Novel chroman derivatives having estrogen receptor degradation activity and uses thereof

Abstract

To provide novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions.SOLUTION: Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 947,213, filed on December 12, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] Field of the Disclosure The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of diseases and conditions, such as cancer.

Background Art

[0003] Background of the Disclosure Estrogen is a female hormone that regulates a wide range of physiological processes (e.g., development of the female reproductive system, maintenance of bone mass, and protection of cardiovascular and central nervous tissues) by binding to its cognate estrogen receptors ERα and ERβ. When estrogen binds to an estrogen receptor ("ER"), the receptor undergoes a conformational change and dimerizes. The ER homodimer then binds to estrogen response elements ("ERE") present within the promoters of a specific set of target genes and cooperates with transcriptional co - regulatory factors to control the expression of the target genes. Thousands of putative ER target genes have been identified, many of which regulate cell proliferation and survival.

[0004] Since ER signaling is involved in many pathways, it is well known that uncontrolled cell proliferation and ultimately cancer can occur when the regulation of ER signaling, particularly via ERα, is disrupted. ER + breast cancer accounts for approximately 75% of all diagnosed breast cancers, and some ovarian and endometrial cancers are also similar. Investigations have been carried out over several decades due to the prevalence of ER + cancers, and anti - estrogens have been developed as therapeutic agents.

[0005] Anti-estrogen (i.e., hormonal) therapy is the first choice for the treatment of most ER+ breast cancers. There are three main classes of anti-estrogen therapeutic agents, including aromatase inhibitors (e.g., letrozole and anastrozole); selective estrogen modulators (e.g., tamoxifen, toremifene, and raloxifene); and selective estrogen receptor degraders (e.g., fulvestrant). These classes of anti-estrogen therapeutic agents act through different mechanisms of action, such as inhibition of the aromatase enzyme, competition for binding to ERα, and / or degradation of ERα.

[0006] The aforementioned treatments can cause adverse effects. For example, administration of an aromatase inhibitor can reduce bone density, thereby increasing the risk of fracture. Administration of a selective estrogen modulator can cause the development of endometrial cancer and / or cardiovascular tissue (e.g., deep vein thrombosis and pulmonary embolism). Furthermore, the aforementioned treatments may have insufficient clinical efficacy.

[0007] Therefore, there is a need to treat ER+ cancer without causing the known adverse side effects of current treatments. One approach to achieving this ultimate goal may be to utilize the naturally occurring ubiquitin-mediated degradation of cells. Without being bound by any theory, it is thought that ERα degradation can occur when both ERα and a ubiquitin ligase bind and are in proximity.

[0008] Cereblon ("CRBN") E3 ubiquitin ligase is an ubiquitin ligase in which CRBN forms an E3 ubiquitin ligase complex together with damaged DNA binding protein 1 and Cullin 4. Cereblon E3 ubiquitin ligase functions as a substrate receptor by bringing substrates into proximity for ubiquitination and subsequent degradation by the proteasome. Recently, it has been discovered that small molecule drugs, such as thalidomide and its close analogs lenalidomide and pomalidomide, can interact simultaneously with CRBN and several other proteins. By doing so, CRBN can be utilized for the proteolysis of target proteins such as IKZF1 and IKZF3. This is thought to explain the anti-myeloma effect of thalidomide and related compounds. Summary of the Invention Means for Solving the Problems

[0009] Summary of the Disclosure In some embodiments, a compound of formula (I):

Chemical formula

[0010] In some embodiments, the compounds of formula (I) can include both cis and trans isomers. In some embodiments, the compounds of formula (I) can be a mixture of cis and trans isomers. In some embodiments, the compounds of formula (I) can be the cis isomer.

[0011] In some embodiments, the compounds of formula (I) can include both stereoisomers and mixtures of stereoisomers. In some embodiments, the compounds of formula (I) are stereoisomers. In some embodiments, the compounds of formula (I) can include both racemic and enantiomeric isomers.

[0012] In some embodiments, the compounds of formula (I) * :

Chemical Structure

[0013] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

Brief Description of the Drawings

[0014] Brief Description of the Drawings The foregoing summary and the following detailed description of the present disclosure will be better understood when read in conjunction with the accompanying drawings. For purposes of illustration of the present disclosure, the accompanying drawings illustrate some, but not all, alternative embodiments. It should be understood, however, that the disclosure is not strictly limited to the arrangements and means shown. These figures, which are incorporated into the specification and form a part thereof, assist in explaining the principles of the present disclosure.

[0015]

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Mode for Carrying Out the Invention

[0022] Detailed Description Definition As used herein, "cancer" refers to diseases, disorders, and conditions involving abnormal cell growth that have the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0023] "Subject" refers to an animal, e.g., a mammal, that is or will be the subject of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

[0024] As used herein, "treatment" or "treating" refers to amelioration of a disease or disorder or at least one distinguishable symptom thereof. In another embodiment, "treatment" or "treating" refers to amelioration of at least one measurable physical parameter that may not necessarily be distinguishable by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibition of the progression of a disease or disorder, either physically (e.g., stabilization of a distinguishable symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder. For example, treatment of a cholesterol disorder may include a reduction in blood cholesterol levels.

[0025] As used herein, "prevention" or "preventing" refers to a reduction in the risk of acquiring a given disease or disorder.

[0026] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CN is attached via a carbon atom.

[0027] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl" as defined below. One of ordinary skill in the art will understand that for a group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically unrealistic, synthetically infeasible, and / or inherently unstable.

[0028] When a range of values is recited, it is intended to include each value and subrange within the range. For example, "C 1 ~C 6 alkyl" includes C 1, C 2 , C 3 , C 4 , C 5 , C 6 , C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 is intended to include alkyl.

[0029] As used herein, the term "acyl" refers to an R-C(O)- group (including, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, etc.), where the aforementioned groups are attached to the parent molecular structure via the carbonyl functionality. In some embodiments, acyl is C 1~10 an acyl moiety, which refers to, for example, the total number of chain or ring atoms of an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety and the carbonyl carbon of the acyl. For example, C 4 -acyl has three other ring or chain atoms and the carbonyl.

[0030] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond, such as (C 2 ~C 8)Refers to a straight-chain or branched-chain group of 2 to 8 carbon atoms called alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-buten)-pentenyl.

[0031] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon, e.g., herein (C 1 ~C 8 )Refers to a straight-chain or branched-chain group of 1 to 8 carbon atoms called alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, "alkyl" is a straight-chain hydrocarbon. In some embodiments, "alkyl" is a branched-chain hydrocarbon.

[0032] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon triple bond, e.g., herein (C 2 ~C 8 )Refers to a straight-chain or branched-chain group of 2 to 8 carbon atoms called alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0033] As used herein, the term "aryl" refers to a monocyclic, bicyclic or other polycyclic aromatic ring system of carbon having 5 to 14 ring atoms. An aryl group may be optionally fused to one or more rings selected from aryl, cycloalkyl, heteroaryl and heterocyclyl. The aryl groups of the present disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl and benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups include, but are not limited to, a monocyclic aromatic ring system containing 6 carbon atoms, referred to herein as "C 6 -aryl".

[0034] As used herein, the term "cyano" refers to -CN.

[0035] As used herein, the term "cycloalkyl" refers to 3 to 16 carbons or 3 to 8 carbons (referred to herein as "(C 3 ~C 8Refers to a saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group (referred to as "cycloalkyl"). Exemplary cycloalkyls include, but are not limited to, cyclohexane, cyclohexene, cyclopentane and cyclopentene. The cycloalkyl group may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. The cycloalkyl group may be fused to another cycloalkyl group (saturated or partially unsaturated), aryl group or heterocyclyl group to form a bicyclic, tetracyclic, etc. The term "cycloalkyl" also includes bridged ring structures and spiro fused ring structures (which may or may not contain heteroatoms).

[0036] As used herein, the term "halo" or "halogen" refers to -F, -Cl, -Br and / or -I.

[0037] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or other polycyclic aromatic ring system containing one or more heteroatoms, such as 1 to 4 heteroatoms, such as nitrogen, oxygen and sulfur. Heteroaryl may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryl may also be fused to a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, herein referred to as "(C 2 ~C 5 )heteroaryl", a monocyclic aromatic ring in which the ring contains 2 to 5 carbon atoms and 1 to 3 heteroatoms.

[0038] As used herein, the terms "heterocyclic", "heterocyclyl" or "heterocyclic ring" each refer to a saturated or unsaturated 3- to 18-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. The heterocyclic ring can be aromatic (heteroaryl) or non-aromatic. The heterocyclic ring may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Examples of the heterocyclic ring also include bicyclic groups, tricyclic groups and tetracyclic groups in which any of the above heterocyclic rings is condensed with 1 or 2 rings independently selected from aryl, cycloalkyl and heterocyclic rings. Exemplary heterocyclic rings include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl.

[0039] As used herein, the terms "hydroxy" and "hydroxyl" refer to -OH.

[0040] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coating agents, isotonic agents, absorption delaying agents and the like that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional or enhanced therapeutic functions.

[0041] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated with one or more pharmaceutically acceptable carriers.

[0042] As used herein, the term "pharmaceutically acceptable prodrug" refers to a prodrug of a compound of the present disclosure that is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, commensurate with a reasonable benefit / risk ratio, effective for its intended use, and, if possible, in the zwitterionic form of the compounds of the present disclosure. Higuchi et al., ‘‘Prodrugs as Novel Delivery Systems,’’ ACS Symposium Series, Vol. 14 and Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (both of which are incorporated herein by reference) are discussed.

[0043] The term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds contained in the compositions of the present invention that are essentially basic can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions (sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, metaphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumaric acid, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate))), but are not limited thereto). Compositions contained in the compositions of the present invention containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the above acids. Compounds contained in the compositions of the present invention that are essentially acidic can form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts, and iron salts.

[0044] Chemical names were generated using PerkinElmer ChemDraw® Professional, version 17.

[0045] Since the compounds of the present disclosure may contain one or more chiral centers and / or double bonds, they may exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. As used herein, the term "stereoisomers" consists of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S" depending on the configuration of the substituents around the stereogenic carbon atoms. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be designated "(±)" by nomenclature, but those skilled in the art will recognize that the structure may indicate a chiral center. In some embodiments, the enantiomers or stereoisomers may be provided substantially free of the corresponding enantiomers.

[0046] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds in which the individual compounds of the mixture predominantly exist in the (S)- or (R)-isomer configuration. For example, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or higher. In other embodiments, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher. In other embodiments, the mixture of compounds has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or higher. In some other embodiments, the mixture of compounds has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher.

[0047] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or a racemic mixture can be prepared and subsequently prepared by resolution methods well known to those skilled in the art. These resolution methods include (1) binding of the enantiomeric mixture to a chiral auxiliary, separation by recrystallization or chromatography of the resulting mixture of diastereomers, and separation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, or (3) direct separation of a mixture of optical enantiomers by a chiral chromatography column. Mixtures of stereoisomers can also be resolved into their component stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

[0048] Geometric isomers may also be present in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting a double bond include both the E and Z isomers.

[0049] Alternatively, substituents around a carbon-carbon double bond can be referred to as "cis" or "trans", where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on the opposite side of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans". The term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on the opposite side of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is designated as "cis / trans".

[0050] The compounds disclosed in this specification may exist as tautomers, and even if only one tautomeric structure is shown, both tautomeric forms are intended to be encompassed by the scope of this disclosure.

[0051] In addition, unless otherwise specified, the structures described in this specification are also meant to include compounds that differ only in that one or more atoms are enriched in isotopes. For example, replacement of hydrogen with deuterium ( 2 H) or tritium ( 3 H), or replacement of carbon with 13 C- or 14 C-carbon atoms, compounds having this structure are within the scope of this disclosure. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents. Compound In some embodiments, the compound of formula (I):

Chemical formula

[0052] In some embodiments, R 1 is H, or C 1 ~C 6 alkyl, each of which is optionally substituted with zero, one, two, or three R 6 groups. In some embodiments, R 1 can be selected from H or methyl, each of which is optionally substituted with zero, one, two, or three R 6 groups. In some embodiments, R 1 can each independently be H or methyl.

[0053] In some embodiments, R 1 can be H. In some embodiments, R 1 can be methyl.

[0054] In some embodiments, R 2 and R 3 are each independently selected from H, C 1 ~C3 alkyl, or C 1 ~C 3 haloalkyl, each of which is optionally substituted with zero, one, two, or three R 6 groups. In some embodiments, R 2 and R 3 are each independently selected from H and methyl, each of which is optionally substituted with zero, one, two, or three R 6 groups. In some embodiments, R 2 and R 3are each independently selected from H and methyl.

[0055] In some embodiments, R 2 can be H, and R 3 can be H. In some embodiments, R 2 can be H, and R 3 can be methyl. In some embodiments, R 2 can be methyl, and R 3 can be H. In some embodiments, R 2 can be methyl, and R 3 can be methyl.

[0056] In some embodiments, each R 4 is independently selected from H, hydroxyl, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxyl, or C 1 ~C 3 haloalkyl, and these are each optionally substituted with 0, 1, 2, or 3 R 6 groups, or two R 4 groups together form an oxo. In some embodiments, each R 4 is independently selected from H, hydroxyl, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxyl, or C 1 ~C 3 haloalkyl, or two R 4 groups together form an oxo. In some embodiments, R 4 is H. In some embodiments, two R 4 groups together form an oxo.

[0057] In some embodiments, R 5 is halogen, hydroxy, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxy, C1 ~C 3 haloalkyl, -N(R 7 ) 2 , and -CN, each of which is substituted with 0, 1, 2, or 3 R 6 's. In some embodiments, R 5 is halogen, hydroxy, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxy, C 1 ~C 3 haloalkyl, -N(R 7 ) 2 , and -CN. In some embodiments, R 5 is selected from halogen. In some embodiments, R 5 can be F.

[0058] In some embodiments, X 1 and X 2 are each independently H, halogen, cyano, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, or C 1 ~C 6 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R 6 's. In some embodiments, X 1 and X 2 are each independently H, halogen, cyano, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, or C 1 ~C 6 haloalkyl. In some embodiments, X 1 and X 2 are each independently selected from H, F, CN, methyl, methoxy, trifluoromethyl.

[0059] In some embodiments, X 1 is H, and X2 is H. In some embodiments, X 1 is F, and X 2 is F. In some embodiments, X 1 is H, and X 2 is methyl. In some embodiments, X 1 is methyl, and X 2 is H. In some embodiments, X 1 is H, and X 2 is F. In some embodiments, X 1 is F, and X 2 is H. In some embodiments, X 1 is H, and X 2 is methoxy. In some embodiments, X 1 is methoxy, and X 2 is H. In some embodiments, X 1 is F, and X 2 is methyl. In some embodiments, X 1 is methyl, and X 2 is F. In some embodiments, X 1 is F, and X 2 is methoxy. In some embodiments, X 1 is methoxy, and X 2 is F. In some embodiments, X 1 is F, and X 2 is trifluoromethyl. In some embodiments, X 1 is trifluoromethyl, and X 2 is F.

[0060] In some embodiments, X 3 and X 4 are each independently selected from H or halo. In some embodiments, X 3 and X 4 are each independently selected from H or F.

[0061] In some embodiments, X 3 is H, and X 4is H. In some embodiments, X 3 is F, and X 4 is F. In some embodiments, X 3 is H, and X 4 is F. In some embodiments, X 3 is F, and X 4 is H.

[0062] In some embodiments, L can be a linker having a length of 1 to 22 carbon atoms, and one or more of the carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 5 . In some embodiments, L can be a linker having a length of 1 to 20 carbon atoms, and one or more of the carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 5 . In some embodiments, L can be a linker having a length of 1 to 18 carbon atoms, and one or more of the carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 5 . In some embodiments, L can be a linker having a length of 1 to 16 carbon atoms, and one or more of the carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 4 , S, C2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected from, and each of these is, 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker having a length of 1 to 14 carbon atoms, and one or more carbon atoms are C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected from, and each of these is, 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker having a length of 1 to 12 carbon atoms, and one or more carbon atoms are C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected from, and each of these is, 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker having a length of 1 to 10 carbon atoms, and one or more carbon atoms are C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected from, and each of these is, 0, 1, 2, or 3 R 5 and is independently substituted.

[0063] In some embodiments, L can be a linker having a length of 1 to 8 carbon atoms, and one or more carbon atoms are C(O), O, NR 4 , S, C 2 -alkenyl, C2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker having a length of 1 to 6 carbon atoms, and one or more of the carbon atoms can be C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker having a length of 1 to 4 carbon atoms, and one or more of the carbon atoms can be C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each independently optionally replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 5 and is independently substituted.

[0064] In some embodiments, L can be a linker, and two carbon atoms are each independently replaced by a heterocycle, each of which is independently substituted with 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker, one carbon atom is replaced by a heterocycle, and one carbon atom is replaced by a cycloalkyl, each of which is independently substituted with 0, 1, 2, or 3 R 5 and is independently substituted. In some embodiments, L can be a linker, and more than one carbon atom can be C(O), O, NR 4 , S, C 2 -alkenyl, C 2-each independently replaced by a group selected from alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is, 0, 1, 2 or 3 R 5 and is substituted. In some embodiments, L can be a linker and more than one carbon atom is independently replaced by a group selected from C(O), O, and NR 4 each of which is, 0, 1, 2 or 3 R 5 and is substituted.

[0065] In some embodiments, L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0066] In some embodiments, the compound of formula (I) is a cis isomer.

[0067] In some embodiments, the compound of formula (I) is a stereoisomer.

[0068] In some embodiments, the compound of formula (I) * :

Chemical formula

[0069] In some embodiments, a compound selected from the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof is provided herein.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

[0070] The pharmaceutical composition of the present disclosure comprises at least one compound of formula (I), its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. The most suitable dosage form in any given case will depend on the degree and severity of the condition being treated, as well as the nature of the particular compound being used.

[0071] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, troches, or tablets, each containing a predetermined amount of a compound of the present disclosure as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion. As shown, such formulations can be prepared by any suitable formulation method that includes combining at least one compound of the present invention as an active compound with a carrier or excipient, which may constitute one or more accessory ingredients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not being harmful to the recipient. The carrier can be solid or liquid or both and can contain from about 0.05% to about 95% by weight of at least one active compound, and unit dosage formulations, such as tablets, can be formulated with at least one compound described herein as an active compound. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present disclosure can be prepared by any of the well-known formulation techniques that essentially consist of mixing the ingredients.

[0072] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmacologically administrable liquid compositions can be prepared, for example, by dissolving or dispersing at least one of the active compounds of the present disclosure described herein and, optionally, a pharmaceutical adjuvant in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, and the like, thereby forming a solution or suspension. Generally, suitable formulations can be prepared by uniformly and intimately admixing at least one of the active compounds of the present disclosure with a liquid or a micronized solid carrier or both, and then, optionally, shaping the product. For example, tablets can be prepared by compressing or shaping a powder or granules of at least one of the compounds of the present disclosure, which can be combined, optionally, with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, a flowable form, such as a powder or granules, of at least one of the compounds of the present disclosure, which can be mixed, optionally, with a binder, a lubricant, an inert diluent, and / or a surfactant / dispersant(s). Molded tablets can be produced by shaping, in a suitable machine, a powder form of at least one of the compounds of the present disclosure moistened with an inert liquid diluent.

[0073] Formulations suitable for oral (sublingual) administration include troches, which contain at least one of the compounds of the present disclosure in a flavor base, usually sucrose and acacia or tragacanth, and lozenges, which contain at least one compound in an inert base such as gelatin and glycerol or sucrose and acacia.

[0074] The formulations of the present disclosure suitable for parenteral administration comprise a sterile aqueous preparation of at least one compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, and hydrate thereof, which is substantially isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration can also be achieved by subcutaneous, intramuscular or intradermal injection. Such preparations can conveniently be prepared by admixing at least one compound described herein with water, sterilizing the resulting solution and rendering it isotonic with the blood. The injectable compositions of the present disclosure can contain from about 0.1 to about 5% w / w of the active compound.

[0075] Formulations suitable for rectal administration are presented as unit dose suppositories. These can be prepared by admixing at least one compound described herein with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0076] Formulations suitable for topical application to the skin can take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers and excipients that can be used include petrolatum, lanolin, polyethylene glycol, alcohols and combinations of two or more of them. The active compound (i.e., at least one compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, and hydrate thereof) is generally present at a concentration of from about 0.1% to about 15% w / w of the composition, for example from about 0.5 to about 2%.

[0077] The amount of the active compound administered may depend on the subject being treated, the body weight of the subject, the mode of administration, and the judgment of the prescribing physician. For example, the dosing schedule may involve once-daily or twice-daily administration of an encapsulated compound at a recognized dosage of from about 1 μg to about 1000 mg. In another embodiment, intermittent dosing (e.g., monthly or annually) of the encapsulated compound may be used. Encapsulation facilitates access to the site of action and theoretically allows for the co-administration of active ingredients that produce a synergistic effect. In accordance with standard dosing regimens, a physician will be able to readily determine the optimal dosage and easily modify the administration to achieve such dosage.

[0078] The therapeutically effective amount of the compounds or compositions disclosed herein may be measured by the therapeutic efficacy of the compound. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to achieve a maximum plasma concentration. For example, a preliminary dosage determined according to animal tests and the scaling of the dosage for human administration are carried out according to the conventions recognized in the art.

[0079] Toxicity and therapeutic efficacy can be determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LD 50 (lethal dose for 50% of the population) and ED 50 (therapeutically effective dose in 50% of the population). The dose ratio of toxic effect to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD 50 / ED 50 . Compositions showing a large therapeutic index are preferred.

[0080] Data obtained from cell culture assays or animal studies can be used to establish the dosage range for use in humans. For use in another animal, including humans, the therapeutically effective dosage achieved in an animal model can be converted using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following table regarding equivalent surface area dosage coefficients). [Table 2]

[0081] The dosage of such a compound is preferably within the range of circulating concentrations that includes 50 and has little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration utilized. In general, the therapeutically effective amount can vary with the age, condition and sex of the subject, as well as the severity of the medical condition in the subject. The dosage is determined by a physician and can be adjusted, if necessary, to fit the observed treatment effect. Method of treatment

[0082] In some embodiments, a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered to a subject in need of treating cancer to treat the cancer. In some embodiments, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is ERα-positive. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered as a pharmaceutical composition. In some embodiments, the subject has been previously treated with tamoxifen.

[0083] In some embodiments, provided herein is the use of a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, in a therapeutic treatment. In some embodiments, the therapeutic treatment is for the treatment of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of breast cancer. In some embodiments, the therapeutic treatment is for the treatment of lung cancer. In some embodiments, the therapeutic treatment is for the treatment of ovarian cancer. In some embodiments, the therapeutic treatment is for the treatment of endometrial cancer. In some embodiments, the therapeutic treatment is for the treatment of prostate cancer. In some embodiments, the therapeutic treatment is for the treatment of esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of estrogen-related diseases and symptoms. In some embodiments, the therapeutic treatment is for the treatment of infertility. In some embodiments, the therapeutic treatment is for the treatment of ovulatory dysfunction. In some embodiments, the therapeutic treatment is for the treatment of postmenopausal osteoporosis. In some embodiments, the therapeutic treatment is for the treatment of estrogen-related gynecomastia. In some embodiments, the therapeutic treatment is for the treatment of dyspareunia resulting from amenorrhea. In some embodiments, the therapeutic treatment is for the treatment of retroperitoneal fibrosis. In some embodiments, the therapeutic treatment is for the treatment of idiopathic sclerosing mesenteritis.

[0084] In some embodiments, provided herein is the use of a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, in the preparation of a medicament. In some embodiments, provided herein is a method of inhibiting cell proliferation comprising contacting a cell with a compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell may express ERα.

[0085] In one embodiment, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with another therapeutic agent. The other therapeutic agent can provide an additive or synergistic value compared to administration of the compounds of the present disclosure alone. Therapeutic agents include, for example, hormones and hormone analogs; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite neoplastic agents; antibiotic neoplastic agents; alkylating agents; anti-microtubule agents; platinum coordination complexes; aromatase inhibitors; and anti-mitotic agents.

[0086] In some embodiments, the therapeutic agent can be a hormone or hormone analog. In some embodiments, the therapeutic agent can be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent can be an antimetabolite neoplastic agent. In some embodiments, the therapeutic agent can be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent can be an alkylating agent. In some embodiments, the therapeutic agent can be an anti-microtubule agent. In some embodiments, the therapeutic agent can be a platinum coordination complex. In some embodiments, the therapeutic agent can be an aromatase inhibitor. In some embodiments, the therapeutic agent can be an anti-mitotic agent.

[0087] In some embodiments, the aromatase inhibitor can be selected from anastrozole, letrozole, vorozole, fadrozole, exemestane, and formestane. In some embodiments, the aromatase inhibitor is anastrozole. In some embodiments, the aromatase inhibitor can be letrozole. In some embodiments, the aromatase inhibitor can be vorozole. In some embodiments, the aromatase inhibitor can be fadrozole. In some embodiments, the aromatase inhibitor can be exemestane. In some embodiments, the aromatase inhibitor can be formestane.

[0088] In some embodiments, the anti-mitotic agent can be selected from paclitaxel, docetaxel, and abraxane. In some embodiments, the anti-mitotic agent can be paclitaxel. In some embodiments, the anti-mitotic agent can be docetaxel. In some embodiments, the anti-mitotic agent can be abraxane.

[0089] In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with a hormone or a hormone analog. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with a signaling pathway inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with an antimetabolite neoplastic agent. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with a topoisomerase I inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with a topoisomerase II inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with an aromatase inhibitor. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with one or more anticancer agents.

[0090] In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with an anticancer agent, and the aforementioned anticancer agent is tamoxifen. In some embodiments, the compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, can be administered in combination with an anticancer agent, and the aforementioned anticancer agent is fulvestrant.

Examples

[0091] The examples and preparations provided below further illustrate and exemplify the compounds disclosed herein and methods for preparing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations.

[0092] The chemical substances described in this specification can be synthesized according to one or more of the exemplary schemes of this specification and / or techniques well known in the art. Unless otherwise specified, the reactions described in this specification are carried out at atmospheric pressure, generally within a temperature range of about -10°C to about 200°C. Further, unless otherwise specified, the reaction times and conditions are approximate and can be carried out, for example, at approximately atmospheric pressure, within a temperature range of about -10°C to about 200°C, for a period that can be, for example, about 1 to about 24 hours; in some embodiments, a reaction left to proceed overnight can be for an average period of about 16 hours.

[0093] The isolation and purification of the chemical substances and intermediates described in this specification can, if desired, be carried out by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or combinations of these procedures. See, for example, Carey et al., Advanced Organic Chemistry, 3 rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 nd Ed., 2005 Hoboken, NJ: J.Wiley & Sons. Specific descriptions of suitable separation and isolation procedures are given by reference to the following examples. However, other equivalent separation or isolation procedures can also be used.

[0094] In all methods, it is well understood that protecting groups for sensitive or reactive groups can be used if necessary, in accordance with general chemical principles. Protecting groups are manipulated according to standard organic synthesis methods (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd(Ed., John Wiley & Sons). These groups can be removed at a convenient stage of compound synthesis using methods that will be readily apparent to those skilled in the art.

[0095] Optionally, the (R)- and (S)-isomers of the exemplary compounds, if present, can be separated by methods known to those skilled in the art, such as by formation of diastereoisomeric salts or complexes that can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives that can be separated, for example, by crystallization, gas - liquid or liquid chromatography; by selective reaction of one enantiomer with an enantioselective reagent, such as enzymatic oxidation or reduction, followed by separation of the modified enantiomer and the unmodified enantiomer; or by resolution in a chiral environment, such as by gas - liquid or liquid chromatography on a chiral support, such as silica having a bonded chiral ligand, or in the presence of a chiral solvent. Alternatively, a particular enantiomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by converting one enantiomer to the other by asymmetric transformation.

[0096] The compounds described herein can be contacted, optionally, with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be contacted, optionally, with a pharmaceutically acceptable base to form the corresponding base addition salts.

[0097] In some embodiments, the disclosed compounds can generally be synthesized by appropriate combinations of generally known synthetic methods. The techniques useful in the synthesis of these chemical entities will be readily apparent and available to those skilled in the relevant art based on the present disclosure. Many of the starting compounds and other reactants, which are optionally substituted, are commercially available, for example, from Millipore Sigma, or can be readily prepared by those skilled in the art using commonly employed synthetic methods.

[0098] The following discussion is provided to illustrate some of the various methods available for use in the preparation of the disclosed compounds and is not intended to limit the scope of the reactions or reaction sequences that may be used in the preparation of the compounds provided herein. One of ordinary skill in the art will understand that, unless otherwise specified, in the naming of groups or compounds, standard valences apply to all compounds disclosed herein. The following abbreviations have the definitions shown below: 1. BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 2. CbzCl: benzyloxycarbonyl chloride 3. DCE: 1,2-dichloroethane 4. DCM: dichloromethane 5. DIEA or DIPEA: N,N-diisopropylethylamine 6. DMEM: Dulbecco's Modified Eagle Medium 7. DMSO: dimethyl sulfoxide 8. DMF: N,N-dimethylformamide 9. EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 10. ESI-TOF: electrospray ionization time-of-flight mass spectrometry 11. EtOAc: ethyl acetate 12. FBS: fetal bovine serum 13. HOAt: 1-hydroxy-7-azabenzotriazole 14. HPLC: high performance liquid chromatography 15. HRMS: high resolution mass spectrometry 16. IBX: 2-iodoxybenzoic acid 17. MeOH: methanol 18. MCF-7: Michigan Cancer Foundation-7 breast cancer cell line 19. MTBE: methyl tert-butyl ether 20. NBS: N-bromosuccinimide 21. NMR: nuclear magnetic resonance 22. NCS: N-chlorosuccinimide 23. Pd(dppf)Cl2: Bis(diphenylphosphino)ferrocene palladium dichloride 24. RPMI: Roswell Park Memorial Institute medium 25. SDS: Sodium dodecyl sulfate 26. SFC: Supercritical fluid chromatography 27. TBAB: Tetrabutylammonium bromide 28. TBST: Tris-buffered saline containing Tween 20 29. TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy 30. p-TSA or TsOH: p-Toluenesulfonic acid 31. THF: Tetrahydrofuran Example 1. Synthesis of the compounds of the present disclosure.

[0099] Chemical basic procedures. HPLC spectra of all compounds were obtained using an Agilent 1200 series system equipped with a DAD detector. Chromatography was performed on a 2.1×150 mm Zorbax 300SB-C18 5 μm column with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.4 mL / min. The gradient program was as follows: 1% B (0 - 1 min), 1 - 99% B (1 - 4 min), and 99% B (4 - 8 min). High-resolution mass spectrum (HRMS) data were obtained in positive ion mode using an Agilent G1969A API-TOF equipped with an electrospray ionization (ESI) ion source. Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer at 600 MHz or 400 MHz for protons ( 1 1H NMR) and 150 MHz for carbon ( 13 13C NMR); chemical shifts are reported in (δ). Preparative HPLC was performed on an Agilent Prep 1200 series equipped with a UV detector set at 254 nm and 220 nm. Samples were injected at room temperature onto a Phenomenex Luna 75×30 mm, 5 μm, C 18 column. The flow rate was 40 mL / min. H 2A linear gradient from 10% (or 50%) MeOH (A) in 0.1% TFA-containing water (O) to 100% MeOH (B) was used. HPLC was used to establish the purity of the target compounds. All final compounds were determined to have a purity of over 95% when analyzed according to the above HPLC method.

[0100] Compounds having the structure of formula (I) as recited in the claims of this application can be prepared by connecting two ligands with a linker. Generally, the molecules recited in the claims can be reached in a stepwise manner or a modular manner. The following schemes represent the general methods used in preparing these compounds. However, since these can also be prepared by those skilled in synthetic chemistry, the synthesis of formula (I) is not limited to these representative methods. Scheme 1: Synthesis of Compound 1 [Chemical formula] Scheme 2: Synthesis of Compound 2 [Chemical formula] Scheme 3: Synthesis of Compound 3 [Chemical formula] Scheme 4: Synthesis of Compound 4 [Chemical formula] Scheme 5: Synthesis of Compounds 5 - 8 [Chemical formula] Scheme 6: Synthesis of Compounds 9 - 11 [Chemical formula] Scheme 7: Synthesis of Compounds 12 - 25 [Chemical formula] [Chemical formula] Scheme 8: Synthesis of Compounds 26, 28 - 31

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0101] The synthesis of Compounds 46, 47, 48, 49, 58, 59, 66, 67, 81 - 83, and 88 can follow the schemes described in Schemes 8, 9, and 12. Example 1: Synthesis of cis - 2 - (2,6 - dioxopiperidin - 3 - yl) - 5 - (4 - ((1 - (4 - (7 - hydroxy - 3 - phenylchroman - 4 - yl)phenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)isoindoline - 1,3 - dione (Compound 36).

Chem.

Chem.

[0102] To a mixture of 1-bromo-4-iodobenzene (100 g, 353 mmol, 1.00 eq) and piperidin-4-ylmethanol (52.8 g, 459 mmol, 1.30 eq) in DMSO (500 mL), cis-4-hydroxy-L-proline (9.22 g, 70.5 mmol, 0.200 eq), CuI (13.4 g, 70.5 mmol, 0.200 eq), and K 3 PO 4 (150 g, 0.705 mol, 2.00 eq) were added. The mixture was stirred at 80 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.80, Rf (product) = 0.30) indicated complete consumption of the starting material. The mixture was poured into ice water (2.50 L) and extracted with EtOAc (1.00 L × 2). The combined organic layers were washed with ammonium hydroxide solution (500 mL × 3, 30 mL of ammonium hydroxide in 210 mL of H 2 O). The organic layer was washed with brine (500 mL) and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford (1-(4-bromophenyl)piperidin-4-yl)methanol as an off-white solid. Project 2: Preparation of 1-(4-bromophenyl)piperidine-4-carbaldehyde.

[0103] To a solution of (1-(4-bromophenyl)piperidin-4-yl)methanol (80.0 g, 296 mmol, 1.00 eq) in DMSO (220 mL) and DIPEA (193 g, 1.49 mol, 261 mL, 5.00 eq), pyridine·sulfur trioxide (143 g, 901 mmol, 3.00 eq) was added at 0 - 10 °C. The mixture was stirred at 0 - 10 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf (starting material) = 0.30, Rf (product) = 0.60) indicated complete consumption of the starting material. This mixture was poured into ice water (2.00 L) and extracted with EtOAc (500 mL × 3), and the combined organic phases were washed with Na2 SO 4 It was dried with SO, filtered, and concentrated in vacuo. The residue was triturated with petroleum ether:MTBE = 10:1 (150 mL), and 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, crude) was obtained as a black-brown solid. Step 3: Preparation of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine.

[0104] To a solution of 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, 258 mmol, 1.00 eq) and CH(OMe) 3 (82.9 g, 780 mmol, 85.5 mL, 3.00 eq) in MeOH (210 mL) was added TsOH (897 mg, 5.21 mmol, 0.020 eq). The mixture was then stirred at 65 °C for 16 h. TLC (petroleum ether:ethyl acetate = 5:1, Rf (starting material) = 0.30, Rf (product) = 0.50) indicated complete consumption of the starting material. The resulting mixture was poured into saturated NaHCO 3 (100 mL), extracted with EtOAc (100 mL × 3), and the combined organic phases were dried over Na 2 SO 4 dried, filtered, and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, 0 - 100 ethyl acetate / petroleum ether gradient, 60 mL / min). The desired 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (70.0 g, crude) was obtained as a white solid. 1H NMR (400 MHz CDCl 3 ) δ 7.32 (d, J = 8.9 Hz, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.08 (d, J = 7.2 Hz, 1 H), 3.66 (br d, J = 12.4 Hz, 2 H), 3.38 (s, 6 H), 2.66 (td, J = 12.4, 2.0 Hz, 2 H), 1.67 - 1.91 (m, 3 H), 1.45 (qd, J = 12.4, 4.1 Hz, 2 H). Step 4: Preparation of 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one.

[0105] To a solution of resorcinol (230 g, 2.09 mol, 348 mL, 1.00 equiv) and 3-chloropropanoic acid (249 g, 2.30 mol, 1.10 equiv) at 40 °C was added CF 3 SO 3 H (1.10 kg, 7.31 mol, 645 mL, 3.50 equiv), and then the mixture was stirred at 80 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.21, Rf (product) = 0.35) indicated that the starting material was completely consumed. The obtained 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, crude) was used directly in the next step. Step 5: Preparation of 7-hydroxychroman-4-one.

[0106] The crude 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, 2.09 mol, 1.00 equiv) was mixed with NaOH (584 g, 14.6 mol, 7.00 equiv) in H 2 O (1.59 L), and then the mixture was stirred at 0 °C for 30 min. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.40, Rf (product) = 0.60) indicated that the starting material was completely consumed. The reaction mixture was first adjusted to about pH 5 with 6N HCl and then extracted with EtOAc (2 × 1.50 L). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain the desired crude product (342 g, crude) as a brown gummy substance. Step 6: Preparation of 7-(benzyloxy)chroman-4-one.

[0107] A solution of 7-hydroxycoumarin-4-one (342 g, 2.08 mol, 1.00 equiv) in DMF (1.50 L) was added with K 2 CO 3 (575 g, 4.17 mol, 2.00 equiv) and benzyl bromide (391 g, 2.29 mol, 272 mL, 1.10 equiv), and then the mixture was stirred at 15 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.20, Rf (product) = 0.50) indicated that the starting material was completely consumed. The mixture was poured into H 2 O (7.50 L) and extracted with EtOAc (2.00 L × 2). The combined organic layers were washed with brine (2.00 L), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 15:1 to 8:1) to give 7-(benzyloxy)coumarin-4-one (185 g) as a white solid. LCMS m / z 255 (M+H)+. Step 7: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)coumarin-4-ol.

[0108] To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (63.0 g, 200 mmol, 1 equiv) in 2-methyl-tetrahydrofuran (440 mL) was added n-BuLi (2.5 M, 96.2 mL, 1.30 equiv), and the mixture was stirred at -78 °C for 1 h. Then 7-(benzyloxy)coumarin-4-one (50.9 g, 200 mmol, 1.00 equiv) was added, and the mixture was stirred at -78 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.15) indicated that the starting material was completely consumed. The mixture was poured into H 2 O (300 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL), dried over Na 2 SO4 It was dried, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether:EtOAc (500 mL) at 15 °C for 30 minutes to obtain 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (72.0 g, crude) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.46 (m, 5 H), 7.25 (d, 2 H), 6.87 - 6.93 (m, 3 H), 6.48 - 6.53 (m, 2 H), 5.04 (s, 2 H), 4.35 - 4.42 (m, 1 H), 4.20 (dt, J = 11.2 Hz, 1 H), 4.09 (d, J = 7.2 Hz, 1 H), 3.72 (br d, J = 12.0 Hz, 2 H), 3.38 (s, 6 H), 2.68 (br t, J = 11.2 Hz, 2 H), 2.25 (m, 1H), 2.15 (m, 1H), 2.10 (s, 1H, OH), 1.86 (br d, J = 13.2 Hz, 2 H), 1.75 (ddq, J = 11.2 Hz, 1 H), 1.46 (br dd, J = 12.0 Hz, 2 H). Step 8: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0109] A solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (66.0 g, 134 mmol, 1.00 equiv) in MeOH (198 mL) was treated with TsOH (512 mg, 2.70 mmol, 2.07e-2 equiv), and the mixture was stirred at 78 °C for 30 min. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.30, Rf (product) = 0.60) indicated complete consumption of the starting material. The mixture was stirred at 25 °C for 30 min, filtered, and the cake was dried in vacuo to afford 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, crude) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.46 (m, 5 H), 7.23 (br d, J = 8.2 Hz, 2 H), 6.92 - 7.02 (m, 3 H), 6.56 (s, 1 H), 6.50 (dd, J = 8.3 Hz, 2.3 Hz, 1 H), 5.62 (t, J = 4.0 Hz, 1 H), 5.05 (s, 2 H), 4.81 (d, J = 3.8 Hz, 2 H), 4.11 (d, J = 7.1 Hz, 1 H), 3.77 (br d, J = 12.0 Hz, 2 H), 3.39 (s, 6 H), 2.72 (t, J = 12.4 Hz, 2 H), 1.88 (br d, J = 13.6 Hz, 2 H), 1.74 - 1.82 (m, 1 H), 1.41 - 1.53 (m, 2 H). Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0110] A solution of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, 139 mmol, 1.00 equiv) and DIEA (36.1 g, 279 mmol, 48.7 mL, 2.00 equiv) in DMF (300 mL) was added pyridinium tribromide (71.6 g, 223 mmol, 1.60 equiv) at 0 °C, and the mixture was stirred at 15 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) indicated that the starting material was completely consumed. The mixture was poured into H 2 O (700 mL), extracted with EtOAc (300 mL×2), the organic layer was washed with brine (300 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 30:1 to 0:1) to give 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (40.0 g, crude) as a yellow oil. LCMS m / z 550.2 and 552.2 [M+H]+; 1H NMR (400 MHz, CDCl 3 ) δ 7.30 - 7.45 (m, 5 H), 7.14 (br d, J = 8.4 Hz, 2 H), 6.98 (br d, J = 8.4 Hz, 2 H), 6.67 (d, J = 8.6 Hz, 1 H), 6.52 (d, J = 1.7 Hz, 1 H), 6.43 (dd, J = 8.7 and 1.7 Hz, 1 H), 5.03 (s, 2H), 4.97 (s, 2H), 4.12 (d, J = 7.2 Hz, 1 H), 3.80 (br d, J = 12.4 Hz, 2 H), 3.40 (s, 6 H), 2.74 (br t, J = 11.8 Hz, 2 H), 1.89 (br d, J = 13.2 Hz, 2 H), 1.74 - 1.84 (m, 1 H),1.43 - 1.56 (m, 2 H). Step 10: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0111] To a solution of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (33.0 g, 59.9 mmol, 1.00 equivalent) in DMF (140 mL) and H 2 O (14 mL) were added phenylboronic acid (10.9 g, 89.9 mmol, 1.50 equivalents), K 2 CO 3 (16.5 g, 119 mmol, 2.00 equivalents), and Pd(dppf)Cl 2 (855 mg, 1.17 mmol, 0.02 equivalent), and the mixture was stirred at 70 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) indicated complete consumption of the starting material. The mixture was poured into H 2 O (500 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The crude product was triturated with MeOH (100 mL) at 25 °C for 30 min to give 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (30.0 g, crude) as a gray solid. Step 11: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol.

[0112] To a solution of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (30.0 g, 54.7 mmol, 1.00 equivalent) in THF (30.0 mL) and EtOH (300 mL) were added Pd / C (3.00 g, purity 10.0%) and Pd(OH) 2 / C (3.00 g, purity 20.0%) under N2 It was added under an atmosphere. The suspension was degassed and purged three times with H 2 . The mixture was stirred at 60 °C for 12 hours under H 2 (50 psi). TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.20) indicated that the starting material had been completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was triturated with petroleum ether:EtOAc = 10:1 (50.0 mL) at 25 °C for 30 minutes to give cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid. LCMS m / z 460.2 [M+H]+; 1H NMR (400 MHz, CDCl 3 ) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.77 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.08 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.57 (t, J = 10.8 Hz, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.38 - 1.49 (m, 2 H). Steps 12 - 15: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride

[0113] This compound was prepared as the hydrochloride salt in four steps as described in the scheme. LC / MS 343.1 [M+H]+; 1H-NMR (400 MHz, CD 3 OD) δ ppm 7.76 (d, J = 8.36 Hz, 1 H), 7.47 (s, 1 H), 7.35 (dd, J = 8.36, 1.54 Hz, 1 H), 5.09 (br dd, J = 12.8, 5.40 Hz, 1 H), 3.67 - 3.74 (m, 4 H), 3.37 - 3.42 (m, 4 H), 2.63 - 2.94 (m, 3 H), 2.07 - 2.17 (m, 1 H). Steps 16 - 17: Preparation of cis - 2 - (2,6 - dioxopiperidin - 3 - yl) - 5 - (4 - ((1 - (4 - (7 - hydroxy - 3 - phenylchroman - 4 - yl)phenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)isoindoline - 1,3 - dione (Compound 36).

[0114] To a solution of cis - 4 - (4 - (4 - (dimethoxymethyl)piperidin - 1 - yl)phenyl) - 3 - phenylchroman - 7 - ol (50 mg, 0.11 mmol) in 2 mL of THF was added 2 M aqueous sulfuric acid solution (2 mL, 4 mmol). The mixture was stirred at 70 °C for 30 minutes until all starting materials were consumed. The mixture was adjusted to pH = 9 with 1 N NaOH solution and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure to obtain the crude product aldehyde (50 mg). LC / MS m / z 413.9[M + H]+. The above - mentioned crude aldehyde (50 mg, 0.09 mmol) was mixed with 2 - (2,6 - dioxopiperidin - 3 - yl) - 5 - (piperazin - 1 - yl)isoindoline - 1,3 - dione hydrochloride (37.8 mg, 0.1 mmol), TEA (18.2 mg, 0.18 mmol) in DCM (10 mL), and then MgSO 4 (108 mg, 0.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, NaBH(AcO) 3(47.7 mg, 0.225 mmol) was added portionwise over 3 hours. The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo to afford the crude product. The crude product was purified by preparative TLC using MeOH:DCM = 1:10 to give the title compound (19.8 mg, 27.6%). LC / MS m / z 740.3 [M+H]+; 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H, NH), 9.30 (s, 1H, OH), 7.69 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.19 - 7.14 (m, 3H), 6.78 (d, J = 3.2 Hz, 2H), 6.69 - 6.60 (m, 3H), 6.39 (d, J = 8.2 Hz, 2H), 6.33 - 6.27 (m, 2H), 5.08 (dd, 1H), 4.33 (t, J = 11 Hz, 1H), 4.22 - 4.17 (m, 2H), 3.60 - 3.51 (m, 3H), 3.44 (br s, 4H), 2.91 - 2.85 (m, 1H), 2.64 - 2.48 (m, 8H), 2.20 (br d, J = 7.4 Hz, 2H), 2.06 - 1.97 (m, 1H), 1.82 - 1.75 (m, 2H), 1.74 - 1.61 (m, 1H), 1.16 - 1.24 (m, 2H); calculated exact mass 739.3370 for C44H45N5O6 by HRMS, found [M+1] + 740.3421. Example 2: Synthesis of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (Compound 87). [Chemical formula] Step 1: Preparation of (1-(2-Fluoro-4-nitrophenyl)piperidin-4-yl)methanol.

[0115] To a solution of 1,2-difluoro-4-nitrobenzene (100 g, 628 mmol, 69.4 mL, 1.00 equiv) and K 2 CO 3 (130 g, 942 mmol, 1.50 equiv) in DMF (500 mL) was added piperidin-4-ylmethanol (76.0 g, 660 mmol, 1.05 equiv) at 0 °C, and then the mixture was stirred at 25 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.30) indicated that the starting material was completely consumed. The mixture was poured into H 2 O (2.50 L), stirred for 20 min, filtered, and the cake was concentrated in vacuo to give (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 621 mmol, 98.8% yield) as a yellow solid. Step 2: Preparation of (1-(4-Amino-2-fluorophenyl)piperidin-4-yl)methanol.

[0116] To a solution of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 424 mmol, 1.00 equiv) in MeOH (1.00 L) was added Pd / C (1.60 g, 10% purity) under argon. The suspension was degassed under vacuum and purged several times with H 2 . The mixture was stirred at 50 °C for 12 h under H 2 (50 psi). TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.30, Rf (product) = 0.10) indicated that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo to give (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol as a brown solid. Step 3: Preparation of (1-(2-Fluoro-4-iodophenyl)piperidin-4-yl)methanol.

[0117] A solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (90.0 g, 401 mmol, 1.00 equiv) in MeCN (360 mL) cooled to 0 °C was added with HCl (12 M, 100 mL, 3.00 equiv), and then NaNO2 (33.2 g, 481 mmol, 1.20 equiv) in H2O (40.0 mL) was added dropwise at 0 °C. After the mixture was stirred for 0.5 h, KI (166 g, 1.00 mol, 2.50 equiv) in H2O (100 mL) at 0 °C was added. The mixture was stirred at 15 °C for 11 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf (starting material) = 0.25, Rf (product) = 0.10) indicated that the starting material was completely consumed. The mixture was filtered, and the cake was triturated with saturated NaOH (4 M, 500 mL) at 15 °C for 30 min, filtered, and the cake (brown solid) was used in the next step. 2 A solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (90.0 g, 401 mmol, 1.00 equiv) in MeCN (360 mL) cooled to 0 °C was added with HCl (12 M, 100 mL, 3.00 equiv), and then NaNO2 (33.2 g, 481 mmol, 1.20 equiv) in H2O (40.0 mL) was added dropwise at 0 °C. After the mixture was stirred for 0.5 h, KI (166 g, 1.00 mol, 2.50 equiv) in H2O (100 mL) at 0 °C was added. The mixture was stirred at 15 °C for 11 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf (starting material) = 0.25, Rf (product) = 0.10) indicated that the starting material was completely consumed. The mixture was filtered, and the cake was triturated with saturated NaOH (4 M, 500 mL) at 15 °C for 30 min, filtered, and the cake (brown solid) was used in the next step. 2 A solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (90.0 g, 401 mmol, 1.00 equiv) in MeCN (360 mL) cooled to 0 °C was added with HCl (12 M, 100 mL, 3.00 equiv), and then NaNO2 (33.2 g, 481 mmol, 1.20 equiv) in H2O (40.0 mL) was added dropwise at 0 °C. After the mixture was stirred for 0.5 h, KI (166 g, 1.00 mol, 2.50 equiv) in H2O (100 mL) at 0 °C was added. The mixture was stirred at 15 °C for 11 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf (starting material) = 0.25, Rf (product) = 0.10) indicated that the starting material was completely consumed. The mixture was filtered, and the cake was triturated with saturated NaOH (4 M, 500 mL) at 15 °C for 30 min, filtered, and the cake (brown solid) was used in the next step. Step 4: Preparation of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde.

[0118] NaHCO in H2O (750 mL) 3 (46.8 g, 558 mmol, 1.70 equiv) and Na 2 CO 3To a solution of (6.05 g, 57.1 mmol, 0.174 eq) was added (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol (110 g, 328 mmol, 1 eq) in DCM (750 mL), then TBAB (10.6 g, 33.1 mmol, 0.101 eq), TEMPO (1.29, 8.21 mmol, 0.020 eq), and NCS (54.7 g, 410 mmol, 1.00 eq) were added at 0 °C, and the mixture was stirred at 0 °C for 1.5 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.25, Rf (product) = 0.50) indicated that the starting material was completely consumed. The mixture was extracted with DCM (500 mL × 2). The combined organic layers were washed with saturated Na2SO3 solution (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g, crude) as a brown solid. Step 5: Preparation of 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine.

[0119] To a solution of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g, 270 mmol, 1.00 eq) in MeOH (600 mL) was added CH(OCH3)3 (43.0 g, 405 mmol, 1.50 eq) and TsOH (6.98 g, 40.5 mmol, 0.150 eq), then the mixture was stirred at 65 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.35, Rf (product) = 0.60) indicated that the starting material was completely consumed. The pH was adjusted to 9 by gradually adding saturated NaHCO 3 The mixture was concentrated under vacuum, then the mixture was added to H 2 O (200 mL), extracted with EtOAc (500 mL × 2), the combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2 Purified with petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to obtain 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (90.0 g, 237 mmol, yield 87.7%) as a yellow solid. Step 6: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol.

[0120] To a solution of 1-(4-iodo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (45 g, 118 mmol, 1.00 equiv) in 2-methyl-tetrahydrofuran (225 mL) was added n-BuLi (2.5 M, 61.5 mL, 1.30 equiv) at -65 °C, and the mixture was stirred at -65 °C for 0.5 h. Then, 7-(benzyloxy)chroman-4-one (22.5 g, 88.9 mmol, 0.750 equiv) in 2-methyl-tetrahydrofuran (100 mL) was added at -65 °C, and the mixture was stirred at -65 °C for 2.5 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.15) indicated that the starting material was completely consumed. The same reaction was repeated again, and the two reactants were combined for work-up. The mixture was poured into H 2 O (300 mL), extracted with EtOAc (50.0 mL × 2), the combined organic layers were washed with brine (50.0 ml), dried over Na 2 SO 4 and filtered, and concentrated under vacuum to obtain 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, crude) as a red solid. Step 7: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0121] A solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, 165 mmol, 1.00 equiv) in MeOH (255 mL) was added TsOH (588 mg, 3.42 mmol, 0.021 equiv) at 15 °C. The mixture was stirred at 75 °C for 0.5 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.30, Rf (product) = 0.60) indicated complete consumption of the starting material. The mixture was stirred at 25 °C for 30 min, filtered, and the cake was dried in vacuo to give 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (75.0 g, 140 mmol, 77.1% yield) as a red solid. 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.46 (m, 5 H), 6.88 - 7.06 (m, 4 H), 6.56 (d, J = 2.3 Hz, 1 H), 6.51 (dd, J = 8.6, 2.4 Hz, 1 H), 5.64 (t, J = 3.9 Hz, 1 H), 5.06 (s, 2 H), 4.80 (d, J = 3.9 Hz, 2 H), 4.12 (d, J = 7.2 Hz, 1 H), 3.53 (br d, J = 11.6 Hz, 2 H), 3.40 (s, 6 H), 2.68 (br t, J = 11.2 Hz, 2 H), 1.87 (br d, J = 12.8 Hz, 2 H), 1.76 (m, 1 H), 1.45 - 1.65 (m, 2H). Step 8: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0122] A solution of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (75.0 g, 153 mmol, 1.00 eq) and DIEA (59.0 g, 459 mmol, 80.0 mL, 3.00 eq) in DMF (350 mL) was added with pyridinium tribromide (73.0 g, 245 mmol, 1.60 eq) at N 2 under ℃. The mixture was stirred at 15 °C for 1 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) indicated that the starting material had been completely consumed. The mixture was poured into H 2 O (1.00 L), extracted twice with EtOAc (300 mL), the organic layer was washed with brine (300 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was triturated with MTBE (250 mL) at room temperature for 30 min to give 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (90.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.49 (m, 5 H), 6.85 - 7.06 (m, 3 H), 6.63 (m, 1 H), 6.53 (d, J = 2.20 Hz, 1 H), 6.44 (dd, J = 8.6, 2.4 Hz, 1 H), 5.03 (s, 2H), 4.98 (s, 2 H), 4.13 (d, J = 7.3 Hz, 1 H), 3.50 - 3.62 (m, 2 H), 3.40 (s, 6 H), 2.71 (br t, J = 11.2 Hz, 2 H), 1.70 - 1.93 (m, 3 H), 1.56 (qd, J = 12.0, 3.6 Hz, 2 H). Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0123] DMF (400 mL) and H 2 A solution of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (85.0 g, 148 mmol, 1.00 equivalent) in H 2 CO 3 O (40.0 mL) was added with phenylboronic acid (25.4 g, 208 mmol, 1.40 equivalents), K 2 CO 2 (45.7 g, 330 mmol, 2.22 equivalents), and Pd(dppf)Cl 2 (2.50 g, 3.429 mmol, 0.023 equivalent). The mixture was stirred at 70 °C under N 3 for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.55) indicated complete consumption of the starting material. The mixture was poured into H 2 O (1.50 L) and stirred at 15 °C for 30 min. The solid was filtered and the cake was dried in vacuo to give 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (60.0 g, crude) as a red solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.30 - 7.49 (m, 5 H), 7.07 - 7.22 (m, 3 H), 6.98 (d, 2 H), 6.72 - 6.88 (m, 4 H), 6.65 (s, 1 H), 6.50 (d, 1 H), 5.06 (br s, 4 H), 4.11 (br dd, J = 5.6, 1.2 Hz, 1 H), 3.46 - 3.53 (m, 2 H), 3.39 (s, 6 H), 2.63 (t, J = 11 Hz, 2 H), 1.87 (br d, 2 H), 1.75 (m, 1 H), 1.45 - 1.63 (m, 2H). Step 10: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0124] A solution of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (30.0 g, 53.1 mmol, 1.00 eq) in THF (75.0 mL) and EtOH (300.0 mL) was added with Pd / C (3 g, purity 10%) under N 2 atmosphere. The suspension was degassed and purged with H 2 three times. The mixture was stirred at 50 °C for 12 h under H 2 (50 psi). TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.20) indicated that the starting material was completely consumed. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The hydrogenation reaction of the same scale was repeated and two batches of the reaction were combined for purification. The crude product was triturated with petroleum ether:EtOAc = 10:1 (200 mL) at 25 °C for 30 min to afford cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (50.0 g, purity 96.8%) as an off-white solid. LCMS m / z 478.2 [M+H]+; 1H NMR (400 MHz, CDCl 3 ) δ 7.12 - 7.23 (m, 3 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.60 - 6.73 (m, 3 H), 6.46 (d, J = 2.4 Hz, 1 H), 6.38 (dd, J = 8.3, 2.6 Hz, 1 H), 6.22 - 6.30 (m, 2 H), 4.72 (br s, 1 H), 4.41 (t, J = 11.2 Hz, 1 H), 4.25 (dd, J = 10.8, 2.4 Hz, 1 H), 4.19 (d, J = 5.2 Hz, 1 H), 4.09 (d, J = 7.4 Hz, 1 H), 3.54 - 3.61 (m, 1 H), 3.37 (s and m, 8 H), 2.54 (broad t, J = 11.8 Hz, 2 H), 1.82 (broad d, J = 12.8 Hz, 2 H), 1.65 - 1.76 (m, 1 H), 1.43 - 1.56 (m, 2 H). Step 11: Preparation of cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (Compound 87).

[0125] This reaction step was carried out using the same method as described in Steps 16 - 17 of Example 1. LC / MS m / z 758.7[M+H]+; 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.36 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.22 - 7.08 (m, 3H), 6.86 - 6.64 (m, 4H), 6.38 - 6.26 (m, 3H), 6.15 (d, J = 14.0 Hz, 1H), 5.08 (dd, J = 13.0, 5.4 Hz, 1H), 4.33 (t, J = 11 Hz, 1H), 4.26 - 4.21 (m, 2H), 3.60 - 3.52 (m, 1H), 3.49 - 3.39 (broad s, 4H), 3.27 - 3.18 (m, 2H), 2.93 - 2.84 (m, 1H), 2.69 - 2.48 (m, 8H), 2.20 (broad d, 2H), 2.07 - 1.96 (m, 1H), 1.83 - 1.73 (m, 2H), 1.70 - 1.60 (m, 1H), 1.16 - 1.24 (m, 2H); Calculated exact mass for C44H44FN5O6 by HRMS is 757.3276, found [M + 1] + 758.3336。 Example 3: Synthesis of (S)-3-(6-Fluoro-5-(4-((1-(2-Fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 41). [Chemical formula] Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate.

[0126] Thionyl chloride (130 g, 1.09 mol) was slowly added to a mixture of 2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) at 10 °C, and the mixture was stirred at 80 °C for 3 hours. TLC indicated that the reaction was complete. The mixture was cooled to room temperature, concentrated, and then partitioned between ethyl acetate and water. The organic layer was washed twice with saturated Na 2 CO 3 and brine, dried over Na 2 SO 4 and concentrated to obtain crude methyl 2-bromo-4,5-difluorobenzoate (210 g, yield: 100%), which was used in the next step without further purification. Step 2: Preparation of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0127] A mixture of methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol), tert-butyl piperazine-1-carboxylate (234 g, 1.25 mol), and K 2 CO 3 (173 g, 1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80 °C for 16 hours. TLC indicated that the reaction was complete. The mixture was added to water (2 L), stirred for 10 minutes, and then ethyl acetate was added. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over Na 2 SO 4It was dried and concentrated to obtain tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (315.8 g, yield: 90%). Step 3: Preparation of tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0128] A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (306 g, 0.73 mol) and CuCN (98 g, 1.09 mol) in DMF (1.2 L) was stirred at 100 °C for 16 h. TLC indicated that the reaction was complete. The mixture was cooled to room temperature. Ethyl acetate (2 L) and ammonium hydroxide (2 L) were added and the mixture was stirred for 30 min. The mixture was filtered. The organic layer was washed with water and dried over Na 2 SO 4 and concentrated to obtain the crude product (254 g). This crude product was taken up in petroleum ether (1 L) under reflux. The mixture was filtered and dried in an oven at 50 °C to obtain tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (215 g, yield: 81%). Step 4: Preparation of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0129] To a solution of pyridine (391 g, 4.95 mol), water (200 mL), and acetic acid (264 g, 4.4 mol) was added tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (200 g, 0.55 mol) and Raney nickel (85% in water, 100 g) at room temperature. The resulting mixture was heated to 60 °C. Sodium hypophosphite (292 g in 500 mL of water) was added dropwise to the mixture. The mixture was stirred at 60 °C for 16 h. TLC indicated that the reaction was not complete. The mixture was stirred for an additional 10 h. The mixture was cooled to room temperature. Ethyl acetate and water were added. The mixture was filtered. The organic layer was washed with water, 1N HCl, and brine, and dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product (208 g, crude), which was further purified by a silica gel pad to give 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (86.5 g, yield: 43%). Step 5: Preparation of tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate.

[0130] To a solution of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl (S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature. Acetic acid (19.8 g, 0.33 mol) was added at 0 °C, followed by slow addition of sodium cyanoborohydride (27.6 g, 0.44 mol). The mixture was stirred at room temperature for 16 h. TLC indicated that the reaction was complete. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated citric acid and brine, and dried over Na 2 SO 4It was dried and concentrated under reduced pressure to obtain a crude product, which was further purified by a silica gel pad to obtain tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (80 g, yield: 69%). Step 6: Preparation of (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonic acid.

[0131] To a solution of (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (67 g, 0.13 mol) in acetonitrile (670 mL) was added benzenesulfonic acid (43 g, 0.26 mol). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature. The mixture was filtered and dried to give (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonic acid (56 g, 86%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H), 2.88-2.91 (m, 1H), 3.30 (br s, 8H), 4.38 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49 (d, J = 8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (s, 2H), 10.99 (s, 1H). LCMS m / z 347.3[M+1] + . Step 7: Preparation of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0132] The racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (50.0 g, 104 mmol) prepared in Step 10 of Compound 87 was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH 3 H 2 O MeOH]; B%: 60% - 60%).

[0133] From the recovered first fraction, (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (15.0 g, purity 99.4%) was obtained as an off-white solid. [α] D 25 = 335.8 (1 g / 100 mL in EtOAc); LCMS m / z 478.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.12 - 7.23 (m, 3 H), 6.65 - 6.86 (m, 4 H), 6.25 - 6.35 (m, 3H), 6.13 (d, 1H), 4.30 (t, 1H), 4.23 (m, 2H), 4.07 (d, J = 6.4 Hz, 1H), 3.53 (m, 1H), 3.25 (s, 6H), 3.15 - 3.24 (m, 2H), 2.42 - 2.50 (m, 2H), 1.57 - 1.72 (m, 3H), 1.22 - 1.40 (m, 2H).

[0134] From the recovered second fraction, (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (16.0 g, purity 98.1%) was obtained as a brown solid. [α] D 25 = -303.9 (0.5 g / 100 mL in EtOAc); LCMS m / z 478.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 1H), 7.16 (m, 3 H), 6.65 - 6.80 (m, 4 H), 6.25 - 6.32 (m, 3H), 6.13 (d, J = 13.6 Hz, 1H), 4.32 (t, 1H), 4.17 - 4.27 (m, 2H), 4.07 (d, J = 6.4 Hz, 1H), 3.55 (m, 1H), 3.25 (s, 6H), 3.16 - 3.25 (m, 2H), 2.40 - 2.50 (m, 2H), 1.57 - 1.72 (m, 3H), 1.22 - 1.37 (m, 2H). Step 8: Preparation of (S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 41).

[0135] The isolated (-)-enantiomer from Step 7 was first deprotected under acidic conditions and then reacted with the product from Step 6 under the same conditions as described in Step 11 for the preparation of Compound 87. LCMS m / z 762.2 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.35 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 7.27 - 7.16 (m, 4H), 6.82 - 6.72 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.35 - 6.28 (m, 3H), 6.15 (d, J = 14.1 Hz, 1H), 5.08 (dd, 1H), 4.43 - 4.18 (m, 5H), 3.63 - 3.53 (m, 1H), 3.32 - 3.30 (m, 2H), 3.26 - 3.20 (m, 2H), 3.12 (br s, 2H), 2.95 - 2.85 (m, 1H), 2.63 - 2.48 (m, 7H), 2.42 - 2.32 (m, 1H), 2.22 (br d, 2H), 2.02 - 1.91 (m, 1H), 1.81 - 1.73 (m, 2H), 1.70 - 1.61 (m, 1H), 1.27 - 1.20 (m, 2H); Calculated exact mass for C44H45F2N5O5 by HRMS is 761.3389, found [M+1] + 762.3593。 Example 4: Synthesis of (S)-3-(6-Fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 42).

Chemical Structure

[0136] The racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol (49.2 g, 108 mmol) prepared in Step 11 of Compound 36 was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10 um); mobile phase: [0.1% NH 3 H 2 O MeOH]; B%: 50% - 50%, 5.5 min). From the recovered first fraction, (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol was obtained as an off-white solid (19.0 g, purity 97.8%). [α] D 25 = 360.4 (1.34 g / 100 mL in EtOAc); LCMS m / z 460.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.84 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.08 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.58 (dt, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.38 - 1.49 (m, 2 H). From the recovered second fraction, (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol was obtained as an off-white solid (19.0 g, purity 99.8%). [α] D 25=-386.8 (0.39 g / 100 mL in EtOAc); LCMS m / z 460.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 - 7.20 (m, 3 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.62 - 6.73 (m, 4 H), 6.43 - 6.51 (m, 3 H), 6.35 (dd, J = 8.2, 2.5 Hz, 1 H), 4.79 (br s, 1 H, OH), 4.43 (t, J = 11.2 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 4.07 (d, J = 7.4 Hz, 1 H), 3.53 - 3.65 (m, 3 H), 3.37 (s, 6 H), 2.58 (dt, 2 H), 1.82 (br d, J = 12.8 Hz, 2 H), 1.66 - 1.77 (m, 1 H), 1.35 - 1.49 (m, 2 H). Step 2: Preparation of (S)-3-(6-fluoro-5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 42).

[0137] This compound was prepared using the isolated (-)-enantiomer from Step 1 under the same conditions as described for the synthesis of Compound 41. LCMS m / z 744.2 [M+H] + ; 11H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.29 (s, 1H), 7.43 (d, J = 11.3 Hz, 1H), 7.27 - 7.12 (m, 4H), 6.80 - 6.74 (m, 2H), 6.69 - 6.59 (m, 3H), 6.38 (d, J = 8.1 Hz, 2H), 6.33 - 6.24 (m, 2H), 5.08 (dd, 1H), 4.42 - 4.15 (m, 5H), 3.67 - 3.50 (m, 3H), 3.23 (m, 2H), 3.12 (br s, 2H), 2.95 - 2.85 (m, 1H), 2.67 - 2.50 (m, 7H), 2.41 - 2.30 (m, 1H), 2.20 (br d, 2H), 2.02 - 1.90 (m, 1H), 1.82 - 1.74 (m, 2H), 1.69 - 1.60 (m, 1H), 1.26 - 1.10 (m, 2H); HR Calculated exact mass for C44H46FN5O5 by HRMS 743.3483, found [M + 1] + 744.3681. Example 5: Synthesis of (S)-3-(5-(4-((1-(2-Fluoro-4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 86).

Chemical Structure

[0138] This compound was prepared using the same method as for the preparation of Compound 41. The desired compound was obtained as a purified neutral white solid. LCMS m / z 743.7 [M + H] + ; 11H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.37 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.17 (m, 3H), 7.07 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.84 - 6.71 (m, 3H), 6.69 (d, J = 8.3 Hz, 1H), 6.37 - 6.27 (m, 3H), 6.16 (br d, J = 12 Hz, 1H), 5.06 (dd, J = 12.5 Hz, 4.2 Hz, 1H), 4.40 - 4.18 (m, 5H), 3.57 (m, 1H), 3.32 - 3.17 (m, 6H), 2.96 - 2.87 (m, 1H), 2.60 - 2.48 (m, 7H), 2.40 - 2.33 (m, 1H), 2.22 (br d, 2H), 2.00 - 1.90 (br d, 1H), 1.80 - 1.75 (m, 2H), 1.70 - 1.60 (m, 1H), 1.28 - 1.20 (m, 2H); Calculated exact mass for C44H46FN5O5 by HRMS is 743.3483, found [M+1] + 744.3567. Example 6: Synthesis of (S)-3-(5-(4-((1-(2-Fluoro-4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 45).

Chem.

[0139] This compound was prepared using the same method as the preparation method of Compound 41. LCMS m / z 743.5 [M+H] + ; 1 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.37 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.20 - 7.06 (m, 5H), 6.82 - 6.78 (m, 2H), 6.78 - 6.72 (m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.34 - 6.29 (m, 3H), 6.16 (d, J = 14.3 Hz, 1H), 5.06 (dd, J = 13.2, 4.8 Hz, 1H), 4.43 - 4.09 (m, 5H), 3.59 - 3.54 (m, 1H), 3.34 - 3.19 (m, 6H), 2.94 - 2.86 (m, 1H), 2.69 - 2.48 (m, 7H), 2.46 - 2.31 (m, 1H), 2.20 (br, 2H), 1.98 - 1.92 (m, 1H), 1.85 - 1.60 (m, 3H), 1.29 - 1.20 (m, 2H); Calculated exact mass for C44H46FN5O5 by HRMS is 743.3483, found [M+1] + 744.3567。 Example 7: Synthesis of (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 33).

Chem.

[0140] This compound was prepared using the same method as the method for preparing Compound 41. LCMS m / z 725.7 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.31 (s, 1H), 7.53 - 7.51 (m, 1H), 7.25 - 7.02 (m, 5H), 6.77 (m, 2H), 6.73 - 6.60 (m, 3H), 6.40 (d, J = 8.3 Hz, 2H), 6.33 - 6.25 (m, 2H), 5.06 (dd, 1H), 4.39 - 4.31 (m, 2H), 4.26 - 4.17 (m, 3H), 3.64 - 3.50 (m, 3H), 3.28 - 3.25 (br s, 4H), 2.94 - 2.89 (m, 1H), 2.64 - 2.48 (m, 7H), 2.41 - 2.33 (m, 1H), 2.19 (br, 2H), 2.00 - 1.93 (m, 1H), 1.86 - 1.60 (m, 3H), 1.29 - 1.12 (m, 2H); Calculated exact mass for C44H47N5O5 by HRMS is 725.3577, found [M+1] + 726.3675. Example 8: Synthesis of (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 34). [Chemical formula] This compound was prepared using the same method as the preparation method of Compound 41. LCMS m / z 725.5 [M+H] + ; H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.32 (s, 1H), 7.62 - 7.58 (m, 1H), 7.34 - 7.30 (m, 1H), 7.19 - 7.06 (m, 4H), 6.83 - 6.74 (m, 2H), 6.72 - 6.54 (m, 3H), 6.40 (d, J = 7.5 Hz, 2H), 6.35 - 6.20 (m, 2H), 5.07 (br d, J = 8.8 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.27 - 4.14 (m, 3H), 3.64 - 3.51 (m, 3H), 3.31 - 3.27 (m, 4H), 2.94 - 2.87 (m, 1H), 2.70 - 2.54 (m, 7H), 2.40 - 2.31 (m, 1H), 2.24 - 2.15 (m, 2H), 2.03 - 1.65 (m, 4H), 1.30 - 1.20 (m, 2H); Calculated exact mass for C44H47N5O5 by HRMS is 725.3577, found [M+1] + 726.3702。 Example 9: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 32).

Chemical Structure

[0141] This compound was prepared using the same procedure as described in Example 11. LC / MS: 757.5 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 9.35 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.16 - 7.02 (m, 3H), 6.98 (d, J = 7.8 Hz, 1H), 6.75 (t, J = 8.9 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.51 (s, 1H), 6.30 - 6.24 (m, 3H), 6.16 (d, J = 13.9 Hz, 1H), 5.06 (dd, 1H), 4.38 - 4.10 (m, 5H), 3.52 - 3.47 (m, 1H), 3.30 - 3.20 (m, 6H), 2.95 - 2.87 (m, 1H), 2.72 - 2.48 (m, 7H), 2.42 - 2.30 (m, 1H), 2.22 - 2.19 (br, 2H), 2.15 (s, 3H), 1.99 - 1.90 (m, 1H), 1.78 (m, 2H), 1.70 - 1.63 (m, 1H), 1.25 - 1.10 (m, 2H); Calculated exact mass for C45H48FN5O5 by HRMS is 757.3639, measured value [M+1] + 758.3681. Example 13: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 84). [Chemical formula]

[0142] This compound was prepared using the same procedure as described in Example 11. LC / MS: m / z 779.4 [M+1] + ; 1 1H NMR (400 MHz, DMSO) δ = 10.95 (s, 1H), 9.38 (s, 1H), 7.53 - 7.51 (m, 1H), 7.28 - 7.21 (m, 1H), 7.08 - 7.04 (m, 2H), 6.88 - 6.74 (m, 2H), 6.69 - 6.66 (m, 2H), 6.34 - 6.23 (m, 4H), 5.06 (dd, 1H), 4.35 - 4.15 (m, 5H), 3.65 - 3.54 (m, 1H), 3.33 - 3.23 (m, 6H), 2.98 - 2.84 (m, 1H), 2.62 - 2.41 (m, 7H), 2.38 - 2.34 (m, 1H), 2.20 (br d, 2H), 2.03 - 1.93 (m, 1H), 1.80 - 1.69 (m, 2H), 1.68 - 1.60 (m, 1H), 1.26 - 1.16 (m, 2H); Calculated exact mass for C44H44F3N5O5 by HRMS is 779.3295, measured value [M+1] + 780.3345. Example 14: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-Hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 56) [Chemical formula] Step 1: Preparation of 1-(4-(7-(Benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine A solution of 1-{4-[7-(Benzyloxy)-3-bromo-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine (100 mg, 0.18 mmol), 3-methoxyphenylboronic acid (41.02 mg, 0.27 mmol) and potassium carbonate (74.63 mg, 0.54 mmol) in DMF / H 2 O (20 mL, DMF / H 2 O = 5:1) was stirred at room temperature under nitrogen. To this solution, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (26.34 mg, 0.036 mmol) was added. The reaction mixture was stirred at 60 °C for 5 hours under nitrogen. The reaction mixture was filtered and evaporated in vacuo to obtain a crude product. The crude product was dissolved in DCM (200 mL), washed with water (20 mL), the organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The obtained residue was purified by preparative TLC (PE:EA = 5:1) to obtain the desired product (80 mg, 0.14 mmol, yield 76.1%) as a yellow solid. LC / MS: 578.1 [M+1] + . Step 2: Preparation of cis-4-(4-(4-(Dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol A solution of 1-{4-[7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl]phenyl}-4-(dimethoxymethyl)piperidine (100 mg, 0.17 mmol) in THF (15 mL) stirred at room temperature under hydrogen was added palladium / carbon (180 mg). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and evaporated in vacuo to afford the desired product (80 mg, 0.16 mmol, 96.1%) as a yellow solid. LC / MS: 489.9 [M+1] + 。 Step 3: Preparation of cis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde THF / H 2 SO 4 (10% aqueous solution) (20 mL, THF / H 2 SO 4 = 1 / 1) of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol (100 mg, 0.2 mmol) was stirred at 70 °C for 2 h. The reaction mixture was adjusted to about pH 12 with sodium hydroxide solution (2 mol / L), extracted with DCM (200 mL), dried over sodium sulfate and evaporated in vacuo to afford the desired product (80 mg, 0.18 mmol, 88% yield) as a yellow solid. LC / MS: 443.3 [M+1] + 。 Step 4: Preparation of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 56) A solution of cis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonic acid (24.32 mg, 0.05 mmol), TEA (0.25 mmol), and MgSO 4 (60 mg, 0.5 mmol) in DCM (5 mL) was stirred at room temperature for 30 minutes under nitrogen. Then, sodium triacetoxyborohydride (31.79 mg, 0.15 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, the organic layer was washed with water, and extracted with DCM (50 mL) to obtain the crude product. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the desired product (45 mg, 0.06 mmol, 53%) as a white solid. LC / MS: 756.2 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.27 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.15 - 6.99 (m, 3H), 6.74 - 6.59 (m, 4H), 6.42 (d, J = 8.6 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 6.34 - 6.16 (m, 3H), 5.06 (dd, 1H), 4.41 - 4.15 (m, 5H), 3.61 - 3.52 (m, 5H), 3.50 - 3.44 (m, 1H), 3.28 (br s, 4H), 2.98 - 2.84 (m, 1H), 2.66 - 2.51 (m, 7H), 2.37 - 2.31 (m, 1H), 2.19 (br d, 2H), 2.02 - 1.90 (m, 1H), 1.80 - 1.73 (m, 2H), 1.69 - 1.60 (m, 1H), 1.25 - 1.16 m, 2H); Calculated exact mass for C45H49N5O6 by HRMS is 755.3683, found [M+H] + 756.3753. Example 15: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(4-Fluoro-3-methoxyphenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 63)

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0143] T47D cells were plated at 1.5×10 5 cells / well in 24-well plates containing RPMI growth medium supplemented with 10% FBS and 1× penicillin streptomycin. MCF7 cells were plated at 1.5×10 5 cells / well in 24-well plates containing DMEM growth medium supplemented with 10% FBS and 1× penicillin streptomycin. CAMA1 cells were plated at 2×10 5 cells / well in 24-well plates containing RPMI growth medium supplemented with 20% FBS and 1× penicillin streptomycin. They were then incubated overnight at 37°C. The next day, the test compounds were administered to the cells by using 1000× compound stock solutions prepared in DMSO at various concentrations. After administration of the compounds, the cells were then incubated at 37°C for 6 hours.

[0144] Once completed, cells were washed with PBS and proteins were collected in Laemmli sample buffer (1X; VWR International). Proteins in cell lysates were separated by SDS-PAGE and transferred to an Odyssey nitrocellulose membrane (Licor) using an iblot® dry blotting transfer system (ThermoFisher). Nonspecific binding was blocked by incubating the membrane with Intercept Blocking Buffer (Licor) for 1 hour at room temperature with gentle shaking. The membrane was then incubated overnight at 4 °C with primary antibodies rabbit anti-ER (Cell Signaling, 8644) and mouse anti-GAPDH (1:5,000, Santa Cruz Biotechnology, sc-47724) diluted in Intercept Blocking Buffer containing 0.1% Tween 20. After washing three times with TBS-T, the membrane was incubated for 1 hour with IRDye® 800CW goat anti-mouse IgG (1:20,000, Licor) or IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor). After washing with TBS-T, the membrane was rinsed in TBS and scanned with an Odyssey® CLx Imaging System (Licor). Bands were quantified using Image Studio™ software (Licor).

[0145] Figures 1A - 1D show the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds 85, 60, 32, and 52 of the present disclosure. Figures 2A and 2B show the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds 87 and 84 of the present disclosure. Figures 4A and 4B show the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds 86 and 33 of the present disclosure. Figures 6A - 6C show the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds 41, 42, and 63 of the present disclosure. Figures 7A - 7D show the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds 89, 56, 90, and 74 of the present disclosure.

[0146] Table 3 shows the ERα degradation activity in the T47D cell line 6 hours after administration of exemplary compounds of the present disclosure. [Table 3]

[0147] Figures 3A and 3B show the ERα degradation activity in the MCF7 cell line 6 hours after administration of exemplary compounds 86 and 33 of the present disclosure.

[0148] Figures 5A and 5B show the ERα degradation activity in the CAMA1 cell line 6 hours after administration of exemplary compounds 86 and 33 of the present disclosure.

[0149] Many features and advantages of the present disclosure are apparent from the detailed description, and it is intended that the appended claims cover all such features and advantages of the present disclosure that are within the true spirit and scope of the present disclosure. Further, since those skilled in the art will readily envision numerous modifications and variations, it is not desirable to limit the present disclosure to the exact constructions and operations illustrated and described, and thus it can be said that all suitable modifications and equivalents fall within the scope of the present disclosure.

[0150] Also, those skilled in the art will recognize that the underlying concepts of the present disclosure can be readily used as a basis for designing other structures, methods, and systems for carrying out some of the purposes of the present disclosure. Accordingly, the claims should not be regarded as limited by the foregoing description or examples. In one embodiment, for example, the following items are provided. (Item 1) A compound of formula (I): [Chemical formula] , its stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, or hydrates, wherein R 1 is H, or C 1 ~C 6 alkyl, and each of these is substituted with 0, 1, 2 or 3 R 6 groups; R 2 and R 3 are each independently H, C 1 ~C 3 alkyl, or C 1 ~C 3 haloalkyl, and each of these is substituted with 0, 1, 2 or 3 R 6 groups; Each R 4 is independently selected from H, hydroxyl, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxyl, or C 1 ~C 3 haloalkyl, and each of these is substituted with 0, 1, 2 or 3 R 6 groups, or two R 4 groups together form oxo; R 5 is halogen, hydroxy, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxy, C 1 ~C 3 haloalkyl, -N(R 7 ) 2 , and -CN, and each of these is substituted with 0, 1, 2 or 3 R 6 groups; X 1 and X 2 are each independently H, halogen, cyano, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, or C 1 ~C 6 haloalkyl, and each of these is substituted with 0, 1, 2 or 3 R 6is replaced by; X 3 and X 4 are each independently selected from H or halo; L is a linker of 1 to 22 carbon atoms, and one or more carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each optionally independently replaced by 0, 1, 2, or 3 R 6 and is replaced by; Each R 6 is independently selected from C 1 ~C 6 alkyl, halo, cyano, and hydroxy, Each R 7 is independently selected from hydrogen, C 1 ~C 6 alkyl, and acyl, and these are each optionally replaced by 0, 1, 2, or 3 R 6 or two R 7 groups together form a 3- to 6-membered heterocycle or heteroaryl, a compound, a stereoisomer or a mixture of stereoisomers thereof, a pharmaceutically acceptable salt, or a hydrate. (Item 2) R 1 is H, or C 1 ~C 6 alkyl selected from, and these are each optionally replaced by 0, 1, 2, or 3 R 6 The compound according to item 1 or a pharmaceutically acceptable salt thereof as described above. (Item 3) R 1 is selected from H or methyl, and these are each optionally replaced by 0, 1, 2, or 3 R 6 The compound according to item 2 or a pharmaceutically acceptable salt thereof as described above. (Item 4) R 1The compound according to item 3, or a pharmaceutically acceptable salt thereof, wherein [the relevant group] is selected from H or methyl. (Item 5) R 1 The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is H. (Item 6) R 1 The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is methyl. (Item 7) R 2 and R 3 are each independently selected from H, C 1 ~C 3 alkyl, or C 1 ~C 3 haloalkyl, and these are each substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof. (Item 8) R 2 and R 3 are each independently selected from H and methyl, and these are each substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 7, or a pharmaceutically acceptable salt thereof. (Item 9) R 2 and R 3 are each independently selected from H and methyl. The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof. (Item 10) R 2 and R 3 are each H. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof. (Item 11) R 2 and R 3 are each methyl. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof. (Item 12) R 2 and R 3 are each H and methyl, respectively, the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof. (Item 13) Each R 4 is independently selected from H, hydroxyl, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxyl, or C 1 ~C 3 haloalkyl, and these are each substituted with 0, 1, 2, or 3 R 6 or two R 4 groups together form oxo, the compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof. (Item 14) Each R 4 is independently selected from H, hydroxyl, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxyl, or C 1 ~C 3 haloalkyl, or two R 4 groups together form oxo, the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof. (Item 15) R 4 is H, the compound according to any one of items 1 to 14 or a pharmaceutically acceptable salt thereof. (Item 16) Two R 4 groups together form oxo, the compound according to any one of items 1 to 14 or a pharmaceutically acceptable salt thereof. (Item 17) R 5 is halogen, hydroxy, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxy, C 1 ~C 3 haloalkyl, -N(R7 ) 2 and -CN, each of which is independently selected from 0, 1, 2, or 3 R 6 substituents, and is a compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof. (Item 18) R 5 is halogen, hydroxy, C 1 ~C 3 alkyl, C 1 ~C 3 alkoxy, C 1 ~C 3 haloalkyl, -N(R 7 ) 2 and -CN, and is a compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof. (Item 19) R 5 is selected from halogen, and is a compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof. (Item 20) R 5 is F, and is a compound according to any one of items 1 to 19 or a pharmaceutically acceptable salt thereof. (Item 21) X 1 and X 2 are each independently selected from H, halogen, cyano, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, or C 1 ~C 6 haloalkyl, each of which is independently substituted with 0, 1, 2, or 3 R 6 substituents, and is a compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof. (Item 22) X 1 and X 2 are each independently selected from H, halogen, cyano, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxyl, or C1 ~C 6 A compound according to any one of items 1 to 21 or a pharmaceutically acceptable salt thereof, selected from haloalkyl. (Item 23) X 1 and X 2 are each independently H, F, CN, methyl, methoxy, trifluoromethyl, a compound according to any one of items 1 to 22 or a pharmaceutically acceptable salt thereof. (Item 24) X 1 and X 2 are each H, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 25) X 1 and X 2 are each F, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 26) X 1 and X 2 are each H and methyl, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 27) X 1 and X 2 are each H and F, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 28) X 1 and X 2 are each H and methoxy, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 29) X 1 and X 2 are each F and methyl, a compound according to any one of items 1 to 23 or a pharmaceutically acceptable salt thereof. (Item 30) X 1 and X 2The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each is F and methoxy. (Item 31) X 1 and X 2 The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each is F and trifluoromethyl. (Item 32) X 3 and X 4 The compound according to any one of items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H or halo. (Item 33) X 3 and X 4 The compound according to any one of items 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H or F. (Item 34) X 3 and X 4 The compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein each is H. (Item 35) X 3 and X 4 The compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein each is F. (Item 36) X 3 and X 4 The compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein each is H and F. (Item 37) L is a linker having a length of 1 to 22 carbon atoms, and one or more carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently optionally replaced by 0, 1, 2, or 3 R 6The compound according to any one of items 1 to 36 or a pharmaceutically acceptable salt thereof, which is independently substituted. (Item 38) L is a linker having 1 to 20 carbon atoms in length, and one or more carbon atoms are each independently replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently replaced, if necessary, by 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 37 or a pharmaceutically acceptable salt thereof, which is independently substituted. (Item 39) L is a linker having 1 to 18 carbon atoms in length, and one or more carbon atoms are each independently replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently replaced, if necessary, by 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, which is independently substituted. (Item 40) L is a linker having 1 to 16 carbon atoms in length, and one or more carbon atoms are each independently replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently replaced, if necessary, by 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 39 or a pharmaceutically acceptable salt thereof, which is independently substituted. (Item 41) L is a linker having 1 to 14 carbon atoms in length, and one or more carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 40 or a pharmaceutically acceptable salt thereof. (Item 42) L is a linker having 1 to 12 carbon atoms in length, and one or more carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 41 or a pharmaceutically acceptable salt thereof. (Item 43) L is a linker having 1 to 10 carbon atoms in length, and one or more carbon atoms are each independently optionally replaced by a group selected from C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and these are each independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 42 or a pharmaceutically acceptable salt thereof. (Item 44) L is a linker having 1 to 8 carbon atoms in length, and one or more carbon atoms are each independently optionally replaced by a group selected from O, NR 7 , S, C 2 -alkenyl, C 2-alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each optionally independently replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 43 or a pharmaceutically acceptable salt thereof, which is independently substituted with 6 . (Item 45) L is a linker having 1 to 8 carbon atoms in length, and one or more carbon atoms are C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each optionally independently replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 44 or a pharmaceutically acceptable salt thereof, which is independently substituted with 6 . (Item 46) L is a linker having 1 to 6 carbon atoms in length, and one or more carbon atoms are C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each optionally independently replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 6 The compound according to any one of items 1 to 45 or a pharmaceutically acceptable salt thereof, which is independently substituted with 6 . (Item 47) L is a linker having 1 to 4 carbon atoms in length, and one or more carbon atoms are C(O), O, NR 7 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each optionally independently replaced by a group selected therefrom, each of which is independently substituted with 0, 1, 2, or 3 R 6The compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, which is independently substituted by (Item 48) L is a linker, and two carbon atoms are each independently replaced by a heterocycle, and each of these is substituted by 0, 1, 2 or 3 R 6 The compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, which is independently substituted by L is a linker, one carbon atom is replaced by a heterocycle, and one carbon atom is replaced by a cycloalkyl, and each of these is substituted by 0, 1, 2 or 3 R 6 The compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, which is independently substituted by (Item 50) L is a linker, and more than one carbon atom is each independently replaced by a group selected from C(O), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, and each of these is substituted by 0, 1, 2 or 3 R 6 The compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, which is substituted by (Item 51) L is a linker, and more than one carbon atom is each independently replaced by a group selected from C(O), O, and NR 4 and each of these is substituted by 0, 1, 2 or 3 R 6 The compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, which is substituted by (Item 52) L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

[Claim 1] The invention described in this specification.

Images