further aspect of the present invention, a method for treating cancer is provided, comprising the step of administering a combination of a compound or pharmaceutical composition of formula (I) disclosed herein and other clinically relevant cytotoxic or non-cytotoxic agents to a subject requiring them.

[0019] These and other features, aspects and advantages of the subject matter of the present invention will be better understood by referring to the following description. This summary is provided to introduce selected concepts in a simplified form. This summary is not intended to identify any important or essential features of the present invention, nor is it intended to be used to limit the scope of the subject matter. [Modes for carrying out the invention]

[0020] Detailed description of the present invention Those skilled in the art will recognize that the present invention is subject to variations and modifications other than those specifically described. It should be understood that the present invention includes all such variations and modifications. The present invention also includes all steps, features, compositions and compounds referenced or indicated individually or collectively in this specification, as well as any or any combination of any or any of such steps or features.

[0021] definition For convenience, before further describing the present invention, certain terms and examples used herein are summarized here. These definitions should be read in view of the remainder of the invention and should be understood by those skilled in the art. The terms used herein have meanings that are recognized and known to those skilled in the art; however, for convenience and completeness, specific terms and their meanings are stated below.

[0022] The articles "a," "an," and "the" are used to refer to one or more (i.e., at least one) grammatical objects of the article.

[0023] The term "compound" includes the compounds disclosed in this invention.

[0024] In this context, the term "or" means "and / or" unless otherwise specified.

[0025] The terms “comprise” and “comprising” are used in an inclusive, non-restrictive sense, meaning that additional elements may be included. Throughout this specification, unless otherwise required by context, the word “comprise” and its variations, such as “comprises” and “comprising,” are understood to imply that they include the elements or processes, or groups of elements or processes, described, but do not exclude any other elements or processes, or groups of elements or processes.

[0026] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are interchangeable.

[0027] In the structural formulas given herein and throughout the present invention, unless otherwise specifically stated, the following terms have the meanings indicated.

[0028] Furthermore, the compound of formula (I) may also be its derivatives, analogues, tautomers, enantiomers, diastereomers, geometric isomers, polymorphs, solvates, intermediates, metabolites, prodrugs, or pharmaceutically acceptable salts and compositions.

[0029] The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, for example, double bond isomers (i.e., geometric isomers), positional isomers, enantiomers, or diastereomers. Accordingly, the chemical structures shown herein encompass all possible enantiomers and stereoisomers of the illustrated or specified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be separated into component enantiomers or component stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in multiple tautomer forms, including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures shown herein encompass all possible tautomer forms of the illustrated or specified compounds. It is also understood that some isomeric forms, such as diastereomers, enantiomers, and geometric isomers, can be separated by physical and / or chemical methods by those skilled in the art. A pharmaceutically acceptable solvate may be a hydrate and may contain crystalline forms of other solvents, such as alcohols and ethers.

[0030] According to the present invention, the compounds provided herein include all of the corresponding enantiomers and stereoisomers, i.e., stereoisomers in pure forms in terms of geometric isomers, enantiomers, or diastereomers, and mixtures of the enantiomers and stereoisomers of the said compounds. Furthermore, mixtures of enantiomers and stereoisomers can be separated into pure components by methods known to those skilled in the art, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization, and the use of chiral derivatizing agents. Pure enantiomers and stereoisomers can also be obtained from intermediates or metabolites, as well as reagents in the form of pure enantiomers and stereoisomers, by known asymmetric synthesis methods.

[0031] The term "pharmaceutically acceptable" refers to a compound or composition that is physiologically tolerable and, typically, does not cause an allergic reaction or similar adverse reaction, including but not limited to stomach upset or dizziness, when administered to a subject.

[0032] Examples of pharmaceutically acceptable salts forming part of the present invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn, ammonium, substituted ammonium salts, and aluminum salts; and salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, and hydroxyethylpiperidine. Other examples of salts include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, and guanidine. Examples of salts include acid addition salts, such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, fumarates, formates, citrates, succinates, lactates, mesylates, trifluoroacetates, acetates, besylates, propionates, mandelates, hydrobroms, hydrochlorides, palmoate, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbic acid, glycerophosphates, and ketoglutarates.

[0033] The term "intermediate" refers to a compound that has the same core structure as the compound of formula (I) but differs in certain possible positions (e.g., alkyl chain).

[0034] As used herein, the term “substituted” is intended to include all acceptable substituents of the organic compound. In a broad range of embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. Examples of substituents include, for example, those listed above. The acceptable substituents may be one or more for a given organic compound, and may be the same or different. For the purposes of this invention, a heteroatom, for example, nitrogen, may have a hydrogen substituent and / or any acceptable substituent of the organic compound described herein that satisfies the valence of the heteroatom. It is understood that substituents may be further substituted.

[0035] The term "alkyl" refers to a linear or branched aliphatic hydrocarbon group having a specific number of carbon atoms, attached to the rest of the molecule by a single atom, and optionally substituted by one or more substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, and octyl.

[0036] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system of approximately 3 to 10 carbon atoms, which may optionally be substituted with one or more substituents. A polycyclic ring is a hydrocarbon system containing two or more ring systems with one or more ring carbon atoms in common, i.e., exhibiting a spiro, condensed, or crosslinked structure. Preferred cycloalkyl groups, but are not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, crosslinked cyclic groups, or spiro-dicyclic groups, such as spiro[4.4]nonal-2-yl.

[0037] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen bond, which may optionally be substituted with one or more substituents. An alkoxy group refers to a compound having 1 to 10 carbon atoms, and preferred alkoxy groups include, but are not limited to, -OCH3 and -OC2H5.

[0038] The term "halo" or "halogen" means, alone or in combination with other terms, fluorine, chlorine, bromine, or iodine.

[0039] The term "amino" refers to the -NH2 group.

[0040] The term "hydroxyl" refers to the -OH group.

[0041] The term "oxo" refers to the =O group.

[0042] The term "cyano" refers to the -CN group.

[0043] As used herein, the term "heteroatom" refers to a sulfur, nitrogen, or oxygen atom.

[0044] The term "haloalkyl" refers to an alkyl group having one or more halogen atoms. In the present invention, the term haloalkyl refers to a compound having 1 to 10 carbon atoms, and examples of haloalkyls, though not limited to them, include -CH2F, -CHF2, -CF3, and -C2H4F.

[0045] The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, which may optionally be substituted with one or more substituents. Preferred aryl groups include, but are not limited to, phenyl.

[0046] The term "heteroaryl" refers to the aromatic heterocyclic ring group defined above. Heteroaryl ring groups can be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable structure. A heteroaryl is an aromatic ring having one or more heteroatoms selected from N, O, or S, and having between 2 and 10 carbon atoms.

[0047] The term "heterocyclyl" refers to a heterocyclic ring group, which may optionally be substituted with one or more substituents. The heterocyclyl ring group can be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable structure.

[0048] Furthermore, the term "heterocyclyl" refers to a stable 2- to 20-membered ring group consisting of a carbon atom and a heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For the purposes of this invention, the heterocyclic ring group may be monocyclic, bicyclic, or tricyclic, and the nitrogen, phosphorus, carbon, or sulfur atoms within the heterocyclic ring group may optionally be oxidized to various oxidation states. In addition, the nitrogen atom may optionally be quaternized, and the ring group may be partially or completely saturated. Preferred heterocyclyl groups include, but are not limited to, azetidinil, acridinil, benzodioxolyl, benzodioxanil, benzofuranil, carbazolyl, sinnolinil, dioxolanil, indolidinil, naphthilidinil, perhydroazepinil, phenadinil, phenothiazinil, phenoxadinil, phthalazinil, pyridyl, pteridinil, purinil, quinazolinil, quinoxalinil, quinolinil, isoquinolinil, tetrazolyl, imidazolyl, tetrahydroisoquinolinil, piperidinil, piperazinil, homopiperazinil, 2-oxoazepinil, azepinil, pyrrolyl, 4-piperidonil, pyrrolidinil, pyrazinil, pyrimidinil, pyridadi Examples include nyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranil, benzothiazolyl, benzoxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranil, chromanil, and isochromanil.

[0049] The term "heterocyclyl" refers to a monocyclic or polycyclic ring, and a polycyclic ring system refers to a ring system containing two or more rings, preferably a bicyclic or tricyclic ring, where the rings may be fused, bridged, or spirocyclic, or any combination thereof. As used herein, a fused ring means that two rings are bonded to each other through two adjacent ring atoms common to both rings. A fused ring may contain 1 to 4 heteroatoms independently selected from N, O, or S. The rings can be fused by either nitrogen or a -CH- group.

[0050] The term "alkylaryl" refers to an aryl group directly bonded to an alkyl group, which may optionally be substituted with one or more substituents. For the purposes of the present invention, the arylalkyl group of the present invention refers to a compound having between 7 and 16 carbon atoms, which includes alkyl groups having 1 to 6 carbon atoms and aryl rings having 6 to 10 carbon atoms. Preferred alkylaryl groups, though not limited to these, include -CH2-phenyl, -C2H4-phenyl, and C3H6-phenyl.

[0051] The term "arylalkyl" refers to an aryl group directly bonded to an alkyl group, which may optionally be substituted with one or more substituents. For the purposes of the present invention, the arylalkyl group of the present invention refers to a compound having between 7 and 16 carbon atoms, which includes an aryl ring having 6 to 10 carbon atoms and an alkyl group having 1 to 6 carbon atoms. Preferred arylalkyl groups include, but are not limited to, -C6H5-CH2- and -C6H5-C2H4-.

[0052] The term "alkylalkoxy" refers to an alkyl group attached to an alkoxy group. For the purposes of this invention, the term alkylalkoxy group refers to a compound having between 2 and 10 carbon atoms, which includes alkyl groups having 1 to 9 carbon atoms and alkoxy groups having 1 to 9 carbon atoms, but the total number of carbon atoms is between 2 and 10.

[0053] The term "alkylheteroaryl" refers to an alkyl group attached to a heteroaryl group, which may be optionally substituted. For the purposes of the present invention, alkylheteroaryl refers to a compound having between 3 and 20 carbon atoms, which includes an alkyl group having 1 to 10 carbon atoms and a heteroaryl ring having 2 to 10 carbon atoms and one or more heteroatoms selected from N, O, or S.

[0054] The term "alkyl heterocyclyl" refers to an alkyl group attached to a heterocyclyl group, which may be optionally substituted. For the purposes of this invention, the term "alkyl heterocyclyl" refers to a compound having between 2 and 20 carbon atoms, which includes an alkyl group having 1 to 10 carbon atoms and a heterocyclyl ring having 1 to 10 carbon atoms and one or more heteroatoms selected from N, O, or S. The heterocyclyl ring may be a bridged, condensed, or spiral ring as defined herein.

[0055] Certain compounds disclosed herein may exist as N-oxides. For example, pyrazoles are known to form N-oxides upon treatment with a suitable oxidizing agent. Similarly, pyridine ring nitrogen is known to be oxidized upon treatment with a suitable oxidizing agent to form N-oxides.

[0056] It is understood that the family of compounds of formula (I) includes isomeric forms, such as diastereomers, enantiomers, tautomers, and geometric isomers in the "E" or "Z" configuration, or mixtures of "E" and "Z" isomers. It is also understood that some isomeric forms, such as diastereomers, enantiomers, and geometric isomers, can be separated by physical and / or chemical methods by those skilled in the art.

[0057] The compounds disclosed herein can exist as a single stereoisomer, and / or as a mixture of enantiomers and / or diastereomers. All such single stereoisomers, and mixtures thereof, are intended to be within the scope of the subject matter described.

[0058] The compounds disclosed herein may incorporate isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine, and sulfur, such as, but not limited to, 2 H(D), 3 H(T), 11 C, 13 C, 14 C, 15 N, 18 F, 35 S, 36 Cl and 125 I. Compounds of the invention in which an atom is isotopically labeled, such as a radioactive isotope, such as, 3 H, 13 C and 14 C etc. can be used in metabolic studies and kinetic studies. Compounds of the invention in which hydrogen is replaced by deuterium can improve the metabolic stability of the drug and pharmacokinetic properties, such as the in vivo half-life.

[0059] Prodrugs of the compounds of formula (I) are described herein which, upon administration, undergo chemical conversion by metabolic processes to yield an active pharmacological substance. Generally, such prodrugs are functional derivatives of the compounds of the invention that are readily convertible in vivo to the compounds of the invention.

[0060] The compounds described herein can also be prepared in any solid or liquid physical form, for example, the compounds can be in crystalline form, amorphous form, and can have any particle size. Further, the compound particles may be micronized or nanonized, aggregated, or in any other form of particulate granules, powders, oils, oil suspensions, or any other form of solid or liquid physical form.

[0061] The compounds described herein may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. The term polymorphism refers to a specific crystalline state of a substance having specific physical properties, such as X-ray diffraction, IR spectrum, and melting point.

[0062] The terms “PD-1 / PD-L1 inhibitor or inhibitory compound” or “inhibitor of PD-1 / PD-L1 activation” are used to identify compounds that can interfere with the PD-1 / PD-L1 pathway, thereby preventing inhibitory signaling from cancer cells and inducing an immune response in CTLs against target / cancer cells, and thus treating cancer and other diseases or conditions related to PD1 / PD-L1 activation.

[0063] The terms “cytotoxic agent” or “inhibitor” are used to identify any drug or substance that can kill cells, including cancer cells. These drugs or inhibitors can stop the growth and division of cancer cells and reduce the size of tumors.

[0064] The terms "non-cytotoxic agent" or "inhibitor" are used to identify any drug or inhibitor that does not directly kill cells, but instead affects their transport and metabolic functions, ultimately leading to cell death.

[0065] The terms "immune checkpoint inhibitor" or "immunomodulator" are used to identify any drug or inhibitor that interferes with certain proteins produced by certain types of immune system cells, such as T cells and some cancer cells. These proteins help suppress the immune response, preventing T cells from killing cancer cells. When these proteins are inhibited, the "brakes" in the immune system are released, allowing T cells to kill cancer cells more effectively. Examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2. The terms "immunomodulator" and "immune checkpoint inhibitor" are used interchangeably throughout this invention.

[0066] The term “composition” is intended to encompass products containing specified components in specified amounts, and any products obtained directly or indirectly from combinations of specified components in specified amounts. “Pharmacovigilant” means that carriers, diluents, or excipients must be compatible with the other components of the formulation and must not be harmful to its recipient.

[0067] The term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and a conventionally pharmaceutically acceptable carrier.

[0068] The pharmaceutical compositions of the present invention can be administered orally, for example, in the form of tablets, sugar-coated tablets, pills, capsules, granules, or elixirs. However, administration may also be done enterally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly, or subcutaneously, in the form of sterile solutions or suspensions for injection, or topically, for example in the form of ointments or creams, or transdermally, in the form of patches, or by other methods, for example, in the form of aerosols or nasal sprays.

[0069] The pharmaceutical composition typically contains about 1% to 99% by mass, for example, about 5% to 75% by mass or about 10% to 30% by mass, of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be in the range of about 1 mg to about 1000 mg, or about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or in a broader range of 1 mg to 1000 mg, or in any range greater or less than the above ranges.

[0070] The terms “treat,” “treating,” and “treatment” refer to any treatment of a disease in a mammal, including (a) inhibiting the disease, i.e., slowing or suppressing the onset of clinical symptoms; and / or (b) alleviating the disease, i.e., reducing clinical symptoms; and / or (c) reducing or suppressing the disease and / or associated symptoms.

[0071] The terms “prevent,” “preventing,” and “prevention” refer to methods of preventing the onset of a disease and / or associated symptoms, or preventing a person from acquiring a disease. As used herein, “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and / or associated symptoms, and reducing the risk of a person acquiring a disease.

[0072] The term "therapeutic dose" refers to the amount of compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing a desired therapeutic response in a particular patient suffering from a disease or disorder, particularly in use in diseases or disorders related to cancer; or the amount of a composition containing compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. In particular, the term "therapeutic dose" includes the amount of compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, is sufficient to induce a positive change in the disease or disorder being treated, or to prevent or to some extent reduce the manifestation of one or more symptoms of the disease or disorder being treated, in the subject. With respect to the therapeutic dose of the compound, the amount of the compound used for the treatment of the subject should be sufficiently small, within the bounds of appropriate medical judgment, to avoid excessive or serious side effects. The therapeutically effective amount of compound or composition varies depending on the specific condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent treatments, the age and physical condition of the end user, the specific compound or composition used, and the specific pharmacopoeia-acceptable carrier used.

[0073] Once a term is used, it shall have the same meaning throughout this patent.

[0074] As discussed in the background, the identification and development of novel PD-1 / PD-L1 inhibitor compounds that treat cancer and other diseases or conditions related to PD-1 / PD-L1 activation will open up broad opportunities in the treatment of PD-1 / PD-L1-related diseases, conditions, or cancers.

[0075] In embodiments of the present invention, the compound of formula (I): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, X is selected from O or NR', Ring A is C 6~10 Ariel, C 3~10Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclyl, where C 6~10 Aryl, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl,-CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 The heterocyclyl is optionally halogen, hydroxy, C 1~10 Alkyl, C 1~10 Alkoxy, C 1~10 Haloalkyl, C 2~10 Alkylalkoxy, -CH2-NR a C(O)R b , -CR a R b -OR c , -CR a R b -NR c R d or -CH2-NHC(O)NR a R b Substituted with one or more groups selected from, where R a , R b , R c and R d Are independently hydrogen, halogen, C 1~10 Alkyl, -C(O)R", C 3~10 Cycloalkyl, C 1~10 Haloalkyl or C 1~10 Selected from alkoxy, R' is hydrogen or C 1~10 Selected from alkyl, R1 is hydrogen, cyano or C 1~10 Selected from alkyl, R2 is hydrogen, C 1~10 Alkyl, C 6~10 Aryl, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C7~16 alkylaryl, C 2~10 heteroaryl, C 3~20 alkylheteroaryl, C 2~20 heterocyclyl or C 3~20 alkylheterocyclyl, where C 1~10 alkyl, C 6~10 aryl, C 3~10 cycloalkyl, C 1~10 haloalkyl, C 7~16 alkylaryl, C 2~10 heteroaryl, C 3~20 alkylheteroaryl, C 2~20 heterocyclyl or C 3~20 alkylheterocyclyl is optionally substituted by one or more groups selected from halogen, cyano, hydroxy, -C(O)NH2, C 1~10 alkyl or C 6~10 aryl, R3 is halogen, C 6~10 aryl or C 2~10 heteroaryl, where C 6~10 aryl or C 2~10 heteroaryl is optionally substituted by one or more groups selected from halogen, haloalkyl, cyano, hydroxy, amino, C 1~10 alkyl, OR", C 6~10 aryl, C 2~20 heterocyclyl or C 2~10 heteroaryl, R" is hydrogen, halogen, C 1~10 alkyl or C 1~10 haloalkyl, R4 is hydrogen or C 1~10 alkyl, m is 1 - 5, n is 0 - 5, l is 1 - 5, provided that the compound of formula (I) is

Chemical formula

[0076] In embodiments of the present invention, compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [wherein X is selected from O, Ring A is C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, C 1~10 Alkoxy, C 1~10 Haloalkyl, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen, halogen, and C 1~10 Alkyl, -C(O)R", C 3~10 Cycloalkyl, C 1~10 Haloalkyl or C 1~10 Selected from alkoxy, R1 is hydrogen, cyanoacrylate, or C1 1~10 Selected from alkyl groups, R2 is hydrogen, C 1~10 Alkyl, C 6~10 Ariel, C3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Selected from alkyl heterocyclyl, where C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Alkyl heterocyclyls can be optionally halogenated, cyano, hydroxy, -C(O)NH2, or C 1~10 Alkyl or C 6~10 Substituted by one or more groups selected from aryl groups, R3 is halogen, C 6~10 Aryl or C 2~10 Selected from heteroaryls, where C 6~10 Aryl or C 2~10 Heteroaryls can be optionally halogenated, haloalkyl, cyano, hydroxy, amino, or C. 1~10 Alkyl, OR, C 6~10 Ariel, C 2~20 Heterocyclyl or C 2~10 Substituted with one or more groups selected from heteroaryls, Here, R'' represents hydrogen, halogen, and C. 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~10 Selected from alkyl groups, [m is 1 to 5, n is 0 to 5, and l is 1 to 5].

[0077] Embodiments of the present invention refer to compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [wherein X is O, R1 is cyano or C]. 1~6 It is alkyl, and R2 is C 1~6 Haloalkyl, C 6~10 Ariel, C 7~12 Alkylaryl, C 3~16 Alkyl heteroaryl or C 3~20 Selected from alkyl heterocyclyl, where C 1~6 Haloalkyl, C 6~10 Ariel, C 7~12 Alkylaryl, C 3~16 Alkyl heteroaryl or C 3~20 Alkyl heterocyclyl is optional, C 1~6 It is substituted with one or more groups selected from alkyl, cyano, hydroxy, or -C(O)NH2, where R3 is halogen, C 6~8 Aryl or C 2~10 It is a heteroaryl, where C 6~8 Aryl or C 2~10 Heteroaryls can be optionally halogenated, haloalkyl, hydroxyl, amino, or C. 1~10 Alkyl, OR, or C 2~20 It is substituted with one or more groups selected from heterocyclines, and ring A is C 2~10 Heterocyclyl, CO-C 2~10 Heterocyclyl or -C(O)NR4-C 2~10 Selected from heterocyclines, where C 2~10 Heterocyclyl, CO-C 2~10 Heterocyclyl or -C(O)NR4-C 2~10 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~6 Alkyl, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R d or -CH2-NHC(O)NR a Rb It is substituted by one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen and C 1~6 [Selected from alkyl or -C(O)R", where R4 is hydrogen and n is 0-1].

[0078] Embodiments of the present invention refer to compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [wherein X is O and R1 is C]. 1~6 It is alkyl, and R2 is C 3~10 It is an alkyl heteroaryl, where C 3~10 Alkyl heteroaryls are optional, C 1~6 It is substituted with one or more groups selected from alkyl or cyano, and R3 is C 6~8 It is an aryl ring, and ring A is C 2~10 It is a heterocycline and can be optionally -CH2OR c It is replaced by, where R c [where is hydrogen, m is 1, n is 1, and l is 1].

[0079] Embodiments of the present invention provide compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [wherein m is 1 to 2, n is 0 to 2, and l is 1 to 2]. Another embodiment of the present invention provides compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [wherein m is 1, n is 1, and l is 1].

[0080] In embodiments of the present invention, compounds of formula (I), stereoisomers thereof, N-oxides thereof, or pharmaceutically acceptable salts [wherein A is [ka] Selected from, Here, [ka] teeth [ka] And, R I , R II , R III , R IV , R V and R VI These are, independently, hydrogen and C 1~10 Alkyl, -C(O)R", -C(O)NH-R", -CH2-OR", halogen or C 1~10 [Provides a selection from haloalkyl]

[0081] In embodiments of the present invention, the compound of formula (II): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, X is selected from O or NR', Ring A is C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, C 1~10 Alkoxy, C 1~10 Haloalkyl, C 2~10 Alkylalkoxy, -CH2-NR aC(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen, halogen, and C 1~10 Alkyl, -C(O)R", C 3~10 Cycloalkyl C 1~10 Haloalkyl or C 1~10 Selected from alkoxy, R' is either hydrogen or C 1~10 Selected from alkyl groups, R1 is hydrogen, cyanoacrylate, or C1 1~10 Selected from alkyl groups, R2 is hydrogen, C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Selected from alkyl heterocyclyl, where C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Alkyl heterocyclyls can be optionally halogenated, cyano, hydroxy, -C(O)NH2, or C 1~10 Alkyl or C 6~10 Substituted by one or more groups selected from aryl groups, R stands for hydrogen, halogen, C 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~10 Selected from alkyl groups, m is 1-5, n is 0-5, and l is 1-5. To provide.

[0082] In embodiments of the present invention, the compound of formula (IA): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, X is selected from O, Ring A is C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen and C 1~10 Selected from alkyl or -C(O)R", R1 is cyano or C 1~10 Selected from alkyl groups, R2 is C 6~10Ariel, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 3~20 Selected from alkyl heterocyclyl, where C 6~10 Ariel, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 3~20 Alkyl heterocyclyls are optionally cyano, hydroxy, -C(O)NH2, or C 1~10 Substituted with one or more groups selected from alkyl groups, R3 is halogen, C 6~10 Aryl or C 2~10 Selected from heteroaryls, where C 6~10 Aryl or C 2~10 Heteroaryls can be optionally halogenated, haloalkyl, hydroxyl, amino, or C. 1~10 Alkyl, OR, or C 2~20 Substituted by one or more groups selected from heterocyclines, R" is C 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen, n is between 0 and 1. To provide.

[0083] In embodiments of the present invention, the compound of formula (IA): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, X is selected from O, Ring A is C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 2~20 Heterocyclyl, -CO-C 2~20Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, -CH2-NR a C(O)R b ,-CR a R b -ORc, -CR a R b -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen and C 1~10 Selected from alkyl or -C(O)R", R1 is cyano or C 1~10 Selected from alkyl groups, R2 is C 6~10 Ariel, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 3~20 Selected from alkyl heterocyclyl, where C 6~10 Ariel, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 3~20 Alkyl heterocyclyls are optionally cyano, hydroxy, -C(O)NH2, or C 1~10 Substituted with one or more groups selected from alkyl groups, R3 is halogen, C 6~10 Aryl or C 2~10 Selected from heteroaryls, where C 6~10 Aryl or C 2~10 Heteroaryls can be optionally halogenated, haloalkyl, hydroxyl, amino, or C. 1~10 Alkyl, OR, or C 2~20 Substituted by one or more groups selected from heterocyclines, R" is C1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen, n is between 0 and 1. However, the compound of formula (IA) is [ka] isn't it] To provide.

[0084] In embodiments of the present invention, the compound of formula (IB): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, Ring A is C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, C 1~10 Alkoxy, C 1~10 Haloalkyl, C 2~10 Alkylalkoxy, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R dor -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen, halogen, and C 1~10 Alkyl, -C(O)R", C 3~10 Cycloalkyl, C 1~10 Haloalkyl or C 1~10 Selected from alkoxy, R1 is hydrogen, cyanoacrylate, or C1 1~10 Selected from alkyl groups, R2 is hydrogen, C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Selected from alkyl heterocyclyl, where C 1~10 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~10 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Alkyl heterocyclyls can be optionally halogenated, cyano, hydroxy, -C(O)NH2, or C 1~10 Alkyl or C 6~10 Substituted by one or more groups selected from aryl groups, R stands for hydrogen, halogen, C 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~10 Selected from alkyl groups, n is between 0 and 1. To provide.

[0085] In embodiments of the present invention, the compound of formula (IC): [ka] Their stereoisomers, their N-oxides, or pharmaceutically acceptable salts [In the formula, Ring A is C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Selected from heterocyclines, where C 6~10 Ariel, C 3~10 Cycloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 2~20 Heterocyclyl, -CO-C 2~20 Heterocyclyl or -C(O)NR4-C 2~20 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~10 Alkyl, C 1~10 Alkoxy, C 1~10 Haloalkyl, C 2~10 Alkylalkoxy, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a R b -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen, halogen, and C 1~10 Alkyl, -C(O)R", C 3~10 Cycloalkyl, C 1~10 Haloalkyl or C 1~10Selected from alkoxy, R2 is hydrogen, C 1~6 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Selected from alkyl heterocyclyl, where C 1~6 Alkyl, C 6~10 Ariel, C 3~10 Cycloalkyl, C 1~6 Haloalkyl, C 7~16 Alkylaryl, C 2~10 Heteroaryl, C 3~20 Alkyl heteroaryl, C 2~20 Heterocyclyl or C 3~20 Alkyl heterocyclyls can be optionally halogenated, cyano, hydroxy, -C(O)NH2, or C 1~10 Alkyl or C 6~10 Substituted by one or more groups selected from aryl groups, R stands for hydrogen, halogen, C 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~6 Selected from alkyl groups] To provide.

[0086] Embodiments of the present invention refer to compounds of formula (IC), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts. [In the formula, Ring A is C 2~10 Selected from heterocyclines, where C 2~10 Heterocyclines can be optionally halogenated, hydroxylated, or C. 1~6 Alkyl, -CH2-NR a C(O)R b ,-CR a R b -OR c ,-CR a Rb -NR c R d or -CH2-NHC(O)NR a R b It is substituted with one or more groups selected from, where R a , R b , R c and R d These are, independently, hydrogen or C 1~10 Selected from alkyl groups, R2 is C 6~10 Ariel, C 1~6 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 2~20 Selected from alkyl heterocyclyl, where C 6~10 Ariel, C 1~6 Haloalkyl, C 7~16 Alkylaryl, C 3~20 Alkyl heteroaryl or C 2~20 Alkyl heterocyclyls are optionally cyano, hydroxy, -C(O)NH2, or C 1~6 Substituted with one or more groups selected from alkyl groups, R stands for hydrogen, halogen, C 1~10 Alkyl or C 1~10 Selected from haloalkyl groups, R4 is hydrogen or C 1~6 Selected from alkyl groups] To provide.

[0087] In embodiments of the present invention, [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E] [Table 1F] The present invention provides compounds of formula (I) selected from, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or N-oxides thereof.

[0088] Embodiments of the present invention provide compounds of formula (I), stereoisomers thereof, N-oxides thereof, or pharmaceutically acceptable salts thereof, wherein the compounds act as inhibitors of PD1 / PD-L1 interaction.

[0089] In embodiments of the present invention, (a) a step of reacting a compound of formula (Ia) with compound A in the presence of a reducing agent and a solvent to obtain a compound of formula (I): [ka] The present invention provides methods for preparing compounds of formula (I), including those of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts.

[0090] Embodiments of the present invention provide a method for preparing the compound of formula (I) disclosed herein, wherein the preparation is carried out at a temperature in the range of 25 to 80°C for a period of 2 to 20 hours, the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride, and the solvent is selected from methanol, ethanol, dimethylformamide, or a combination thereof.

[0091] Embodiments of the present invention provide a method for preparing the compound of formula (I) disclosed herein, wherein formula (I) is reacted with a potassium tertiary butoxide in the presence of a solvent selected from tetrahydrofuran, t-butanol, or a combination thereof.

[0092] Embodiments of the present invention provide a method for preparing compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts, comprising the step of reacting a compound of formula (Ia) with compound A, sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, in the presence of a solvent selected from methanol, ethanol, dimethylformamide, or a combination thereof, at a temperature in the range of 25 to 80°C for a period of 2 to 20 hours, to obtain a compound of formula I.

[0093] Embodiments of the present invention provide a method for preparing compounds of formula (I), their stereoisomers, their N-oxides, or pharmaceutically acceptable salts, comprising the steps of (a) reacting a compound of formula (Ia) with compound A, sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, in the presence of a solvent selected from methanol, ethanol, dimethylformamide, or a combination thereof, at a temperature in the range of 25 to 80°C for a period of 2 to 20 hours, to obtain a compound of formula (I), wherein formula (I) is further reacted with a potassium tertiary butoxide in the presence of a solvent selected from tetrahydrofuran, t-butanol, or a combination thereof.

[0094] Embodiments of the present invention provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, in optionally combination with one or more other pharmaceutical compositions.

[0095] Embodiments of the present invention provide a pharmaceutical composition comprising, optionally, a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, in combination with one or more other pharmaceutical compositions, the pharmaceutical composition being in a form selected from the group consisting of tablets, capsules, powders, syrups, solutions, aerosols, and suspensions.

[0096] Embodiments of the present invention provide a method for treating and / or preventing a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or pharmaceutical composition disclosed herein to a subject suffering from a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer.

[0097] Embodiments of the present invention provide a compound or pharmaceutical composition of formula (I) disclosed herein for use in the manufacture of a pharmaceutical for inhibiting PD-1 / PD-L1 interaction in cells.

[0098] Embodiments of the present invention provide a compound of formula (I) or a pharmaceutical composition of the present invention for use in the treatment and / or prevention of a PD-1 / PD-L1 interaction-mediated condition, proliferative disorder, or cancer, including administration to a subject suffering from a PD-1 / PD-L1 interaction-mediated condition, proliferative disorder, or cancer.

[0099] Embodiments of the present invention provide a method for treating or preventing a disease, proliferative disorder, or cancer, comprising the step of administering to a subject suffering from a disease, proliferative disorder, or cancer a therapeutically effective amount of a compound or pharmaceutical composition of formula (I) disclosed herein, and other clinically relevant cytotoxic or non-cytotoxic agents, to a subject in need thereof.

[0100] Embodiments of the present invention include metastatic cancer, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, neuroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, Pancreatic blastoma, pleuroblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumors, renal cell carcinoma, lymphoma, myeloma, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), metastatic cancer, myeloproliferative neoplasm (MPN), polycythemia vera (PV), essential thrombocythemia The present invention provides a method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of formula (I) disclosed herein, together with other clinically relevant cytotoxic or non-cytotoxic agents, to a subject suffering from a proliferative disorder or cancer, for the treatment or prevention of a disease category including thrombocythemia, essential thrombocytosis (ET), and myelofibrosis (MF), a disease selected from chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), a disease caused by mutations in specific oncogenes, EGFR, KRAS, or RET, or an infectious disease.

[0101] Embodiments of the present invention provide the use of a compound or pharmaceutical composition of formula (I) disclosed herein, together with other clinically relevant cytotoxic or non-cytotoxic agents, for the treatment or prevention of various diseases, including proliferative disorders or cancer, or for the treatment of cancer.

[0102] Embodiments of the present invention provide a method for treating cancer, comprising the step of administering a combination of a compound or pharmaceutical composition of formula (I) disclosed herein and other clinically relevant cytotoxic or non-cytotoxic agents to a subject in need thereof.

[0103] Embodiments of the present invention provide a method for treating cancer, comprising the step of administering a combination of a compound or pharmaceutical composition of formula (I) disclosed herein and other clinically relevant immunomodulators to a subject in need thereof.

[0104] Embodiments of the present invention provide a method for treating and / or preventing a disease or disorder, comprising the step of administering to a patient in need of treatment a composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

[0105] Embodiments of the present invention provide compounds of formula (I) for use in the treatment and / or prevention of diseases, disorders, or conditions. In relevant embodiments, the present invention provides the use of compounds of formula (I) for the manufacture of pharmaceuticals for the treatment and / or prevention of diseases, disorders, or conditions.

[0106] Embodiments of the present invention provide a method for treating or preventing metastatic cancer selected from brain metastases, bladder metastases, breast metastases, colon metastases, kidney metastases, lung metastases, melanoma metastases, ovarian metastases, pancreatic metastases, prostate metastases, rectal metastases, gastric metastases, thyroid metastases, or uterine metastases, comprising the step of administering a combination of a compound or pharmaceutical composition of formula (I) disclosed herein and other clinically relevant immunomodulatory agents to a subject in need thereof.

[0107] Embodiments of the present invention provide a compound or pharmaceutical composition of formula (I) disclosed herein that acts as an inhibitor for PD-1 / PD-L1 interaction for brain metastases.

[0108] Embodiments of this disclosure provide compounds or pharmaceutical compositions of formula (I) for the treatment of brain metastases and for reducing neurotoxicity risks associated with radiotherapy or radiation necrosis.

[0109] Embodiments of the present invention provide compounds that can be administered in combination therapy. “Combination therapy” includes the administration of the subject compound in combination with other bioactive components (e.g., different antineoplastic agents, but not limited to them) and non-pharmacological treatments (e.g., surgery or radiotherapy, but not limited to them). The compounds described herein can be used in combination with other pharmaceutically active compounds, preferably thereby enhancing the effects of the compounds of the present invention. The compounds can be administered simultaneously with or sequentially with other drug treatments.

[0110] In embodiments of the present invention, the subject compound may be combined with antineoplastic agents that inhibit one or more biological targets (e.g., small molecules, cytotoxic reagents, non-cytotoxic reagents, monoclonal antibodies, antisense RNA, and fusion proteins). Such combinations may enhance therapeutic efficacy compared to the efficacy achieved by any of the agents alone, and may prevent or delay the emergence of resistance variants. [Examples]

[0111] The following examples provide details of the synthesis, activity, and applications of the compounds of the present invention. It should be understood that these are representative examples and the present invention is not limited by the details described in these examples.

[0112] We also provide the method shown in Scheme-1 below for the preparation of the compound of formula (I), where all groups are as previously defined. The intermediate aldehyde used for the synthesis was prepared according to the method referred to in International Patent Application Publication No. 2019 / 175897.

[0113] The following abbreviations refer to the terms defined herein: rt (retention time); RT (room temperature); °C (degrees Celsius); DMF (dimethylformamide); h (hour); THF (tetrahydrofuran); HCl (hydrochloric acid); DCM, CH2Cl2 (dichloromethane); TFA (trifluoroacetic acid); TCL (thin-layer chromatography); Na2SO4 (sodium sulfate); ACN / CH3CN (acetonitrile); AcOH (acetic acid); MeOH (methanol); DMSO-d6 (dimethyl sulfoxide-d); HPLC (high-performance liquid chromatography); LCMS (liquid chromatography-mass spectroscopy); NMR (nuclear magnetic resonance); TEA (triethylamine); Cs2CO3 (cesium carbonate); BH3-DMS (borane-DMS); K2CO3 (potassium carbonate); MHz (megahertz); s (singlet); m (multiplet); and d (doublet). NMM (N-methylmorpholine); KO t Bu (potassium tert butoxide); t-BuOH (tert butyl alcohol); LAF (lithium aluminum hydride); LAH (lithium aluminum hydride); MsCl (methanesulfonyl chloride); mCPBA (3-chlorobenzene-1-carboperoxoic acid / meth-chloroperbenzoic acid); Et3N (triethylamine):Na(CN)BH3 / NaBH3CN (sodium borohydride cyanohydride); PPh3 (triphenylphosphine); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); PdCl2(PPh3)2 (bis(triphenylphosphine)palladium(II) dichloride); LiOH (lithium hydroxide); NaBH4 (sodium borohydride); PBr3 (tribromophosphine); POBr3 (tribromophosphine / phosphoryl bromide); HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate / hexafluorophosphate azabenzotriazoletetramethyluronium); DIPEA(N,N-diisopropylethylamine).

[0114] Examples The present invention is not limited to, but is further illustrated by the following examples illustrating the preparation of compounds according to the present invention.

[0115] (Example 1) Synthesis of (S)-5-(((4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile

[0116] [ka]

[0117] Reagents and conditions: AcOH, NaBH3CN, MeOH:DMF (1:1), 70°C, 10h

[0118] A solution of 5-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (1, 0.3 g, 0.63 mmol), (S)-piperidine-2-yl methanol (0.076 g, 0.76 mmol), sodium borohydride cyanohydride (0.118 g, 0.18 mmol), and acetic acid (2 drops) in methanol (5 mL) and N,N-dimethylformamide (5 mL) was heated at 70 °C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 35 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was purified again by reverse-phase preparative HPLC (ammonium acetate buffer) to obtain the title product (Example 1, 0.15 g, 41%) as a white solid. LCMS (ES) m / z = 574.43 [M+H] + ;1 H NMR (400 MHz, DMSO-d6) δ ppm: 1.66 (m, 4H), 1.98 (m, 2H), 2.21 (s, 3H), 2.60 (m, 1H), 2.49-2.86 (m, 5H), 3.16 (m, 1H), 3.40 (m, 1H), 3.68 (m, 1H), 3.96 - 4.02 (m, 2H), 4.28 (m, 1H), 4.65 (m, 1H), 5.13 -5.40 (m, 5H), 6.74-6.88 (bs, 1H), 7.13 (m, 1H), 7.20-7.31 (m, 3H), 7.39 (m, 1H), 7.44-7.48 (m, 3H), 8.49 (m, 1H), 9.02 (m, 2H). HPLC: 98.54%

[0119] The compounds listed in Table 1 (Table 2) below were prepared using the same procedure as described in Example 1, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in Table 2 below.

[0120] [Table 2A] [Table 2B] [Table 2C] [Table 2D] [Table 2E] [Table 2F] [Table 2G] [Table 2H] [Table 2I] [Table 2J] [Table 2K]

[0121] (Example 23) Synthesis of (S)-3-(((7-((2-(hydroxymethyl)piperidine-1-yl)methyl)-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile

[0122] [ka]

[0123] Reagents and conditions: 1. Cs2CO3, DMF, 60°C, 16h; 2. NaBH3CN, AcOH, MeOH:DMF (1:1), 60°C, 10h

[0124] Step 1: Synthesis of 3-(((7-formyl-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile(2)

[0125] [ka]

[0126] To a solution of 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (1, 0.50 g, 1.35 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.0 g, 4 mmol) in N,N-dimethylformamide (8 mL), cesium carbonate (0.39 g, 2.0 mmol) was added, and the mixture was heated at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the desired product (2, 0.3 g, 47%) as a white solid. LCMS (ES) m / z = 452.57 [M+H] + ;

[0127] Step 2: Synthesis of (S)-3-(((7-((2-(hydroxymethyl)piperidine-1-yl)methyl)-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (Example 23)

[0128] [ka]

[0129] A solution of 3-(((7-formyl-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (2, 0.15 g, 0.34 mmol), (S)-piperidine-2-ylmethanol (0.114 g, 0.94 mmol), sodium borohydride (0.061 g, 0.9 mmol), and acetic acid (2 drops) in methanol (3 mL) and N,N-dimethylformamide (3 mL) was heated at 60°C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol (3 × 25 mL) in dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was purified again by reverse-phase preparative HPLC (ammonium acetate buffer) to obtain the title product (Example 23, 0.020 g, 11%) as a white solid. LCMS (ES) m / z = 551.37 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 1.18-1.30 (m, 4H), 1.32-1.42 (m, 1H), 1.55-1.62 (m, 1H), 1.65-1.70 (m, 1H), 1.90-2.02 (m, 3H), 2.22 (bs, 1H), 2.76 (t, J = 7.6 Hz, 2H), 2.80-2.90 (m, 1H), 2.92-3.02 (m, 1H), 3.22 (d, J = 12.4 Hz, 1H), 3.37-3.43 (m, 1H), 3.70-3.76 (m, 1H), 3.92 (d, J = 12.0 Hz, 1H), 4.36 (t, J = 4.8 Hz, 1H), 4.67-4.76 (m, 2H), 5.32 (s, 2H), 6.75 (s, 1H), 7.50-7.64 (m, 6H), 7.76 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H); HPLC purity 97.61%.

[0130] (Example 24) Synthesis of (S)-(1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-yl)methanol

[0131] [ka]

[0132] Example 24 was prepared using 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde as the starting material, following the same procedure as described in Example 23. LCMS (ES) m / z = 540.39 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 1.20-1.34 (m, 2H), 1.55-1.70 (m, 1H), 1.85 (s, 2H), 1.95-2.05 (m, 2H), 2.12 (s, 3H), 2.21 (s, 3H), 2.72-2.76 (m, 2H), 2.85-2.90 (m, 2H), 2.96-3.00 (m, 1H), 3.30 (s, 1H), 3.42-3.48 (m, 1H), 3.70-3.75 (m 1H), 3.87-3.92 (m, 1H), 4.35 (bs, 1H), 4.68-4.76 (m, 2H), 5.14 (s, 2H), 6.77 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 6.4 Hz, 1H), 7.28-7.36 (m, 3H), 7.37-7.42 (m, 1H), 7.44-7.51 (m, 3H); HPLC: 99.57%.

[0133] (Example 25) Synthesis of (S)-5-(((4-((6-(hydroxymethyl)-5-azaspiro[2,4]heptan-5-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile

[0134] [ka]

[0135] Reagents and conditions: 1. BH3-DMS, THF, RT, 24h; 2. 4N HCl in dioxane, dioxane, RT, 6h; 3. TEA, AcOH, RT, 2h, NaBH3CN, DMF:MeOH (1:1) RT, 16h;

[0136] Step 1: Synthesis of tert-butyl(S)-6-(hydroxymethyl)-5-azaspiro[2,4]heptane-5-carboxylate(2)

[0137] [ka]

[0138] A solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (1, 0.8 g, 3.3 mmol) in dry tetrahydrofuran (15 mL) at 0°C was treated with borane-DMS (6.6 mL, 1 M, 2 eq in tetrahydrofuran), and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was quenched with methanol (20 mL) and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL), washed with water (80 mL), saturated sodium bicarbonate solution (80 mL), and brine (80 mL), and concentrated under reduced pressure to obtain the desired product (2, 0.73 g, 96%) as a pale yellow liquid.

[0139] Step 2: Synthesis of (S)-(5-azaspiro[2,4]heptan-6-yl)methanol hydrochloride (3)

[0140] [ka]

[0141] To a solution of tert-butyl(S)-6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate (2, 0.73 g, 3.2 mmol) in 1,4-dioxane (25 mL), 4N hydrochloric acid in 1,4-dioxane (2.5 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the desired product (3, 0.53 g, 98.3%) as a pale yellow solid.

[0142] Step 3: Synthesis of (S)-5-(((4-((6-(hydroxymethyl)-5-azaspiro[2,4]heptan-5-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 25)

[0143] [ka]

[0144] To a solution of 5-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (0.3 g, 0.632 mmol) in N,N-dimethylformamide (5 mL) and methanol (5 mL), (S)-(5-azaspiro[2,4]heptan-6-yl)methanol hydrogen chloride (3, 155 mg, 0.94 mmol), triethylamine (0.096 g, 0.94 mmol), and acetic acid (2 drops) were added and the mixture was stirred for 2 hours. Sodium cyanoborohydride (0.119 g, 1.8 mmol) was added to this mixture, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (15 mL) and extracted with 10% methanol (3 × 30 mL) in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 0-10% methanol in dichloromethane as the eluent to obtain the title product (Example 25, 0.05 g, 13.5%) as a white solid. LCMS (ES) m / z = 586.74 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 0.30-0.45 (m, 4H), 1.45-1.55 (m, 1H), 1.86-2.00 (m, 3H), 2.20 (s, 3H), 2.45 (m, 1H), 2.60-3.00 (m, 5H), 3.25-3.39 (m, 2H), 3.50-3.55 (m, 1H), 3.80-3.86 (m, 1H), 4.25 (bs, 1H), 5.13 (s, 2H), 5.20-5.30 (m, 2H), 6.73 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.26-7.40 (m, 4H), 7.42-7.48 (m, 3H), 8.41 (s, 1H), 8.89-9.02 (m, 2H). The 1H peak is merged with the DMSO residual peak. HPLC: 99.47%.

[0145] (Example 26) (S)-5-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-4-((6-(hydroxymethyl)-5-azaspiro[2,4]heptan-5-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile synthesis

[0146] [ka]

[0147] Example 26 was prepared using the same procedure as described in Example 25, with 5-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile as the starting material. LCMS (ES) m / z = 597.36 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 0.32-0.47 (m, 4H), 1.45-1.53 ​​(m, 1H), 1.84-2.02 (m, 3H), 2.30-2.35 (m, 1H), 2.43-2.48 (m, 2H), 2.70-2.80 (m, 2H), 2.80-3.01 (m, 2H), 3.23-3.30 (m, 1H), 3.35-3.40 (m, 1H), 3.47-3.55 (m, 1H), 3.83 (d, J = 12.0 Hz, 1H), 4.24 (bs, 1H), 5.20-5.5.29 (m, 2H), 5.31 (s, 2H), 6.73 (s, 1H), 7.50-7.62 (m, 6H), 7.70 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 8.40 (s, 1H) 8.98 (dd, J = 8.0, 1.6 Hz, 2H). HPLC: 98.51%.

[0148] (Example 27) Synthesis of (S)-(1-((5-(2-fluoroethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-yl)methanol

[0149] [ka]

[0150] Reagents and conditions: 1. K2CO3, DMF, RT, 16h; 2. NaBH3CN, AcOH, MeOH:DMF (1:1), 70℃, 10h

[0151] Step 1: Synthesis of 5-(2-fluoroethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (2)

[0152] [ka]

[0153] To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (1, 0.7 g, 1.95 mmol) in N,N-dimethylformamide (20 mL), potassium carbonate (0.958 g, 6.84 mmol) and 1-fluoro-2-iodoethane (0.51 g, 2.93 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 0-50% ethyl acetate in hexane as the eluent to obtain the desired product (2, 0.47 g, 58.5%) as a white solid. LCMS (ES) m / z = 405.08 [M+H] + .

[0154] Step 2: Synthesis of (S)-(1-((5-(2-fluoroethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-yl)methanol (Example 27)

[0155] [ka]

[0156] A solution of 5-(2-fluoroethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (2, 0.225 g, 0.55 mmol), (S)-piperidine-2-ylmethanol (0.096 g, 0.83 mmol), sodium borohydride cyanohydride (0.107 g, 1.67 mmol), and acetic acid (2 drops) in methanol (4 mL) and N,N-dimethylformamide (4 mL) was heated at 70°C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol (3 × 35 mL) in dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the title product (Example 27, 0.040 g, 14.28%) as a white solid. LCMS (ES) m / z = 504.23 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.15-1.30 (m, 3H), 1.35-1.43 (m, 1H), 1.55-1.70 (m, 2H), 1.90-2.02 (m, 3H), 2.21 (s, 4H), 2.57-2.61 (m, 1H), 2.70-2.78 (m, 2H), 2.80-2.90 (m, 1H), 2.90-3.00 (m, 1H), 3.18-3.24 (m, 1H), 3.40-3.48 (m, 1H), 3.66-3.76 (m, 1H), 3.85-3.93 (m, 1H), 4.16-4.36 (m, 3H), 4.65-4.82 (m, 2H), 5.14 (s, 2H), 6.64 (s, 1H), 7.20 (d, J = 7.4 Hz 1H), 7.26-7.34 (m, 3H), 7.36-7.40 (m, 1H), 7.44-7.50 (m, 3H); HPLC: 97.24%.

[0157] The compounds listed in Table 2 (Table 3) below were prepared using the same procedure as described in Example 27, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in Table 3 below.

[0158] [Table 3A] [Table 3B] [Table 3C] [Table 3D]

[0159] (Example 34) Synthesis of 3-(((4-((1-(hydroxymethyl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile

[0160] [ka]

[0161] Reagents and conditions: 1. TEA, AcOH, RT, 2h, NaBH3CN, MeOH:DMF (1:1), RT, 16h; 2. LAH, THF, RT, 12h, 50℃, 4h; 3. K2CO3, DMF, RT, 16h.

[0162] Step 1: Synthesis of 2-((5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (2)

[0163] [ka]

[0164] A solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (1, 0.5 g, 1.39 mmol), 2-azabicyclo[4.1.0]heptane-1-carboxylate hydrochloride (0.247 g, 1.67 mmol), triethylamine (0.282 g, 2.79 mmol), and acetic acid (3 drops) was added to N,N-dimethylformamide (7 mL) and methanol (7 mL), and the reaction mixture was stirred for 2 hours. Sodium borocyanohydride (0.259 g, 4.18 mmol) was added to this mixture, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol (2 × 150 mL) in dichloromethane. The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash column chromatography using 0-10% methanol in dichloromethane as the eluent to obtain the desired product (2, 0.25 g, 37%) as an off-white solid. LCMS (ES) m / z = 484.49 [M+H] + , crude product purity (79%).

[0165] Step 2: Synthesis of 4-((1-(hydroxymethyl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-ol(3)

[0166] [ka]

[0167] To a solution of 2-((5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (2, 0.25 g, 0.51 mmol) in dried tetrahydrofuran (8 mL), 2 M lithium aluminum hydride solution in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours, and then heated at 50°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to 0°C, and ethyl acetate was added dropwise to the reaction mixture. The reaction mixture was then diluted with water (10 mL) and extracted with 10% methanol:dichloromethane (2 × 100 mL). The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane as the eluent to obtain the desired product (3, 0.075 g, 30%) as an off-white solid. LCMS (ES) m / z = 477 [M+H] + .

[0168] Step 3: Synthesis of 3-(((4-((1-(hydroxymethyl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Example 34)

[0169] [ka]

[0170] To a solution of 4-((1-(hydroxymethyl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-ol (3, 0.075 g, 0.15 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (0.088 g, 0.63 mmol) and 3-(bromomethyl)benzonitrile (0.062 g, 0.31 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over sodium sulfate and concentrated. The crude product obtained was purified by silica gel flash column chromatography using 0-50% ethyl acetate in hexane as the eluent to obtain the title product (Example 34, 0.020 g, 21%) as a white solid. LCMS (ES) m / z = 585.45 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 0.40- 0.45 (m, 1H), 0.50-0.55 (m, 1H), 1.00-1.12 (m, 2H), 1.50 (bs, 1H), 1.53-1.80 (m, 2H), 1.93-2.03 (m, 2H), 2.14-2.23 (m, 5H), 2.72-2.90 (m, 3H), 3.00-3.13 (m, 2H), 3.48-3.60 (m, 3H), 4.06 (t, J = 7.2 Hz, 1H), 5.11 (s, 2H), 5.20 (s, 2H), 6.69 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.30-7.34 (m, 2H), 7.36- 7.48 (m, 4H), 7.60 (t, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 2H), 7.95 (s, 1H); HPLC purity 98.85%.

[0171] The compounds listed in Table 3 (Table 4) below were prepared using the same procedure as described in Example 34, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in the table below (Table 4).

[0172] [Table 4]

[0173] (Example 37) Synthesis of (S)-5-(((4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide

[0174] [ka]

[0175] Reagents and conditions: KO t Bu (1M in THF), t-BuOH, RT, 10h.

[0176] To a solution of (S)-5-(((4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 1, 0.29 g, 0.5 mmol) in tert butanol (10 mL), potassium tert butoxide (1 M in tetrahydrofuran, 10 mL) was added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 55 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was purified again by reverse-phase preparative HPLC (ammonium acetate buffer) to obtain the title product (Example 37, 0.030 g, 10%) as a white solid. LCMS (ES) m / z = 592.22 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 1.15 -1.40 (m, 5H), 1.55-1.65 (m, 2H), 1.88-2.00 (m, 3H), 2.21 (s, 4H), 2.70-3.00 (m, 4H), 3.15-3.22 (m, 1H), 3.35-3.45 (m, 1H), 3.70 (m, 1H), 3.90-3.95 (m, 1H), 4.28 (bs, 1H), 5.13 (s, 2H), 5.20-5.28 (m, 2H), 6.76 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.30-7.40 (m, 3H), 7.44-7.48 (m, 3H), 7.62 (s, 1H), 8.18 (s, 1H), 8.32 (s, 1H), 8.84 (s, 1H), 8.98 (s, 1H); HPLC purity 98.12%.

[0177] (Example 38) Synthesis of (S)-3-(((4-((2-(hydroxymethyl)pyrrolidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide

[0178] [ka]

[0179] Example 38 was prepared using (S)-3-(((4-((2-(hydroxymethyl)pyrrolidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile as the starting material, following the same procedure as described in Example 37. LCMS (ES) m / z = 577.45 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 1.70-2.15 (m, 6H), 2.22 (s, 3H), 2.78-2.84 (m, 2H), 2.90-3.40 (m, 6H), 3.60-3.80 (m, 2H), 4.20 (m, 1H),4.40 (m, 1H), 5.20 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.36-7.50 (m, 5H), 7.66 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 8.04 (m, 2H), 8.63 (bs, 1H); HPLC: 96.9%.

[0180] (Example 39) Synthesis of (S)-(1-((5-((1-methyl-1H-pyrazole-4-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-yl)methanol

[0181] [ka]

[0182] Reagents and conditions: 1. K2CO3, DMF, RT, 16h; 2. NaBH3CN, DMF:MeOH, AcOH, 70℃, 16h.

[0183] Step 1: Synthesis of 5-((1-methyl-1H-pyrazole-4-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (2)

[0184] [ka]

[0185] To a stirred solution of 5-hydroxy-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (1, 1 g, 2.79 mmol) in N,N-dimethylformamide (20 mL), dipotassium carbonate (1.16 g, 3 eq., 8.37 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (0.699 g, 4.18 mmol) were added at room temperature. The reactants were stirred for a further 16 hours at the same temperature. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel using 40% ethyl acetate in hexane to obtain the desired product (3, 0.8 g, 63.36%) as a yellow solid. LCMS (ES) m / z = 453.3 [M+H] + .

[0186] Step 2: Synthesis of (S)-(1-((5-((1-methyl-1H-pyrazole-4-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-yl)methanol (Example 39)

[0187] [ka]

[0188] To a stirred solution of 5-[(1-methyl-1H-pyrazole-4-yl)methoxy]-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (3, 0.15 g, 3.31 mmol) and [(2S)-piperidine-2-yl]methanol (0.057 g, 14.9 mmol) in dimethylformamide (15 mL) and methanol (15 mL), acetic acid (0.95 mL, 16.6 mmol) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at 70 °C for 6 hours. Sodium cyanoborohydride (0.625 g, 9.94 mmol) was added to this reaction mixture, and the mixture was stirred for a further 16 hours at the same temperature. The reaction was monitored by TLC, and after completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was further purified by reverse-phase preparative HPLC to obtain the title product (Example 39, 0.055 g, 30.1%) as a yellow solid. 1H LCMS (ES) m / z = 552.21 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.71 (s, 1H), 7.49-7.43 (m, 4H), 7.39-7.35 (m, 1H), 7.33-7.29 (m, 3H), 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 6.74 (s, 1H), 5.17 (s, 2H), 4.97 (s, 2H), 4.30 (bs, 1H), 3.85 (bs, 1H), 3.81 (s, 3H), 3.67 (dd, J = 10.8, 4.4 Hz, 1H), 3.46 (bs, 1H), 3.20 (bs, 1H), 2.92-2.90 (m, 1H), 2.84-2.78 (m, 1H), 2.74 (t, J = 7.2 Hz, 2H), 2.28-2.13 (m, 4H), 1.99-1.93 (m, 2H), 1.91 (s, 2H), 1.70-1.54 (m, 2H), 1.44-1.36 (m, 1H), 1.35-1.17 (m, 3H). HPLC: 95.15%.

[0189] The compounds listed in Table 4 (Table 5) below were prepared using the same procedure as described in Example 39, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in Table 5 below.

[0190] [Table 5]

[0191] (Example 42) Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol

[0192] [ka]

[0193] Reagents and conditions: 1. MsCl, DCM, Et3N; 2. K2CO3, DMF, RT, 16h; 3. Na(CN)BH3, DMF, MeOH, 70℃, 16h. Step 1: Synthesis of pyrimidine-5-ylmethylmethanesulfonate (2)

[0194] [ka]

[0195] To a solution of (pyrimidine-5-yl)methanol (0.1 g, 0.908 mmol) in dichloromethane (4 mL), triethylamine (0.276 g, 2.72 mmol) and methanesulfonyl chloride (0.171 mL, 1.82 mmol) were sequentially added at 0°C. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with dichloromethane (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the desired compound (2, 0.12 g crude product), which was used in the next step without further purification. Step 2: Synthesis of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (3)

[0196] [ka]

[0197] To a solution of 5-hydroxy-7-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-1H-indene-4-carbaldehyde (0.57 g, 1.59 mmol) in N,N-dimethylformamide (4 mL), potassium carbonate (0.66 g, 4.78 mmol) and (pyrimidine-5-yl)methylmethanesulfonate (2, 0.3 g, 1.59 mmol) were sequentially added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column chromatography to obtain the desired compound (3, 0.16 g, crude product) as a brown solid. LCMS (ES) m / z = 451.35 [M+H] + . Step 3: Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol (Example 42)

[0198] [ka]

[0199] To a solution of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (3, 0.16 g, 0.35 mmol) and azetidine-2-ylmethanol (0.212 g, 1.74 mmol) in dimethylformamide (3 mL) and methanol (7 mL), acetic acid (0.2 mL) was added. The reaction mixture was stirred at 70 °C for 0.5 hours, and sodium borohydride (0.059 g, 0.932 mmol) was added. The reaction mixture was stirred at 70 °C for a further 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (40 mL) and extracted with 10% methanol (3 × 30 mL) in dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography in dichloromethane with 5% methanol to obtain the title compound (Example 42, 0.008 g, 4.2%) as a white solid. LCMS (ES) m / z = 522.35 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.17 (s, 1H), 8.95 (s, 2H), 7.46 (t, J = 6.8 Hz, 3H), 7.40-7.36 (m, 1H), 7.33-7.31 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 5.21(s, 2H), 5.16 (s, 2H), 4.21 (bs, 1H), 3.53 (d, J = 12 Hz, 1H), 3.43 (d, J = 12.4 Hz, 1H), 3.21-3.10 (m, 3H), 3.03-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 3H), 2.21 (s, 3H), 2.00-1.90 (m, 2H), 1.87-1.80 (m, 1H), 1.75-1.65 (m, 1H). HPLC: 96.47%.

[0200] (Example 43) Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(oxazol-4-ylmethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol

[0201] [ka]

[0202] Example 43 was prepared using oxazole-4-ylmethanol as the starting material, following the same procedure as described in Example 42. LCMS (ES) m / z = 511.42 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (s, 1H), 8.18 (s, 1H), 7.50-7.42 (M, 3H), 7.40-7.36 (m, 1H), 7.35-7.26 (m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 6.79 (s, 1H), 5.17 (s, 2H), 5.03 (s, 2H), 4.24 (bs, 1H), 3.51 (bs, 2H), 3.28-3.18 (m, 3H), 3.02 (bs, 1H), 2.95-2.79 (m, 3H), 2.74 (t, J = 7.2 Hz, 2H), 2.22 (s, 3H), 2.00-1.93 (m, 2H), 1.83 (bs, 1H), 1.71 (bs, 1H); HPLC: 92.63%.

[0203] (Example 44) Synthesis of (S)-3-cyano-5-(((4-((2-(hydroxymethyl)pyrrolidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)pyridine 1-oxide

[0204] [ka]

[0205] Reagents and conditions: mCPBA, DCM, 0°C to RT, 16h.

[0206] To a stirred solution of 5-{[(4-{[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]methyl}-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyridine-3-carbonitrilate (1, 0.5 g, 0.89 mmol) in dichloromethane (10 mL), 3-chlorobenzene-1-carboperoxoic acid (0.231 mg, 1.34 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction competition, the reactants were filtered through a Celite pad, the organic layer was concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (Example 44, 0.064 g, 12.4%) as a white solid. LCMS (ES) m / z = 576.30 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (dd, J = 12, 1.6 Hz, 2H), 8.49 (t, J = 1.6 Hz, 1H), 8.46 (bs, 1H), 7.48-7.44 (m, 3H), 7.38 (t, J = 7.2 Hz, 1H), 7.33-7.31 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 6.85 (s, 1H), 5.27 (s, 2H), 5.21 (s, 2H), 4.48 (d, J = 13.2 Hz, 2H), 4.34 (d, J = 12.8 Hz, 1H), 4.11 (d, J = 11.6 Hz, 1H), 3.39-3.33 (m, 2H), 3.26- 3.18 (m, 2H), 2.94-2.90 (m, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.30-2.25 (m, 1H), 2.21 (s, 3H), 2.03-1.91 (m, 3H), 1.87-1.78 (m, 1H), 1.74-1.65 (m, 1H); HPLC: 99.93%.

[0207] (Example 45) Synthesis of (S)-3-cyano-5-(((4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)pyridine 1-oxide

[0208] [ka]

[0209] Example 45 was prepared using the same procedure as described in Example 44, with (S)-5-(((4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile as the starting material. LCMS (ES) m / z = 590.35 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (dd, J = 8.4, 2.0 Hz, 2H), 8.80 (bs, 1H), 8.47 (s, 1H), 7.48-7.44 (m, 3H), 7.41-7.25 (m, 4H), 7.20 (d, J = 6.4 Hz, 1H), 6.82 (s, 1H), 5.29 (s, 2H), 5.20 (s, 2H), 4.59 (d, J = 12 Hz, 1H), 4.43 (d, J = 12.8 Hz, 2H), 3.47-3.37 (m, 2H), 3.21 (d, J = 10.4 Hz, 1H), 2.95-2.83 (m, 2H), 2.76 (t, J = 7.2 Hz, 3H), 2.42-2.37 (m, 2H), 2.21 (s, 3H), 2.05-1.78 (m, 3H), 1.65-1.45 (m, 2H), 1.39-1.21 (m, 2H); HPLC: 98.39%.

[0210] (Example 46) Synthesis of (S)-5-(((7-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-((2-(hydroxymethyl)piperidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile

[0211] [ka]

[0212] Reagents and conditions: 1. Cs2CO3, Pd(dppf)Cl2, toluene, 100℃, 12h; 2. LiOH, MeOH:H2O (1:1), RT, 4h; 3. TEA, ethyl chloroformate, NaBH4, THF, RT, 16h; 4. PBr3, DCM, 0℃, 12h; 5. K2CO3, ACN:DMF, RT, 16h; 6. K2CO3, DMF, RT, 16h; 7. AcOH, NaBH3CN, DMF:MeOH, 70℃, 16h.

[0213] Step 1: Synthesis of methyl 4'-fluoro-2-methyl-[1,1'-biphenyl]-3-carboxylate (2)

[0214] [ka]

[0215] To a stirred solution of methyl 3-bromo-2-methylbenzoate (1, 10 g, 43.7 mmol) in toluene (100 mL), cesium carbonate (42.7 g, 131 mmol) and (4-fluorophenyl)boronic acid (9.16 g, 65.5 mmol) were added at room temperature. The reaction mixture was degassed by passing nitrogen gas through the reactants, and then Pd(dppf)Cl2 (3.19 g, 4.37 mmol) was added. The resulting reaction mixture was stirred at 100 °C for 12 hours. After monitoring by TLC and confirming completion of the reaction, water (50 mL) was added and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the desired product (2, 10.2 g, 95% yield) as a white solid. LCMS (ES) m / z = 245.2 [M+H] + .

[0216] Step 2: Synthesis of 4'-fluoro-2-methyl-[1,1'-biphenyl]-3-carboxylic acid (3)

[0217] [ka]

[0218] To a stirred solution of methyl-4'-fluoro-2-methyl-[1,1'-biphenyl]-3-carboxylate (2,5 g, 20.5 mmol) in methanol (10 mL) and water (10 mL), lithium hydroxide (4.9 g, 205 mmol) was added at room temperature and the mixture was stirred for 4 hours. The reactants were acidified to pH 2 using 2 M hydrochloric acid solution and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography to obtain the desired product (3, 5.2 g, 87%) as a white solid. LCMS (ES) m / z = 231.3 [M+H] + .

[0219] Step 3: Synthesis of {4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methanol (4)

[0220] [ka]

[0221] To a stirred solution of 4'-fluoro-2-methyl-[1,1'-biphenyl]-3-carboxylic acid (3, 2.2 g, 9.56 mmol) in tetrahydrofuran (44 mL), triethylamine (2.66 mL, 19.1 mmol) was added at room temperature. The reactants were cooled to 0°C, and ethyl chloroformate (1 mL, 10.5 mmol) was added over a period of 10 minutes. The reaction mixture was stirred at 0°C for 2 hours, then sodium borohydride (1.08 g, 28.7 mmol) was added in small increments, and the mixture was stirred for 16 hours. The reactants were quenched by the addition of water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the desired product (4, 1.5 g, 73%) as a colorless oil. LCMS (ES) m / z = 217.2 [M+H] + .

[0222] Step 4: Synthesis of 3-(bromomethyl)-4'-fluoro-2-methyl-1,1'-biphenyl (5)

[0223] [ka]

[0224] To a stirred solution of {4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methanol (4, 950 mg, 4.39 mmol) in dichloromethane (15 mL), tribromophosphan (0.46 mL, 4.83 mmol) was added under a nitrogen atmosphere at 0°C. The resulting solution was stirred for a further 2 hours. The reaction mixture was quenched with aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (5, 1.2 g, 97%) as a white solid. LCMS (ES) m / z = 280.1 [M+H] + .

[0225] Step 5: Synthesis of 7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methyl)-5-hydroxy-2,3-dihydro-1H-inden-4-carbaldehyde (6)

[0226] [ka]

[0227] To a stirred solution of 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.6 g, 3.37 mmol) in acetonitrile (20 mL) and N,N-dimethylformamide (10 mL), dipotassium carbonate (1.4 g, 10.1 mmol) and 3-(bromomethyl)-4'-fluoro-2-methyl-1,1'-biphenyl (5, 940 mg, 3.37 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After monitoring by TLC and confirming completion of the reaction, the solvent was evaporated, the mixture was diluted with water (30 mL), and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography to obtain the desired product (6, 0.5 g, 40%) as a brown solid. LCMS (ES) m / z = 377.1 [M+H] + .

[0228] Step 6: Synthesis of 5-({[7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrile (7)

[0229] [ka]

[0230] To a stirred solution of 7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (6, 0.38 g, 1.01 mmol) in N,N-dimethylformamide (10 mL), dipotassium carbonate (0.698 g, 5.05 mmol) and (5-cyanopyridine-3-yl)methylmethanesulfonate (0.428 g, 2.02 mmol) were added at room temperature. The reactants were stirred for a further 16 hours at the same temperature. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel using ethyl acetate in hexane to obtain the desired product (7, 0.3 g, 60.33%) as a yellow solid. LCMS (ES) m / z = 493.5 [M+H] +

[0231] Step 7: Synthesis of 5-({[7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-4-{[(2S)-2-(hydroxymethyl)piperidine-1-yl]methyl}-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrile (Example 46)

[0232] [ka]

[0233] To a stirred solution of 5-({[7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrile (7, 0.650 g, 1.32 mmol) and [(2S)-piperidine-2-yl]methanol (0.228 g, 1.98 mmol) in N,N-dimethylformamide (5 mL) and methanol (5 mL), acetic acid (0.396 g, 6.6 mmol) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at 70 °C for 6 hours. Sodium cyanoborohydride (0.249 g, 3.96 mmol) was added to this reaction mixture, and the mixture was stirred for a further 16 hours at the same temperature. The reaction was monitored by TLC, and after completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was further purified by reverse-phase preparative HPLC to obtain the title compound (20 mg, 33.8 μmol) (Example 46, 0.020 g, 2.56%) as a white solid. LCMS (ES) m / z = 592.35 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (dd, J = 14.4, 2.0 Hz, 2H), 8.41 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.38-7.34 (m, 2H), 7.30-7.24 (m, 3H), 7.18 (d, J = 6.8 Hz, 1H), 6.73 (s, 1H), 5.32-5.23 (m, 2H), 5.13 (s, 2H), 4.29 (bs,1H), 3.98 (d, J = 12.4 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.41 (bs, 1H), 3.14 (d, J = 12.0 Hz, 1H), 2.99-2.80 (m, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.52 (bs, 1H), 2.20 (bs, 4H), 1.98-1.86 (m, 3H), 1.66-1.60 (m, 2H), 1.39 (bs, 1H), 1.31 - 1.25 (m, 3H). HPLC: 95.58%.

[0234] The compounds listed in Table 5 (Table 6) below were prepared using the same procedure as described in Example 46, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in the table below (Table 6).

[0235] [Table 6A] [Table 6B]

[0236] (Example 49) Synthesis of 5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-N-(1-methylpiperidine-4-yl)-2,3-dihydro-1H-indene-4-carboxamide

[0237] [ka]

[0238] Reagents and conditions: 1. Sodium chlorite, sulfamic acid, THF:H2O, 5°C~RT, 30 minutes; 2. HATU, DIPEA, DMF, RT, 16 hours.

[0239] Step 1: Synthesis of 5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carboxylic acid (2)

[0240] [ka]

[0241] To a stirred solution of 5-({[4-formyl-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrile (1, 1 g, 2.11 mmol) in tetrahydrofuran (20 mL) and water (7 mL), sodium chlorite (0.572 g, 6.32 mmol) and sulfamic acid (0.614 g, 6.32 mmol) were added at 5°C. The reaction mixture was stirred at 5°C for 10 minutes, then stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The precipitate was collected by filtration to obtain the desired product (2, 0.850 g, 82%) as an off-white solid. LCMS (ES) m / z = 491.2 [M+H] +

[0242] Step 2: Synthesis of 5-[(5-cyanopyridine-3-yl)methoxy]-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-N-(1-methylpiperidine-4-yl)-2,3-dihydro-1H-indene-4-carboxamide (Example 49)

[0243] [ka]

[0244] A stirred solution of 5-[(5-cyanopyridine-3-yl)methoxy]-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-indene-4-carboxylic acid (2, 0.350 g, 0.713 mmol) and 4-azaniumyl-1-methylpiperidine-1-ium (0.166 g, 1.43 mmol) in N,N-dimethylformamide (17.5 mL) was prepared by adding hexafluoro-λ. 5 -Phosphanuid 1-[bis(dimethylamino)methylidene]-1H-1λ 5 -[1,2,3]triazolo[4,5-b]pyridine-3-ium-1-ylium-3-oleate (0.543 g, 1.43 mmol) and ethylbis(propan-2-yl)amine (0.32 mL, 1.78 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours and monitored by LC-MS. After the reaction was complete, the reaction mixture was quenched with ice-cold water (15 mL). The precipitate was collected by filtration to obtain the title compound (Example 49, 0.15 g, 35.83%) as a white solid. LCMS (ES) m / z = 587.35 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.37 (t, J = 2.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.47-7.44 (m, 3H), 7.39-7.36 (m, 1H), 7.33-7.30 (m, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 6.4 Hz, 1H), 6.81 (s, 1H), 5.25 (s, 2H), 5.21 (s, 2H), 3.69-3.62 (m, 1H), 2.81 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.2 Hz, 2H), 2.69-2.66 (m, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 2.01-1.89 (m, 4H), 1.68 (d, J = 12 Hz, 2H), 1.46-1.37 (m, 2H). HPLC: 99.04%.

[0245] The compounds listed in Table 6 (Table 7) below were prepared using the same procedure as described in Example 49, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in Table 7 below.

[0246] [Table 7A] [Table 7B]

[0247] (Example 52) Synthesis of N-((1-((5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-yl)methyl)acetamide

[0248] [ka]

[0249] Reagents and conditions: 1. Et3N, DCM, 0°C to RT, 12h; 2. 4N HCl in dioxane, RT, 16h; 3. DMF:MeOH, AcOH, NaBH3CN, 70°C, 16h.

[0250] Step 1: Synthesis of tert-butyl 2-(acetamidomethyl)pyrrolidine-1-carboxylate (2)

[0251] [ka]

[0252] To a stirred solution of tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (1, 0.5 g, 2.5 mmol) in dichloromethane (10 mL), triethylamine (0.69 mL, 4.99 mmol) and acetic anhydride (0.382 mg, 0.374 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The crude product was quenched with ice-cold water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate in hexane to obtain the desired product (2, 0.58 g, 95.8% yield) as a colorless oil. LCMS (ES) m / z = 243.2 [M+H] +

[0253] Step 2: Synthesis of N-(pyrrolidine-2-ylmethyl)acetamide (3)

[0254] [ka]

[0255] A solution of tert-butyl 2-(acetamidomethyl)pyrrolidine-1-carboxylate (2, 0.58 g, 2.39 mmol) in 4N hydrochloric acid (15 mL) in dioxane was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure to obtain the desired product (3, 0.32 g, 94.02% yield) as a colorless oil. LCMS (ES) m / z = 143.1 [M+H] +

[0256] Step 3: Synthesis of N-((1-((5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-yl)methyl)acetamide (Example 52)

[0257] [ka]

[0258] To a stirred solution of 5-({[4-formyl-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrile (0.5 g, 1.05 mmol) and N-[(pyrrolidine-2-yl)methyl]acetamide (3, 0.225 g, 1.58 mmol) in N,N-dimethylformamide (5 mL) and methanol (5 mL), acetic acid (0.18 mL, 3.16 mmol) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at 70 °C for 6 hours. Sodium borocyanohydride (199 mg, 3.16 mmol) was added to the reaction mixture, and the mixture was stirred for a further 16 hours at the same temperature. After monitoring by TLC and confirming completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol (3 × 15 mL) in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired compound. The compound was further purified by reverse-phase preparative HPLC to obtain the title product (41 mg, 68.2 μmol) (Example 52, 0.041 g, 6.48%) as a white solid. LCMS (ES) m / z = 601.40 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J = 2.0 Hz, 2H), 8.42 (s, 1H), 7.49-7.43 (m, 4H), 7.40-7.36 (m, 1H), 7.33-7.31 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 5.32-5.23 (m, 2H), 5.14 (s, 2H), 3.78 (d, J = 12.4 Hz, 1H), 3.35-3.29 (m, 2H), 2.97-2.81 (m, 3H), 2.80-2.68 (m, 4H), 2.21 (s, 3H), 2.20-2.12 (m, 1H), 2.03-1.94 (m, 2H), 1.76 (s, 4H), 1.60-1.40 (m, 3H). HPLC purity 87.59%.

[0259] (Example 53) Synthesis of 5-(((4-((2-(aminomethyl)pyrrolidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile

[0260] [ka]

[0261] Reagents and conditions: 1. HCl in dioxane, RT, 12h; 2. TEA, AcOH, NaBH3CN DMF:MeOH, 70℃, 16h; 3. PPh3, THF, H2O, RT, 12h.

[0262] Step 1: Synthesis of 2-(azidomethyl)pyrrolidine hydrochloride (2)

[0263] [ka]

[0264] To a stirred solution of tert-butyl 2-(azidomethyl)pyrrolidine-1-carboxylate (1, 1.5 g, 6.63 mmol) in dioxane (10 mL), a 12 M hydrochloric acid solution in dioxane was added at 0°C, and the reaction mixture was stirred at room temperature for a further 12 hours. The solvent was removed under reduced pressure to obtain the desired product (2, 0.7 g, crude product) as a hydrochloride salt. The crude material was used directly in the next step.

[0265] Step 2: Synthesis of 5-{[(4-{[2-(azidomethyl)pyrrolidine-1-yl]methyl}7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyridine-3-carbonitrile (3)

[0266] [ka]

[0267] To a stirred solution of 5-({[4-formyl-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitrilate (0.7 g, 1.48 mmol) and 2-(azidomethyl)pyrrolidine hydrochloride (2, 0.36 g, 2.21 mmol) in N,N-dimethylformamide (10 mL) and methanol (10 mL), triethylamine (0.62 mL, 4.43 mmol) and acetic acid (0.42 mL, 7.38 mmol) were added under a nitrogen atmosphere at room temperature, and the reaction mixture was stirred at 70°C for 6 hours. Sodium cyanoborohydride (0.278 g, 4.43 mmol) was added to the reaction mixture, and the mixture was stirred further at the same temperature for 16 hours. The reaction was monitored by TLC, and after completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the desired product (3, 0.45 g, 52.17%) as a brown solid. LCMS (ES): m / z = 585.5 [M+H] + .

[0268] Step 3: Synthesis of 5-(((4-((2-(aminomethyl)pyrrolidine-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 53)

[0269] [ka]

[0270] To a stirred solution of 5-{[(4-{[2-(azidomethyl)pyrrolidine-1-yl]methyl}-7-({2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyridine-3-carbonitrile (3, 0.450 g, 0.77 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL), triphenylphosphine (0.428 g, 1.54 mmol) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 12 hours. After monitoring by TLC and confirming completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine solution, dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound (Example 53, 0.25 g, 58.14%) as a white solid. LCMS (ES) m / z = 559.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.98-8.97 (m, 2H), 8.41 (d, J = 2 Hz, 1H), 8.36 (s, 1H), 7.47-7.36 (m, 4H), 7.33-7.31 (m, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 6.74 (s, 1H), 5.33-5.25 (m, 2H), 5.13 (s, 2H), 3.75 (d, J = 12 Hz, 1H), 3.35 (d, J = 12 Hz, 2H), 2.94-2.86 (m, 3H), 2.76-2.59 (m, 6H), 2.25-1.98 (m, 4H), 2.01-1.92 (m, 2H), 1.89-1.80 (m, 1H), 1.63-1.50 (m, 3H). HPLC: 97.71%.

[0271] (Example 54) 5-(((7-((3-bromo-2-methylbenzyl)oxy)-4-((2-(hydroxymethyl)azetidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile and

[0272] (Example 55) Synthesis of 5-(((7-((4'-hydroxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-((2-(hydroxymethyl)azetidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile

[0273] [ka]

[0274] Reagents and conditions: 1. POBr3, DCM, 0°C, 2h; 2. K2CO3, ACN, RT, 16h; 3. K2CO3, DMF, RT, 6h; 4. Na(CN)BH3, DMF, MeOH, 70°C, 16h; 5. K2CO3, PdCl2(PPh3)2, dioxane:H2O, 90°C, 16h.

[0275] Step 1: Synthesis of 1-bromo-3-(bromomethyl)-2-methylbenzene (2)

[0276] [ka]

[0277] To a stirred solution of (3-bromo-2-methylphenyl)methanol (1, 10 g, 49.7 mmol) in dichloromethane (60 mL), tribromophosphan (21.4 g, 74.8 mmol) was added under a nitrogen atmosphere at 0°C. The resulting solution was stirred for a further 2 hours. The reaction mixture was quenched with aqueous sodium bicarbonate solution (200 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain the desired product (2, 7.91 g, 61% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, J = 8 Hz, 1H), 7.44 (t, J = 7.6 Hz, 3H), 7.12 (t, J = 8 Hz, 1H), 4.88 (s, 2H), 2.41 (s, 3H).

[0278] Step 2: Synthesis of 7-((3-bromo-2-methylbenzyl)oxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (3)

[0279] [ka]

[0280] To a stirred solution of 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (4.2 g, 23.6 mmol) in acetonitrile (150 mL), potassium carbonate (6.51 g, 47.2 mmol) and 1-bromo-3-(bromomethyl)-2-methylbenzene (2, 6.18 g, 23.6 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After monitoring by TLC and confirming completion of the reaction, the reaction mixture was diluted with water (30 mL), the solid suspension was filtered, and dried under reduced pressure to obtain the desired product (3, 6.0 g, 71%) as a brownish solid. LCMS (ES) m / z = 361.26 [M+H] + .

[0281] Step 3: Synthesis of 5-(((7-((3-bromo-2-methylbenzyl)oxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (4)

[0282] [ka]

[0283] To a stirred solution of 7-((3-bromo-2-methylbenzyl)oxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (3, 3.8 g, 10.0 mmol) in N,N-dimethylformamide (60 mL), potassium carbonate (2.76 g, 20 mmol) and (5-cyanopyridine-3-yl)methylmethanesulfonate (2.68 g, 12.02 mmol) were added at room temperature. The reactants were stirred for a further 6 hours at the same temperature. After completion, the reaction mixture was diluted with water (20 mL), and a solid suspension appeared. This solid was filtered and dried under reduced pressure to obtain the desired product (4, 4.5 g, 90%) as a gray solid. LCMS (ES) m / z = 477 [M+H] + .

[0284] Step 4: Synthesis of 5-(((7-((3-bromo-2-methylbenzyl)oxy)-4-((2-(hydroxymethyl)azetidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 54)

[0285] [ka]

[0286] To a stirred solution of 5-({[7-({4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl}methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl]oxy}methyl)pyridine-3-carbonitride (4,3 g, 5.48 mmol) and (azetidine-2-yl)methanol (1.9 g, 13.7 mmol) in N,N-dimethylformamide (45 mL) and methanol (36 mL), acetic acid (0.2 mL) was added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred at 70 °C for 1 hour. Sodium borocyanohydride (1.03 g, 16.4 mmol) was added to the reaction mixture in small amounts, and the mixture was stirred for a further 6 hours at the same temperature. After monitoring by TLC and confirming completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by neutral alumina column chromatography using 10% methanol in dichloromethane as the eluent to obtain the title compound (Example 54, 1.7 g, 56%) as a light brown semi-solid. LCMS (ES) m / z = 548.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.00-8.98 (m, 2H), 8.49 (s, 1H), 7.58 (d, J = 8 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.70 (s, 1H), 5.28-5.13 (m, 2H), 5.13 (s, 2H), 4.23 (bs, 1H), 3.57 (d, J = 9.6 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H), 3.23-3.13 (m, 3H), 3.07-3.00 (m, 1H), 2.95-2.85 (m, 2H), 2.82-2.70 (m, 3H), 2.38 (s, 3H), 2.00-1.91 (m, 2H), 1.90-1.80 (m, 1H), 1.79-1.70 (m, 1H). HPLC: 95.33%.

[0287] Step 5: Synthesis of 5-(((7-((4'-hydroxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-((2-(hydroxymethyl)azetidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 55)

[0288] [ka]

[0289] To a stirred solution of 5-(((7-((3-bromo-2-methylbenzyl)oxy)-4-((2-(hydroxymethyl)azetidine-1-yl)methyl)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Example 54, 0.2 g, 0.36 mmol) in 1,4-dioxane:water (6:1, 12 mL), 4-hydroxybenzeneboronic acid (0.060 g, 0.43 mmol) was added, and the reaction mixture was purged with argon for 10 minutes. Potassium carbonate (0.151 g, 1.09 mmol) and PdCl2(PPh3)2 (0.025 g, 0.36 mmol) were added sequentially. The reaction mixture was sealed and stirred at 90°C for 16 hours. After completion, the reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash column chromatography [neutral Al2O3, gradient of 2% to 3% methanol in dichloromethane] to obtain the title compound (Example 55, 0.021 g, 9%) as a gray solid. LCMS (ES) m / z = 562.37 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (s, 2H), 9.49 (bs, 1H), 8.51 (s, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.10-7.14 (m, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.73 (s, 1H), 5.27 (dd, J = 12.8, 8.4 Hz, 2H), 5.12 (s, 2H), 4.24 (bs, 1H), 3.62-3.52 (m, 1H), 3.50-3.40 (m 1H), 3.23-3.13 (m, 3H), 3.05-3.00 (m, 1H), 2.92-2.83 (m, 2H), 2.80-2.78 (m, 1H), 2.74 (t, J = 7.2 Hz, 2H), 2.20 (s, 3H), 2.00-1.92 (m, 2H), 1.89-1.80 (m, 1H), 1.77-1.70 (m, 1H). HPLC: 96.63%.

[0290] The compounds listed in Table 7 (Table 8) below were prepared using the same procedure as described in Example 55, with appropriate changes to the reactants, reagent amounts, protection and deprotection, solvent, and reaction conditions. The compound characterization data is summarized in Table 8 below.

[0291] [Table 8A] [Table 8B] [Table 8C] [Table 8D] [Table 8E] [Table 8F] [Table 8G] [Table 8H] [Table 8I] [Table 8J] [Table 8K] [Table 8L]

[0292] (Example 78) Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-phenoxy-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol

[0293] [ka]

[0294] Reagents and conditions: 1. K2CO3, ACN, 60°C, 16h; 2. NaCNBH3, DMF, MeOH, 70°C, 16h.

[0295] Step 1: Synthesis of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-phenoxy-2,3-dihydro-1H-inden-4-carbaldehyde (2)

[0296] [ka]

[0297] To a stirred solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (1, 1.0 g, 2.79 mmol) in acetonitrile (10 mL), potassium carbonate (1.15 g, 8.37 mmol) and diphenyliodonium triflate (1.8 g, 4.18 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated, the residue was diluted with water (10 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to obtain the desired product (2, 0.52 g, 46%) as a brownish solid. LCMS (ES) m / z = 435.2 [M+H] + .

[0298] Step 2: Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-phenoxy-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol (Example 78)

[0299] [ka]

[0300] To a stirred solution of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-phenoxy-2,3-dihydro-1H-indene-4-carbaldehyde (2, 0.5 g, 1.16 mmol) and azetidine-2-ylmethanol (0.212 g, 1.74 mmol) in dimethylformamide (7 mL) and methanol (7 mL), acetic acid (0.348 g, 5.80 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 6 hours, and sodium borohydride cyanohydride (0.218 g, 3.48 mmol) was added. The reaction mixture was stirred at the same temperature for a further 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product obtained was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as the eluent to obtain the title compound (Example 78, 0.013 g, 2.23%) as an off-white solid. LCMS (ES) m / z = 506.38 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.48-7.42 (m, 2H), 7.40-7.36 (m, 2H), 7.36-7.27 (m, 4H), 7.24 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.55 (s, 1H), 5.04 (s, 2H), 4.24 (bs, 1H), 3.47 (d, J = 12 Hz, 1H), 3.38-3.30 (m, 1H), 3.28-3.20 (m, 2H), 3.15-3.08 (m, 1H), 3.06-2.98 (m, 2H), 2.95-2.88 (m, 1H), 2.81 (d, J = 7.2 Hz, 2H), 2.74-2.69 (m, 1H), 2.13 (s, 3H), 2.07-1.95 (m, 2H), 1.87-1.78 (m, 1H), 1.72-1.65 (m, 1H). HPLC: 98.6%.

[0301] (Example 79) Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrazine-2-ylmethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol

[0302] [ka]

[0303] Reagents and conditions: 1. Ms-Cl, DCM; 2. K2CO3, DMF; 3. NaCNBH3, DMF, MeOH.

[0304] Step 1: Synthesis of pyrazine-2-ylmethylmethanesulfonate (2)

[0305] [ka]

[0306] To a solution of (pyrimidine-5-yl)methanol (0.1 g, 0.908 mmol) in dichloromethane (4 mL), triethylamine (0.28 g, 2.72 mmol) was added and the mixture was stirred for 10 minutes. Then, methanesulfonyl chloride (0.171 mL, 1.82 mmol) was added at 0°C. The progress of the reaction was monitored by LC-MS and TLC. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (50 mL). The organic layer was concentrated to obtain the desired product (2 g, 0.120 g, crude product) as a brownish semi-solid, which was used in the next step without further purification.

[0307] Step 2: Synthesis of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrazine-2-ylmethoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (3)

[0308] [ka]

[0309] To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.14 g, 3.91 mmol) in N,N-dimethylformamide (20 mL), potassium carbonate (0.162 g, 1.17 mmol) and pyrazine-2-ylmethylmethanesulfonate (2, 0.120 g, 0.446 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column chromatography to obtain the desired product (3, 0.150 g, 86% yield) as a brown solid. LCMS (ES) m / z = 451.3 [M+H] + . Step 3: Synthesis of (1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrazine-2-ylmethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)azetidine-2-yl)methanol (Example 79)

[0310] [ka]

[0311] To a solution of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(pyrazine-2-ylmethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.14 g, 0.311 mmol) and azetidine-2-yl methanol (0.027 g, 0.311 mmol) in N,N-dimethylformamide (7 mL) and methanol (7 mL), acetic acid (0.1 mL) was added at room temperature. The reaction mixture was stirred at 70 °C for 6 hours, and sodium borohydride (0.058 g, 0.93 mmol) was added. The reaction mixture was stirred at the same temperature for a further 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol (2 × 50 mL) in dichloromethane. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to obtain the title compound (Example 79, 0.025 g, 15% yield) as an off-white solid. LCMS (ES) m / z = 522.35 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (s, 1H), 8.70-8.60 (m, 2H), 8.50-7.40 (m, 3H), 7.39-7.34 (m, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 5.28 (s, 2H), 5.14 (s, 2H), 4.20 (bs, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.49 (d, J = 12.0 Hz, 1H), 3.25-3.35 (m, 3H), 3.10-3.00 (m, 1H), 2.98-2.80 (m, 3H), 2.75 (t, J = 7.6 Hz, 2H), 2.21 (s, 3H), 2.00-1.92 (m, 2H), 1.90-1.80 (m, 1H), 1.75-1.67 (m, 1H). HPLC: 90.55%.

[0312] (Example 80) Synthesis of 1-((1-((5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-yl)methyl)-3-methylurea formate

[0313] [ka]

[0314] Reagents and conditions: 1. TEA, DCM, 0°C, 6h; 2. 2N HCl in dioxane, RT, 12h; 3. TEA, AcOH, NaBH3CN, DMF, MEOH, 70°C, 16h.

[0315] Step 1: Preparation of tert-butyl 2-((3-methylureido)methyl)pyrrolidine-1-carboxylate (2)

[0316] [ka]

[0317] To a stirred solution of tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (1, 2 g, 10 mmol) in dichloromethane (20 mL), triethylamine (2.02 g, 20 mmol) and methylcarbamic chloride (1.12 g, 12 mmol) were added at 0°C. The resulting reaction mixture was stirred at the same temperature for a further 6 hours. After monitoring by TLC and confirming completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the desired product (2, 2.1 g, 81% yield) as a wine-colored oil. LCMS (ES) m / z = 258.3 [M+H] +

[0318] Step 2: Preparation of 1-methyl-3-(pyrrolidine-2-ylmethyl)urea hydrochloride (3)

[0319] [ka]

[0320] A solution of tert-butyl 2-((3-methylureido)methyl)pyrrolidine-1-carboxylate (2, 1 g, 3.8 mmol) in 2N hydrochloric acid solution (10 mL) in dioxane was stirred at room temperature for 12 hours. After monitoring by TLC and confirming the completion of the reaction, the reaction mixture was distilled under vacuum to obtain the desired product (3, 0.6 g, 80% yield) as a white solid. LCMS (ES) m / z = 158.1 [M+H] +

[0321] Step 3: Preparation of 1-((1-((5-((5-cyanopyridine-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-yl)methyl)-3-methylurea formate (Example 80)

[0322] [ka]

[0323] To a stirred solution of 5-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (0.4 g, 0.83 mmol) and 1-methyl-3-(pyrrolidine-2-ylmethyl)urea hydrochloride (3, 0.244 g, 1.26 mmol) in dimethylformamide (7 mL) and methanol (7 mL), triethylamine (0.34 g, 3.37 mmol) and acetic acid (0.253 g, 4.21 mmol) were added under a nitrogen atmosphere at room temperature, and the reaction mixture was stirred at 70 °C for 6 hours. Sodium cyanoborohydride (0.159 g, 2.53 mmol) was added to the reaction mixture, and the mixture was stirred further at the same temperature for 16 hours. The reaction was monitored by TLC, and after completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% methanol in dichloromethane (3 × 15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography using 10% methanol in dichloromethane, followed by preparative HPLC, to obtain the title compound as a white solid. LCMS (ES) m / z = 616.34 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz): δ 8.98 (d, J = 1.6 Hz, 2H), 8.42 (bs, 1H), 8.14 (s, 1H), 7.49-7.42 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.76 (s, 1H), 5.92 (bs, 1H), 5.59 (bs, 1H), 5.30-5.20 (m, 2H), 5.15 (s, 2H), 3.83 (bs, 1H), 3.24 (bs, 1H), 3.00-2.80 (m, 3H), 2.80-2.70 (m, 3H), 2.45 (s, 3H), 2.21 (s, 3H), 2.22-1.93 (m, 3H), 1.83-1.75 (m, 1H), 1.63-1.35 (m, 3H). The 2H peak is merged with the DMSO residual peak. HPLC: 95.32%.

[0324] Biological evaluation and determination of metabolic stability PD-L1 Enzyme Assay: Homogeneous Time-Resolved Fluorescence (HTRF) Conjugation Assay All binding studies were performed using the CisBio PD-1 / PD-L1 Binding Assay Kit (catalog # 63ADK000CPAPEG) according to the manufacturer's protocol. The interaction between Tag1-PD-1 and Tag2-PD-1 was found to be anti-Tag1-Eu 3+Detection was performed using PD-1 (HTRF donor) and anti-Tag2-XL665 (HTRF acceptor). When the donor antibody and acceptor antibody are in close proximity due to the binding of PD-1 and PD-L1, excitation of the donor antibody induces fluorescence resonance energy transfer (FRET) toward the acceptor antibody, resulting in specific emission at 665 nm. This specific signal is directly proportional to the PD-1 / PD-L1 interaction. Compounds that interfere with the PD-1 / PD-L1 interaction cause a reduction in the HTRF signal. The necessary reagents were mixed in the following order: 2 μL of compound (or dilution buffer), 4 μL of PD-L1 protein, 4 μL of PD-1 protein. After incubation for 15 minutes, 5 μL of anti-Tag1-Eu 3+ 5 μL of anti-Tag2-XL665 was added. The plate was sealed and incubated at room temperature for 1 hour. Fluorescence emission at two different wavelengths (665 nm and 620 nm) was read using a BMG PheraStar® multi-plate reader. The HTRF ratio was calculated from the 665 nm and 620 nm fluorescence signals as follows: HTRF ratio = (665 nm / 620 nm) × 10⁻⁶ 4 This was expressed in [the document].

[0325] Metabolic stability in liver microsomes The objective of this experiment is to measure the metabolic half-life of NCE in cellular component fractions, e.g., human liver microsomes (HLMs) or mouse liver microsomes (MLMs). This provides an in vitro means to calculate intrinsic hepatic clearance and support predictions of human pharmacokinetics. This approach has been successfully utilized in the early phases of drug discovery planning to reduce metabolic instability and provide SAR input for predicting in vivo hepatic clearance.

[0326] Procedure: Potassium phosphate buffer (66.7 mM, pH 7.4) containing liver microsomes (mouse and human) (1.0 mg / mL) was separately pre-incubated in a 37°C water bath for 5 minutes with the compound (1 μM) and a positive control (verapamil, 1 μM). The reaction was initiated by adding 20 μL of 10 mM NADPH. To exclude non-NADPH metabolism or chemical instability in the incubation buffer, NADPH-free reactions (0 and 30 minutes) were also incubated. All reactions were terminated at 0, 5, 15, and 30 minutes using 200 μL of ice-cold acetonitrile containing an internal standard. The containers were centrifuged at 3000 rpm for 15 minutes. The supernatant thus obtained was analyzed by LC-MS / MS to monitor the disappearance of the test compound.

[0327] Details of animal experiments The Institutional Animal Ethical Committee (IAEC) of Jubilant Biosys, designated by the CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) (IAEC / JDC / 2019 / 188R (for mice) and IAEC / JDC / 2019 / 189R (for rats)), approved the pharmacokinetic experiments in mice and rats. Male Balb / c mice (approximately 6-8 weeks old, with a body weight in the range of 22-25 g) and male SD rats (6-8 weeks old, with a body weight in the range of 200-250 g) were produced by Vivo Biotech (Hyderabad, India). The animals were isolated in Jubilant Biosys' Animal House for a period of 7 days in a 12:12h light-dark cycle, and were classified according to body weight prior to the study.

[0328] Housing: The animals were housed in groups in standard polycarbonate cages with a stainless steel top grill, containing pellet feed and water bottles. Corn cobs were used as bedding material, replaced at least twice a week, or as needed.

[0329] Optional diet: Rodent feed manufactured by Altromin Spezialfutter GmbH & Co. KG. (ImSeelenkamp20. D-32791 Lage) was provided.

[0330] Voluntary water: Purified water was provided to the animals voluntarily in polycarbonate bottles with stainless steel sipper tubes.

[0331] Pharmacokinetic research Procedure for mice: For the IV route, intravenous pharmacokinetic studies were performed at doses of 5 mg / kg and 10 mg / kg, each at a dose volume of 5 mL / kg. Sparse sampling was performed, and at each time point, three mice were used for blood sampling (approximately 100 μL), collected from the retro-orbital plexus at 0.083 (for IV only) and 24 h. For plasma separation, the samples were collected in tubes containing K2 EDTA as an anticoagulant and centrifuged in a refrigerated centrifuge (Biofuge, Heraeus, Germany) at 10,000 rpm for 5 minutes. The blood samples were maintained at 4°C. Group I (IV) received the compound intravenously via the tail vein at a dose of 2 mg / kg in the solution formulation. Blood concentration-time data of the compound were analyzed using the non-compartment method with Phoenix WinNonlin Version 8.1.

[0332] Brain exposure studies in mice Mice were placed in an isoflurane anesthesia chamber, and after achieving complete anesthesia (3-5% isoflurane), blood samples (0.5 mL) were collected from the posterior orbital plexus using a mouse capillary.

[0333] Mice were killed by cervical dislocation. Using a bone cutter, the dorsal surface of the skull was detached from the brain, and using forceps, the dura mater material was gently removed from the brain surface. The brain was gently removed from the head and placed in PBS buffer to remove blood. The brain was placed on absorbent paper to remove blood stains and transferred to a pre-labeled tube. The isolated brain was weighed and homogenized using 5 times the volume of phosphate-buffered saline (pH 7.4). During homogenization, the brain homogenates were kept on ice until processing the samples. The homogenates were processed by specific extraction procedures and analyzed by LC-MS / MS.

[0334] Evaluation of biological activity and metabolic stability: Table 8 (Table 9) below shows the biological activity of the compounds of the present invention in PD1 / PD-L1 inhibition assays. 50 Compounds with a concentration of <100nM are designated as "A", those with a concentration of 100-500nM are designated as "B", and those with a concentration of >500nM are designated as "C".

[0335] [Table 9A] [Table 9B]

[0336] Evaluation of brain exposure data via pathway IV

[0337] [Table 10]

[0338] The compounds mentioned above have the potential to be developed as drugs to treat cancer and other diseases or conditions related to PD1 / PD-L1 activation by reducing PD1 / PD-L1 activity.

Claims

【Request Item 1】 【Table 1A】 Table 1B 【Table 1C】 【Table 1D】 Table 1E Table 1F Compounds selected from, or their stereoisomers, their N-oxides, or pharmaceutically acceptable salts.

2. The compound according to claim 1, stereoisomers thereof, N-oxides thereof, or pharmaceutically acceptable salts thereof, wherein the compound acts as an inhibitor of PD1 / PD-L1 interaction.

3. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, in optionally one or more other pharmaceutical compositions.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or the pharmaceutical composition according to claim 3 for the treatment and / or prevention of a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer.

5. A compound according to claim 1 or a pharmaceutical composition according to claim 3, for use in the manufacture of a pharmaceutical for inhibiting PD-1 / PD-L1 interaction in cells.

6. A compound according to claim 1 or a pharmaceutical composition according to claim 3 for use in treating and / or preventing a PD-1 / PD-L1 interaction-mediated condition, proliferative disorder, or cancer, comprising the step of administering to a subject suffering from a PD-1 / PD-L1-mediated condition, proliferative disorder, or cancer.

7. A pharmaceutical composition comprising, together with other clinically relevant cytotoxic or non-cytotoxic agents, a therapeutically effective amount of the compound according to claim 1 or the pharmaceutical composition according to claim 3 for the treatment or prevention of disease, proliferative disorders, or cancer.

8. A pharmaceutical product for the treatment or prevention of various diseases, proliferative disorders, or cancer, comprising the compound according to claim 1 or the pharmaceutical composition according to claim 3, administered together with other clinically relevant cytotoxic or non-cytotoxic agents.

9. A compound according to claim 1 or a pharmaceutical composition according to claim 3, used in combination with other clinically relevant cytotoxic or non-cytotoxic agents, for the treatment of cancer.

10. A compound according to claim 1 or a pharmaceutical composition according to claim 3 for the treatment of cancer, used in combination with other clinically relevant immunomodulators.

11. Conditions or proliferative disorders or cancers mediated by PD-1 / PD-L1 include metastatic cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, neuroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, pancreaticoblastoma, pleuropulmonary blastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumors, renal cell carcinoma, lymphoma, and bone marrow cancer. A compound or pharmaceutical composition according to claim 10, selected from disease categories including tumors, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), metastatic cancer, myeloproliferative neoplasm (MPN), polycythemia vera (PV), essential thrombocythemia, essential thrombocytosis (ET), and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancers caused by mutations in specific oncogenes, EGFR, KRAS, or RET.

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