Novel chroman derivative with estrogen receptor degradation activity and application thereof

Abstract

The present disclosure relates to novel chroman derivatives having estrogen receptor degrading activity and uses thereof. In particular, the present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of cancer and related diseases and conditions.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202080092528.X, invention name “Novel chroman derivatives with estrogen receptor degradation activity and their uses” and application date April 13, 2020 (PCT application number PCT / US2020 / 027895).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 947,213, filed December 12, 2019, which is incorporated herein by reference in its entirety. Field of the Invention

[0004] The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in preventing and treating diseases and disorders such as cancer. Background Art

[0005] Estrogen is a female sex hormone that controls a wide range of physiological processes, such as the development of the female reproductive system, the maintenance of bone mass, and the protection of cardiovascular tissues and the central nervous system, by binding to its cognate estrogen receptors, ERa and ER. Upon binding of estrogen to the estrogen receptor ("ER"), the receptor undergoes a conformational change, leading to its homodimerization. ER homodimers then bind to estrogen response elements ("ERE") present in the promoters of a specific set of target genes and regulate their expression with the help of transcriptional co-regulators. Thousands of canonical ER target genes have been identified, many of which regulate cell proliferation and survival.

[0006] Because ER signaling involves many pathways, it is well known that dysregulation of ER signaling, particularly through ERα, can lead to uncontrolled cell proliferation and ultimately cancer. ER+ breast cancers account for approximately 75% of all breast cancer diagnoses, as well as some ovarian and endometrial cancers. The prevalence of ER+ cancers has led to decades of research and development of antiestrogens as therapeutic agents.

[0007] Anti-estrogen (i.e., hormone) therapy is the treatment of choice for most ER+ breast cancers. There are three major classes of anti-estrogen therapy, 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 types of anti-estrogen therapy work through different mechanisms, such as inhibiting aromatase, competitively binding to ERα, and / or causing ERα degradation.

[0008] These therapies can lead to adverse effects. For example, the administration of aromatase inhibitors leads to a decrease in bone mineral density, which can increase the risk of fractures. The administration of selective estrogen modulators can lead to the development of endometrial cancer and / or cardiovascular problems, such as deep thrombosis and pulmonary embolism. In addition, these therapies may have insufficient clinical efficacy.

[0009] Therefore, there is a need to treat ER+ cancers without the known harmful side effects of current treatments. One approach to achieve this goal is to exploit naturally occurring cellular ubiquitin-mediated degradation. Without being bound by any theory, it is believed that ERα degradation may occur when both ERα and a ubiquitin ligase are bound and in close proximity.

[0010] Cereblon ("CRBN") E3 ubiquitin ligase is a ubiquitin ligase that forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 and Cullin 4. It acts as a substrate receptor by bringing substrates into close 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 with CRBN and several other proteins simultaneously. In this way, CRBN can be used to target proteins for degradation, such as IKZF1 and IKZF3. This is believed to be the reason for the anti-myeloma effects of thalidomide and related compounds. Summary of the Invention

[0011] In some embodiments, provided herein is a compound of formula (I), a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt or hydrate thereof:

[0012]

[0013] in:

[0014] R 1 Selected from H, C1-C6 acyl, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0015] R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0016] Each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 4 The groups together form an oxo group;

[0017] R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0018] X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0019] X 3 and X 4 are each independently selected from H or halogen;

[0020] L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0021] Each R 6 independently selected from C1-C6 alkyl, halogen, cyano and hydroxy,

[0022] Each R 7 independently selected from hydrogen, C1-C6 alkyl and acyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 7 The groups together form a 3- to 6-membered heterocyclic ring or a heteroaryl group.

[0023] In some embodiments, the compound of formula (I) may include cis isomers and trans isomers. In some embodiments, the compound of formula (I) may be a mixture of cis isomers and trans isomers. In some embodiments, the compound of formula (I) may be a cis isomer.

[0024] In some embodiments, the compounds of formula (I) may include stereoisomers and mixtures of stereoisomers. In some embodiments, the compounds of formula (I) are stereoisomers. In some embodiments, the compounds of formula (I) may include racemic isomers and enantiomers.

[0025] In some embodiments, provided herein are compounds of formula (I)*:

[0026]

[0027] Also provided herein are methods of treating cancer in a subject in need thereof, 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

[0028] The foregoing summary and the following detailed description of the disclosure will be better understood when read in conjunction with the accompanying drawings. To illustrate the present disclosure, the accompanying drawings show some, but not all, alternative embodiments. However, it should be understood that the present disclosure is not limited to the precise arrangements and means shown. The accompanying drawings, which are incorporated in and constitute a part of the specification, help to explain the principles of the present disclosure.

[0029] Figures 1A to 1D The ERa degradation activity of exemplary compounds 85, 60, 32, and 52 of the present disclosure in the T47D cell line is illustrated 6 hours after administration.

[0030] Figure 2A and 2B The ERa degradation activity of exemplary compounds 87 and 84 of the present disclosure in the T47D cell line 6 hours after administration is demonstrated.

[0031] Figure 3A and 3B The ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the MCF7 cell line after 6 hours of administration is illustrated.

[0032] Figure 4A and 4B The ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the T47D cell line 6 hours after administration is illustrated.

[0033] Figure 5A and 5B The ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the CAMA-1 cell line 6 hours after administration is illustrated.

[0034] Figure 6A , 6B and 6C illustrate the ERa degradation activity of exemplary compounds 41, 42 and 63 of the present disclosure in the T47D cell line 6 hours after administration.

[0035] Figure 7A 、 7B , 7C and 7D illustrate the ERa degradation activity of exemplary compounds 89, 56, 90 and 74 of the present disclosure in the T47D cell line 6 hours after administration. DETAILED DESCRIPTION

[0036] definition

[0037] As used herein, "cancer" refers to diseases, disorders, and conditions involving abnormal cell growth that has 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.

[0038] "Subject" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and veterinary applications. In one embodiment, the subject is a human.

[0039] As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder or at least one discernible symptom thereof. In another embodiment, "treatment" refers to the improvement of at least one measurable physical parameter that is not necessarily recognized by the patient. In another embodiment, "treatment" refers to inhibiting the physical progression of a disease or disorder (e.g., stabilization of discernible symptoms), physiological progression (e.g., stabilization of a physical parameter), or both. In another embodiment, "treatment" refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may include lowering blood cholesterol levels.

[0040] As used herein, "prevention" or "preventing" refers to reducing the risk of developing a specified disease or disorder.

[0041] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CN is attached through a carbon atom.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances where it does not. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. One skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0043] When a numerical range is listed, it is intended to encompass every value and sub-range within the range. For example, "C1-C6 alkyl" is intended to encompass C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-6 Alkyl, C2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl, C 4-5 Alkyl and C 5-6 alkyl.

[0044] As used herein, the term "acyl" refers to a RC(O)- group such as, 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)-, wherein the group is attached to the parent molecular structure through a carbonyl functional group. In some embodiments, C 1-10 Acyl refers to, for example, the total number of chain or ring atoms of an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety plus the carbonyl carbon of the acyl group. For example, a C4-acyl group has three other ring or chain atoms plus the carbonyl group.

[0045] The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond, for example, a straight or branched chain group having 2 to 8 carbon atoms, referred to herein as (C 2- C8) 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-butene)-pentenyl.

[0046] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group having 1 to 8 carbon atoms, referred to herein as a (C1-C8) 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, tert-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.

[0047] As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group having 2 to 8 carbon atoms, referred to herein as a (C2-C8)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.

[0048] The term "aryl" as used herein refers to a monocyclic, bicyclic or other polycarbocyclic aromatic ring system having 5 to 14 ring atoms. The aryl group may optionally be fused to one or more rings selected from aryl, cycloalkyl, heteroaryl and heterocyclic groups. The aryl group of the present disclosure may be substituted by a group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, aralkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic group, hydroxyl, ketone, nitro, phosphate, sulfenyl, sulfinyl, sulfonyl, sulfonic acid, sulfonamido and thioketone groups. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties, such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems wherein the ring contains 6 carbon atoms, referred to herein as "C6-aryl."

[0049] As used herein, the term "cyano" refers to -CN.

[0050] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon radical having 3 to 16 carbon atoms, or 3 to 8 carbon atoms (referred to herein as "(C3-C8)cycloalkyl") derived from a cycloalkane. Exemplary cycloalkyl radicals include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl radicals may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, sulfenyl, sulfinyl, sulfonyl, sulfonic acid, sulfonamido, and thioketone. Cycloalkyl radicals may be fused with other cycloalkyl radicals (saturated or partially unsaturated), aryl, or heterocyclyl radicals to form bicyclic, tetracyclic, and the like. The term "cycloalkyl" also includes bridged and spiro-fused ring structures, which may or may not contain heteroatoms.

[0051] As used herein, the term "halo" or "halogen" refers to -F, -Cl, -Br and / or -I.

[0052] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing one or more heteroatoms, for example, 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. A heteroaryl group can be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, keto, nitro, phosphate, sulfenyl, sulfinyl, sulfonyl, sulfonic acid, sulfonamido, and thioketone. A heteroaryl group can also be fused to a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl (pyrazyl), triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, pyrazinyl (pyrazinyl), pyrimidinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, furanyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings wherein the ring contains 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-C5)heteroaryl".

[0053] As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" each refer to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. The heterocycle may be aromatic (heteroaryl) or non-aromatic. The heterocycle may be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, keto, nitro, phosphate, sulfenyl, sulfinyl, sulfonyl, sulfonic acid, sulfonamido, and thioketone. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups, wherein any of the above heterocycles are fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuranyl, dihydroindolinyl, dihydropyranyl, dihydrothiophenyl, dithiazolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thiophenyl, thiomorpholinyl, thiopyranyl, and triazolyl.

[0054] As used herein, the term "hydroxy" refers to -OH.

[0055] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic and 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 supplemental, additional, or enhanced therapeutic function.

[0056] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0057] As used herein, the term "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds of the present disclosure that are, 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 response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as, where possible, zwitterionic forms of the compounds disclosed herein. These are discussed in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Roche, EB, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0058] The term "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present disclosure. Compounds included in the compositions of the present disclosure that are basic in nature are capable of forming 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 those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds included in the compositions of the present disclosure that include an amino moiety can also form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. The compounds contained in the compositions of the present disclosure that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts and iron salts.

[0059] Using PerkinElmer Professional, Edition 17 generates chemical names.

[0060] The disclosed compounds may contain one or more chiral centers and / or double bonds and therefore exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" is comprised of all geometric isomers, enantiomers, or diastereomers. These compounds may be represented by the symbols "R" or "S," depending on the configuration of the substituents around the stereocarbon atom. The disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be referred to as "(±)" in nomenclature, but the skilled artisan will recognize that the structure may implicitly represent a chiral center. In some embodiments, an enantiomer or stereoisomer substantially free of the corresponding enantiomer may be provided.

[0061] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds wherein the individual compounds of the mixture exist primarily as (S)- or (R)-isomers. For example, the (S)-enantiomeric excess of the compound mixture is 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 more. In other embodiments, the compound mixture 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 greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the (R)-enantiomeric purity of the compound mixture is 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 more. In some other embodiments, the compound mixture 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 greater than about 99.5%, greater than about 99% to about 99.5%, or more.

[0062] Individual stereoisomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) coupling the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and freeing the optically pure product from the auxiliary; (2) forming a salt using an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral gas chromatography, chiral 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 synthetic methods.

[0063] Geometric isomers may also exist in the disclosed compounds. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds or the arrangement of substituents around carbocyclic rings. Substituents around carbon-carbon double bonds are designated as "Z" or "E" configurations, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise stated, structures describing double bonds include E and Z isomers.

[0064] Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" indicates that the substituents are on the same side of the double bond and "trans" indicates that the substituents are on opposite sides of the double bond. The arrangement of substituents on a carbon ring is referred to as "cis" or "trans." The term "cis" indicates that the substituents are on the same side of the plane of the ring, while the term "trans" indicates that the substituents are on opposite sides of the ring plane. A mixture of compounds in which substituents are on the same side of the ring plane and on opposite sides is referred to as "cis / trans."

[0065] The compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended to be encompassed within the scope of the disclosure, even though only one tautomeric structure is depicted.

[0066] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the disclosed structure but with deuterium ( 2 H) or tritium ( 3 H) instead of hydrogen, or with 13 C- or 14 C-carbon atoms in place of carbon are within the scope of the present disclosure.Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

[0067] Compound

[0068] In some embodiments, provided herein is a compound of formula (I), a stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, or a hydrate thereof:

[0069]

[0070] in:

[0071] R 1 Selected from H, C1-C6 acyl, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0072] R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0073] Each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 4 The groups together form an oxo group;

[0074] R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0075] X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0076] X 3 and X 4 are each independently selected from H or halogen;

[0077] L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0078] Each R 6independently selected from C1-C6 alkyl, halogen, cyano and hydroxy,

[0079] Each R 7 independently selected from hydrogen, C1-C6 alkyl and acyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 7 The groups together form a 3- to 6-membered heterocyclic ring or a heteroaryl group.

[0080] In some embodiments, R 1 Selected from H, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, R 1 can be selected from H or methyl, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, R 1 Each independently may be H or methyl.

[0081] In some embodiments, R 1 Can be H. In some embodiments, R 1 It may be methyl.

[0082] In some embodiments, R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, R 2 and R 3 Each independently selected from H and methyl, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, R 2 and R 3 are each independently selected from H and methyl.

[0083] In some embodiments, R 2 Can be H and R 3 Can be H. In some embodiments, R 2 Can be and R 3 In some embodiments, R 2 It can be methyl and R 3 Can be H. In some embodiments, R 2 It can be methyl and R 3 It may be methyl.

[0084] In some embodiments, each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6Replace, or two R 4 In some embodiments, each R 4 are independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, or two R 4 In some embodiments, R 4 is H. In some embodiments, both R 4 The groups are taken together to form an oxo group.

[0085] In some embodiments, R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN. In some embodiments, R 5 In some embodiments, R 5 It can be F.

[0086] In some embodiments, X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 In some embodiments, X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. 1 and X 2 Each is independently selected from H, F, CN, methyl, methoxy, and trifluoromethyl.

[0087] In some embodiments, X 1 It's H and X 2 is H. In some embodiments, X 1 It's F and X 2 is F. In some embodiments, X 1 It's H and X 2 In some embodiments, X 1 is methyl and X 2 is H. In some embodiments, X 1 It's H and X 2 is F. In some embodiments, X 1It's F and X 2 is H. In some embodiments, X 1 It's H and X 2 In some embodiments, X 1 is methoxy and X 2 is H. In some embodiments, X 1 It's F and X 2 In some embodiments, X 1 is methyl and X 2 is F. In some embodiments, X 1 It's F and X 2 In some embodiments, X 1 is methoxy and X 2 is F. In some embodiments, X 1 It's F and X 2 In some embodiments, X 1 is trifluoromethyl and X 2 It's F.

[0088] In some embodiments, X 3 and X 4 are each independently selected from H or halogen. In some embodiments, X 3 and X 4 are each independently selected from H or F.

[0089] In some embodiments, X 3 It's H and X 4 is H. In some embodiments, X 3 It's F and X 4 is F. In some embodiments, X 3 It's H and X 4 is F. In some embodiments, X 3 It's F and X 4 It’s H.

[0090] In some embodiments, L can be a linker having a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 20 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R5 In some embodiments, L can be a linker having a length of 1 to 18 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 16 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 14 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 12 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 10 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 replace.

[0091] In some embodiments, L can be a linker having a length of 1 to 8 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 6 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4, S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker having a length of 1 to 4 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 5 replace.

[0092] In some embodiments, L can be a linker wherein two carbon atoms are each independently replaced by a heterocycle, each heterocycle being independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker in which one carbon atom is replaced by a heterocycle and one carbon atom is replaced by a cycloalkyl group, each of which is independently replaced by 0, 1, 2, or 3 R 5 In some embodiments, L can be a linker in which more than one carbon atom is independently replaced by a group selected from the group consisting of: C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 5 In some embodiments, L can be a linker in which more than one carbon atom is independently replaced by a group selected from the group consisting of C(O), O, and NR 4 , each of which is represented by 0, 1, 2 or 3 R 5 replace.

[0093] In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be In some embodiments, L can be

[0094] In some embodiments, the compound of Formula (I) is a cis isomer.

[0095] In some embodiments, the compounds of Formula (I) are stereoisomers.

[0096] In some embodiments, provided herein are compounds of Formula (I)*:

[0097]

[0098] In some embodiments, provided herein is a compound selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0099] Table 1. Exemplary compounds of the present disclosure

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] Pharmaceutical composition

[0114] The present disclosure pharmaceutical composition comprises at least one compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate, which is prepared together with one or more pharmaceutically acceptable carriers. These preparations include those suitable for oral, rectal, local, oral and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the disease to be treated and the property of the specific compound used.

[0115] Formulations suitable for oral administration can be presented as discrete units, such as capsules, cachets, lozenges, 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 or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations can be prepared by any suitable pharmaceutical method, which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more auxiliary ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. The carrier can be a solid or liquid, or both, and can be formulated with at least one compound described herein as the active compound into a unit dosage formulation (e.g., a tablet) that can contain from about 0.05% to about 95% by weight of at least one active compound. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present disclosure can be prepared by any well-known pharmaceutical technique consisting essentially of mixing the components.

[0116] 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, etc. Pharmacologically applicable liquid compositions can be, for example, prepared by the following, for example, dissolving or dispersing at least one active compound of the present disclosure as described herein and optional pharmaceutical excipients in an excipient, such as water, saline, glucose aqueous solution, glycerol, ethanol, etc., to form a solution or suspension. Generally, suitable formulations can be prepared by uniformly and closely mixing at least one active compound of the present disclosure with a liquid or finely ground solid carrier or both, and then, if necessary, forming the product. For example, tablets can be prepared by pressing or molding a powder or granules of at least one compound of the present disclosure, which can optionally be combined with one or more auxiliary ingredients. Compressed tablets can be prepared by pressing at least one compound of the present disclosure in a free-flowing form (such as a powder or granules, which can optionally be mixed with a binder, a lubricant, an inert diluent, and / or a surfactant / dispersant) in a suitable machine. Molded tablets may be made by molding in a suitable machine the powdered form of at least one compound of the present disclosure moistened with an inert liquid diluent.

[0117] Formulations suitable for buccal (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored basis, usually sucrose and acacia or tragacanth, and pastilles comprising at least one compound in an inert basis such as gelatin and glycerin or sucrose and acacia.

[0118] The disclosed formulations suitable for parenteral administration comprise a sterile aqueous preparation of at least one compound of Formula (I) or its tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates, which is approximately isotonic with the blood of the intended recipient. These formulations are administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection. Such formulations can be conveniently prepared by mixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. The injectable compositions of the present disclosure may contain from about 0.1 to about 5% w / w of the active compound.

[0119] Formulations suitable for rectal administration are presented in the form of unit-dose suppositories. These can be prepared by mixing at least one compound described herein with one or more conventional solid carriers (eg, cocoa butter) and shaping the resulting mixture.

[0120] Preparations suitable for topical application to the skin can take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Operable carriers and excipients include vaseline, lanolin, polyethylene glycol, alcohol and two or more combinations thereof. The active compound (that is, at least one compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt and hydrate) is typically present in a concentration of about 0.1% to about 15% w / w of the composition, for example, about 0.5 to about 2%.

[0121] The amount of the active compound used can depend on the subject being treated, the subject's weight, the mode of administration and the judgment of the attending physician. For example, the dosage regimen can include an encapsulated compound of about 1 μg to about 1000 mg of sensory dose administered daily or half a day. In another embodiment, an encapsulated compound of a certain dose can be administered intermittently, for example, on a monthly or annual basis. Encapsulation helps to enter the site of action and allows the active ingredient to be administered simultaneously, theoretically producing a synergistic effect. According to the standard dosage regimen, the doctor will easily determine the optimal dose and will be able to easily adjust the administration to achieve such a dosage.

[0122] The therapeutically effective amount of the disclosed compounds or compositions can be measured by the therapeutic effectiveness of the compound. However, the dosage can vary according to the patient's needs, the severity of the condition to be treated, and the compound used. In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to establish a maximum plasma concentration. Preliminary administration, such as that determined in animal studies, and amplification of the dosage for human administration are performed according to practices recognized in the art.

[0123] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as for determining the LD 50 (dose lethal to 50% of the population) and ED 50(The dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0124] The data obtained from cell culture assays or animal studies can be used to formulate a range of dosages for use in humans. A therapeutically effective dose achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Record 50(4):219-244 (1966) and the equivalent surface area dose factors in the table below).

[0125] Table 2. Equivalent surface area dose factors.

[0126]

[0127] The dosage of the compound lies preferably within a range of circulating concentrations that include the ED with little or no toxicity. 50 The dosage can vary within this range, depending on the dosage form used and the route of administration employed. Generally, the therapeutically effective amount can vary with the age, condition, and sex of the subject, as well as the severity of the subject's condition. The dosage can be determined by a physician and adjusted as needed to suit the observed therapeutic effect.

[0128] Treatment

[0129] In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate is administered to a subject in need thereof to treat 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 positive for ERα. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate is administered as a pharmaceutical composition. In some embodiments, the subject has previously been treated with tamoxifen.

[0130] In some embodiments, provided herein are uses of a compound of Formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof in therapeutic treatments. In some embodiments, the therapeutic treatment is used to treat breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the therapeutic treatment is used to treat breast cancer. In some embodiments, the therapeutic treatment is used to treat lung cancer. In some embodiments, the therapeutic treatment is used to treat ovarian cancer. In some embodiments, the therapeutic treatment is used to treat endometrial cancer. In some embodiments, the therapeutic treatment is used to treat prostate cancer. In some embodiments, the therapeutic treatment is used to treat esophageal cancer. In some embodiments, the therapeutic treatment is used to treat estrogen-related diseases and conditions. In some embodiments, the therapeutic treatment is used to treat infertility. In some embodiments, the therapeutic treatment is used to treat ovulatory dysfunction. In some embodiments, the therapeutic treatment is used to treat postmenopausal osteoporosis. In some embodiments, the therapeutic treatment is used to treat estrogen-related gynecomastia. In some embodiments, the therapeutic treatment is used to treat dyspareunia caused by menopause. In some embodiments, the therapeutic treatment is for treating retroperitoneal fibrosis. In some embodiments, the therapeutic treatment is for treating idiopathic sclerosing mesenteritis.

[0131] In some embodiments, provided herein is the use of a compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate in the preparation of a medicament. In some embodiments, provided herein is a method of inhibiting cell growth, comprising contacting a cell with a compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate. In some embodiments, the cell may express ERα.

[0132] In one embodiment, a compound of formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered in combination with another therapeutic agent. The other therapeutic agent may provide additional or synergistic value relative to administering the disclosed compounds alone. The therapeutic agent may be selected from, for example, hormones and hormone analogs; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite tumor agents; antibiotic tumor agents; alkylating agents; antimicrotubule agents; platinum coordination complexes; aromatase inhibitors; and antimitotic agents.

[0133] In some embodiments, the therapeutic agent may be a hormone or hormone analog. In some embodiments, the therapeutic agent may be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent may be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent may be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent may be an antimetabolite tumor agent. In some embodiments, the therapeutic agent may be an antibiotic tumor agent. In some embodiments, the therapeutic agent may be an alkylating agent. In some embodiments, the therapeutic agent may be an antimicrotubule agent. In some embodiments, the therapeutic agent may be a platinum coordination complex. In some embodiments, the therapeutic agent may be an aromatase inhibitor. In some embodiments, the therapeutic agent may be an antimitotic agent.

[0134] In some embodiments, the aromatase inhibitor may be selected from anastrozole, letrozole, vorozole, fadrozole, exemestane, and formestane. In some embodiments, the aromatase inhibitor is anastrozole. In some embodiments, the aromatase inhibitor may be letrozole. In some embodiments, the aromatase inhibitor may be vorozole. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane.

[0135] In some embodiments, the anti-mitotic agent may be selected from paclitaxel, docetaxel, and Abraxane. In some embodiments, the anti-mitotic agent may be paclitaxel. In some embodiments, the anti-mitotic agent may be docetaxel. In some embodiments, the anti-mitotic agent may be Abraxane.

[0136] In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with a hormone or hormone analog. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with a signal transduction pathway inhibitor. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with an antimetabolite tumor agent. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with a topoisomerase I inhibitor. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with a topoisomerase II inhibitor. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with an aromatase inhibitor. In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, may be administered in combination with one or more anticancer agents.

[0137] In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with an anticancer agent, wherein the anticancer agent is tamoxifen. In some embodiments, the compound of formula (I) or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate can be administered in combination with an anticancer agent, wherein the anticancer agent is fulvestrant.

[0138] Example

[0139] The following examples and preparations are provided to further illustrate and exemplify the compounds disclosed herein and methods for preparing these compounds. It should be understood that the scope of the present disclosure is not limited in any way by the following examples and preparations.

[0140] The chemical entities described herein can be synthesized according to one or more illustrative reaction schemes herein and / or techniques known in the art. Unless otherwise specified, the reactions described herein are typically carried out at atmospheric pressure, typically in a temperature range of about -10°C to about 200°C. In addition, unless otherwise specified, reaction times and conditions are intended to be approximate, for example, at a temperature range of about -10°C to about 200°C, at about atmospheric pressure, for a time of, for example, about 1 to about 24 hours; in some embodiments, reactions placed overnight can average about 16 hours.

[0141] If desired, the separation and purification of the chemical entities and intermediates described herein can be achieved by any suitable separation or purification method (e.g., filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or a combination of these methods). See, for example, Carey et al., Advanced Organic Chemistry, 3rd edition, 1990 New York: Plenum Press; Mundy et al., Name Reactions and Reagents in Organic Synthesis, 2nd edition, 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 may also be used.

[0142] In all methods, it is well known that, according to the general principles of chemistry, protecting groups for sensitive or reactive groups can be used when necessary. Protecting groups are handled according to standard methods for organic synthesis (TW Greene and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups can be removed using methods apparent to those skilled in the art at a convenient stage in the synthesis of compounds.

[0143] When desired, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be separated by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated, for example, by crystallization; by forming diastereomeric derivatives, which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support, such as silica bound to a chiral ligand, or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0144] The compounds described herein can optionally be contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. In addition, the compounds described herein can optionally be contacted with a pharmaceutically acceptable base to form the corresponding base addition salts.

[0145] In some embodiments, disclosed compound can be synthesized by combining known synthetic methods usually.Based on the disclosure, the technology for synthesizing these chemical entities is obvious and can be known to those skilled in the art.Many optional starting compounds and other reactants that replace are commercially available, for example, can be bought from Millipore Sigma, or can be easily prepared by those skilled in the art using synthetic methods commonly used.

[0146] The following discussion is provided to illustrate some of the various methods that can be used to prepare the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used to prepare the compounds provided herein. Those skilled in the art will understand that, unless otherwise indicated, standard valences apply to all compounds in the general or named compounds described herein.

[0147] The following abbreviations have the following definitions:

[0148] 1.BINAP: 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl

[0149] 2.CbzCl: benzyloxycarbonyl chloride

[0150] 3.DCE: 1,2-dichloroethane

[0151] 4.DCM: dichloromethane

[0152] 5.DIEA or DIPEA: N,N-diisopropylethylamine

[0153] 6.DMEM: Dulbecco's modified Eagle's medium

[0154] 7.DMSO: dimethyl sulfoxide

[0155] 8.DMF: N,N-dimethylformamide

[0156] 9.EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0157] 10.ESI-TOF: Electrospray ionization time-of-flight mass spectrometry

[0158] 11. EtOAc: ethyl acetate

[0159] 12.FBS: Fetal Bovine Serum

[0160] 13.HOAt: 1-hydroxy-7-azabenzotriazole

[0161] 14.HPLC: High-pressure liquid chromatography

[0162] 15.HRMS: High-resolution mass spectrometry

[0163] 16.IBX: 2-iodooxybenzoic acid

[0164] 17.MeOH: methanol

[0165] 18.MCF-7: Michigan Cancer Foundation-7 breast cancer cell line

[0166] 19.MTBE: Methyl tert-butyl ether

[0167] 20.NBS: N-bromosuccinimide

[0168] 21.NMR: Nuclear Magnetic Resonance

[0169] 22.NCS: N-chlorosuccinimide

[0170] 23.Pd(dppf)Cl2: bis(diphenylphosphino)ferrocenepalladium dichloride

[0171] 24.RPMI: Roswell Park Memorial Institute medium

[0172] 25.SDS: Sodium dodecyl sulfate

[0173] 26.SFC: Supercritical Fluid Chromatography

[0174] 27.TBAB: Tetrabutylammonium bromide

[0175] 28.TBST: Tris-buffered saline and Tween 20

[0176] 29.TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy

[0177] 30. p-TSA or TsOH: p-toluenesulfonic acid

[0178] 31.THF: Tetrahydrofuran

[0179] Example 1. Synthesis of compounds of the present disclosure.

[0180] General Chemistry Procedures. HPLC spectra for all compounds were obtained using an Agilent 1200 series system with a DAD detector. Chromatography was performed on a 2.1×150 mm Zorbax 300SB-C18 5 μM column at a flow rate of 0.4 mL / min using water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B. 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 spectrometry (HRMS) data were collected in positive ion mode using an Agilent G1969A API-TOF with an electrospray ionization (ESI) source. The ionization reaction was performed in a ionization mode with a ionization reaction for protons ( 1 H NMR) 600 MHz or 400 MHz and for carbon ( 13 Nuclear magnetic resonance (NMR) spectra were obtained on a 150 MHz Bruker spectrometer (C NMR); chemical shifts are reported as (δ). Preparative HPLC was performed on an Agilent Prep 1200 series with UV detectors set at 254 nm and 220 nm. Samples were injected at room temperature onto a Phenomenex Luna 75×30 mm, 5 μm C 18 The column was loaded. The flow rate was 40 mL / min. A linear gradient was used from 10% (or 50%) MeOH (A) / water (with 0.1% TFA) (B) to 100% MeOH (A). HPLC was used to determine the purity of the target compound. When analyzed according to the HPLC method described above, the purity of all final compounds was determined to be greater than 95%.

[0181] The compound with formula (I) structure that the application claims can be prepared by connecting two parts by a connector. Usually, the molecule claimed can be approached in a stepwise or modular manner. The following scheme represents the general method used for preparing these compounds. However, the synthesis of formula (I) is not limited to these representative methods, because they can also be prepared by those skilled in the art of synthetic chemistry.

[0182] Scheme 1: Synthesis of compound 1

[0183]

[0184] Scheme 2: Synthesis of compound 2

[0185]

[0186] Scheme 3: Synthesis of compound 3

[0187]

[0188] Scheme 4: Synthesis of compound 4

[0189]

[0190] Scheme 5: Synthesis of Compounds 5-8

[0191]

[0192] Scheme 6: Synthesis of compounds 9-11

[0193]

[0194] Scheme 7: Synthesis of compounds 12-25

[0195]

[0196]

[0197] Scheme 8: Synthesis of compounds 26, 28-31

[0198]

[0199] Scheme 9: Synthesis of compound 27

[0200]

[0201] Scheme 10: Synthesis of compounds 32-36

[0202]

[0203] Scheme 11: Synthesis of compounds 37 and 44.

[0204]

[0205] Scheme 12: Synthesis of compounds 38-43, 45, 50-57, 60-65, 72-80, 84-87 and 89-90.

[0206]

[0207] Scheme 13: Synthesis of compounds 68-71.

[0208]

[0209] The syntheses of compounds 46, 47, 48, 49, 58, 59, 66, 67, 81-83 and 88 can be carried out according to the schemes described in Schemes 8, 9 and 12.

[0210] 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).

[0211]

[0212]

[0213] Step 1: Preparation of (1-(4-bromophenyl)piperidin-4-yl)methanol.

[0214] 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) was added 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 K3PO4 (150 g, 0.705 mol, 2.00 eq). The mixture was stirred at 80°C for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.80, Rf (product) = 0.30) showed complete consumption of the starting material. The mixture was poured into ice water (2.50 L) and extracted with EtOAc (1.00 L x 2). The organic layers were combined and washed with ammonium hydroxide solution (500 mL x 3, 30 mL of ammonium hydroxide in 210 mL of H O). The organic layer was washed with brine (500 mL) and dried over Na SO. The mixture was filtered and the filtrate was concentrated in vacuo to give (1-(4-bromophenyl)piperidin-4-yl)methanol as an off-white solid.

[0215] Step 2: Preparation of 1-(4-bromophenyl)piperidine-4-carbaldehyde.

[0216] 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) was added pyridine-sulfur trioxide (143 g, 901 mmol, 3.00 eq) at 0-10° C. The mixture was stirred at 0-10° C. for 2 hours. TLC (petroleum ether:ethyl acetate=1:1, Rf(starting material)=0.30, Rf(product)=0.60) showed complete consumption of the starting material. The mixture was poured into ice water (2.00 L) and extracted with EtOAc (500 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether:MTBE=10:1 (150 mL) to give 1-(4-bromophenyl)piperidine-4-carbaldehyde (60.0 g, crude) as a dark brown solid.

[0217] Step 3: Preparation of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine.

[0218] To a solution of 1-(4-bromophenyl)piperidine-4-carboxaldehyde (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 hours. TLC (petroleum ether: ethyl acetate = 5: 1, Rf (starting material) = 0.30, Rf (product) = 0.50) showed that the starting material was completely consumed. The resulting mixture was poured into saturated NaHCO3 (100 mL), extracted with EtOAc (100 mL x 3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column silica gel chromatography ( 40g Purification was performed on a silica gel flash column using a gradient of 0-100 ethyl acetate / petroleum ether at 60 mL / min. The desired 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (70.0 g, crude) was obtained as a white solid. H NMR (400 MHz CDCl₃) δ 7.32 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.08 (d, J = 7.2 Hz, 1H), 3.66 (br d, J = 12.4 Hz, 2H), 3.38 (s, 6H), 2.66 (td, J = 12.4, 2.0 Hz, 2H), 1.67-1.91 (m, 3H), 1.45 (qd, J = 12.4, 4.1 Hz, 2H).

[0219] Step 4: Preparation of 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one.

[0220] To a solution of resorcinol (230 g, 2.09 mol, 348 mL, 1.00 eq) and 3-chloropropionic acid (249 g, 2.30 mol, 1.10 eq) was added CF3SO3H (1.10 kg, 7.31 mol, 645 mL, 3.50 eq) at 40°C, and the mixture was stirred at 80°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.21, Rf (product) = 0.35) showed complete consumption of the starting material. The resulting 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, crude) was used directly in the next step.

[0221] Step 5: Preparation of 7-hydroxychroman-4-one.

[0222] Crude 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (419 g, 2.09 mol, 1.00 eq) was mixed with NaOH (584 g, 14.6 mol, 7.00 eq) in H₂O (1.59 L), and the mixture was stirred at 0°C for 30 minutes. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.40, Rf (product) = 0.60) indicated complete consumption of the starting material. The reaction mixture was first adjusted to pH ~5 with 6N HCl, then extracted with EtOAc (2 x 1.50 L). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield the desired crude product (342 g, crude) as a brown gum.

[0223] Step 6: Preparation of 7-(benzyloxy)chroman-4-one.

[0224] To a solution of 7-hydroxychroman-4-one (342 g, 2.08 mol, 1.00 eq) in DMF (1.50 L) was added KCO (575 g, 4.17 mol, 2.00 eq) and benzyl bromide (391 g, 2.29 mol, 272 mL, 1.10 eq), and the mixture was stirred at 15°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.20, Rf (product) = 0.50) showed complete consumption of the starting material. The mixture was poured into H2O (7.50 L) and extracted with EtOAc (2.00 L x 2). The combined organic layers were washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=15:1 to 8:1) to afford 7-(benzyloxy)chroman-4-one (185 g) as a white solid. LCMS m / z 255 (M+H) + .

[0225] Step 7: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol.

[0226] To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (63.0 g, 200 mmol, 1 eq) in 2-methyltetrahydrofuran (440 mL) was added n-BuLi (2.5 M, 96.2 mL, 1.30 eq). The mixture was stirred at -78°C for 1 hour, followed by the addition of 7-(benzyloxy)chroman-4-one (50.9 g, 200 mmol, 1.00 eq). The mixture was stirred at -78°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.15) indicated complete consumption of the starting material. The mixture was poured into H2O (300 mL) and extracted with EtOAc (50.0 mL x 2). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether:EtOAc (500 mL) at 15 °C for 30 min to give 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (72.0 g, crude) as a white solid. 1H NMR (400MHz, CDCl3) δ7.31-7.46(m,5H),7.25(d,2H),6.87-6.93(m,3H),6.48-6.53(m,2H ),5.04(s,2H),4.35-4.42(m,1H),4.20(dt,J=11.2Hz,1H),4.09(d,J=7.2Hz,1H),3.72(br d,J=12.0Hz,2H),3.38(s,6H),2.68(br t,J=11.2Hz,2H),2.25(m,1H),2.15(m,1H),2.10(s,1H,OH),1.86(br d, J=13.2Hz, 2H), 1.75 (ddq, J=11.2Hz, 1H), 1.46 (br dd, J=12.0Hz, 2H).

[0227] Step 8: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0228] To a solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)chroman-4-ol (66.0 g, 134 mmol, 1.00 eq) in MeOH (198 mL) was added TsOH (512 mg, 2.70 mmol, 2.07 e-2 eq), and the mixture was stirred at 78°C for 30 minutes. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.30, Rf (product) = 0.60) showed complete consumption of the starting material. The mixture was stirred at 25°C for 30 minutes, filtered, and the filter cake dried under vacuum to afford 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, crude) as a white solid. 1H NMR(400MHz,CDCl3)δ7.31-7.46(m,5H),7.23(br d,J=8.2Hz,2H),6.92-7.02(m,3H),6.56(s,1H),6.50(dd,J=8.3Hz,2.3Hz,1H),5.62 (t,J=4.0Hz,1H),5.05(s,2H),4.81(d,J=3.8Hz,2H),4.11(d,J=7.1Hz,1H),3.77(br d,J=12.0Hz,2H),3.39(s,6H),2.72(t,J=12.4Hz,2H),1.88(br d,J=13.6Hz,2H),1.74-1.82(m,1H),1.41-1.53(m,2H).

[0229] Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0230] To a solution of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (60.0 g, 139 mmol, 1.00 eq) and DIEA (36.1 g, 279 mmol, 48.7 mL, 2.00 eq) in DMF (300 mL) at 0°C was added pyridinium tribromide (71.6 g, 223 mmol, 1.60 eq), and the mixture was stirred at 15°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) showed complete consumption of the starting material. The mixture was poured into H2O (700 mL) and extracted with EtOAc (300 mL x 2). The organic layer was washed with brine (300 mL), dried over Na2SO4, 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. LCMSm / z 550.2 and 552.2[M+H]+; 1HNMR (400MHz, CDCl3) δ7.30-7.45(m,5H),7.14(brd,J=8.4Hz,2H),6.98(br d,J=8.4Hz,2H),6.67(d,J=8.6Hz,1H),6.52(d,J=1.7Hz,1H),6.43(dd,J=8.7 and 1.7Hz,1H),5.03(s,2H),4.97(s,2H),4.12(d,J=7.2Hz,1H),3.80(br d,J=12.4Hz,2H),3.40(s,6H),2.74(br t,J=11.8Hz,2H),1.89(br d,J=13.2Hz,2H),1.74-1.84(m,1H),1.43-1.56(m,2H).

[0231] Step 10: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0232] 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 eq) in DMF (140 mL) and H₂O (14 mL) were added phenylboronic acid (10.9 g, 89.9 mmol, 1.50 eq), K₂CO₃ (16.5 g, 119 mmol, 2.00 eq), and Pd(dppf)Cl₂ (855 mg, 1.17 mmol, 0.02 eq), and the mixture was stirred at 70°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) showed complete consumption of the starting material. The mixture was poured into H₂O (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with MeOH (100 mL) at 25°C for 30 minutes to afford 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (30.0 g, crude) as a gray solid.

[0233] Step 11: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol.

[0234] 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 eq) in THF (30.0 mL) and EtOH (300 mL) was added Pd / C (3.00 g, 10.0% purity) and Pd(OH) / C (3.00 g, 20.0% purity) under an N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred at 60° C. under H (50 psi) for 12 hours. TLC (petroleum ether:ethyl acetate=3:1, Rf(starting material)=0.50, Rf(product)=0.20) showed complete consumption of the starting material. 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 min to give cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid. LCMSm / z 460.2[M+H]+; 1H NMR (400MHz, CDCl3) δ7.11-7.20(m,3H),6.82(d,J=8.3Hz,1H),6.62-6.73(m,4H),6.43-6.51(m,3H),6.35(dd,J=8.2,2.5Hz,1H),4.77(br s,1H,OH),4.43(t,J=11.2Hz,1H),4.17-4.27(m,2H),4.08(d,J=7.4Hz,1H),3.53-3.65(m,3H),3.37(s,6H),2.57(t,J=10.8Hz,2H),1.82(br d,J=12.8Hz,2H),1.66-1.77(m,1H),1.38-1.49(m,2H).

[0235] Step 12-15: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride.

[0236] 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, CD3OD) δ ppm 7.76 (d, J = 8.36 Hz, 1H), 7.47 (s, 1H), 7.35 (dd, J = 8.36, 1.54 Hz, 1H), 5.09 (br dd, J = 12.8, 5.40 Hz, 1H), 3.67-3.74 (m, 4H), 3.37-3.42 (m, 4H), 2.63-2.94 (m, 3H), 2.07-2.17 (m, 1H).

[0237] 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).

[0238] 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 (2 mL, 4 mmol). The mixture was stirred at 70° C. for 30 minutes until all the starting material was 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 give the crude aldehyde (50 mg). LC / MS m / z 413.9 [M+H]+.

[0239] The above crude aldehyde (50 mg, 0.09 mmol) was mixed with 2-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione hydrochloride (37.8 mg, 0.1 mmol) and TEA (18.2 mg, 0.18 mmol) in DCM (10 mL), and then MgSO4 (108 mg, 0.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. NaBH(AcO)3 (47.7 mg, 0.225 mmol) was then added in portions over 3 hours. The reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative TLC with MeOH:DCM=1:10 to give the title compound (19.8 mg, 27.6%). LC / MSm / z 740.3[M+H]+; 1H NMR (400MHz, DMSO) δ11.10(s,1H,NH),9.30(s,1H,OH),7.69(d,J=8.5Hz,1H),7.35(s,1H),7.26(d,J=7.5Hz,1H),7.19-7.14(m,3H),6.78(d,J=3.2Hz ,2H),6.69-6.60(m,3H),6.39(d,J=8.2Hz,2H),6.33-6.27(m,2H),5.08(d d,1H),4.33(t,J=11Hz,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); HRMS C44H45N5O6 exact mass calculated value 739.3370, observed value [M+1] + 740.3421.

[0240] 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).

[0241]

[0242] Step 1: Preparation of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol.

[0243] To a solution of 1,2-difluoro-4-nitrobenzene (100 g, 628 mmol, 69.4 mL, 1.00 eq) and KCO (130 g, 942 mmol, 1.50 eq) in DMF (500 mL) at 0°C was added piperidin-4-ylmethanol (76.0 g, 660 mmol, 1.05 eq), and the mixture was stirred at 25°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.30) indicated complete consumption of the starting material. The mixture was poured into H2O (2.50 L), stirred for 20 minutes, filtered, and the filter cake concentrated in vacuo to afford (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 621 mmol, 98.8% yield) as a yellow solid.

[0244] Step 2: Preparation of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol.

[0245] To a solution of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (158 g, 424 mmol, 1.00 eq) in MeOH (1.00 L) was added Pd / C (1.60 g, 10% purity) under argon. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 50 ° C for 12 hours under H2 (50 psi). TLC (petroleum ether: ethyl acetate = 3: 1, Rf (starting material) = 0.30, Rf (product) = 0.10) showed 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.

[0246] Step 3: Preparation of (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol.

[0247] To a solution of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (90.0 g, 401 mmol, 1.00 eq) in MeCN (360 mL) cooled to 0°C was added HCl (12 M, 100 mL, 3.00 eq), followed by the dropwise addition of NaNO (33.2 g, 481 mmol, 1.20 eq) in H2O (40.0 mL) at 0°C. The mixture was stirred for 0.5 h, followed by the addition of KI (166 g, 1.00 mol, 2.50 eq) in H2O (100 mL) at 0°C. 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 complete consumption of the starting material. The mixture was filtered, and the filter cake was triturated with saturated NaOH (4 M, 500 mL) at 15 °C for 30 min, filtered, and the filter cake (brown solid) was used in the next step.

[0248] Step 4: Preparation of 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde.

[0249] To a solution of NaHCO (46.8 g, 558 mmol, 1.70 eq) and NaCO (6.05 g, 57.1 mmol, 0.174 eq) in H O (750 mL) was added (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol (110 g, 328 mmol, 1 eq) in DCM (750 mL), followed by the addition of 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) at 0 ° C. The mixture was stirred at 0 ° C. for 5 hours. TLC (petroleum ether: ethyl acetate = 3: 1, Rf (starting material) = 0.25, Rf (product) = 0.50) showed complete consumption of the starting material. The mixture was extracted with DCM (500 mL x 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 give 1-(2-fluoro-4-iodophenyl)piperidine-4-carbaldehyde (90.0 g, crude) as a brown solid.

[0250] Step 5: Preparation of 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine.

[0251] 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(OCH) (43.0 g, 405 mmol, 1.50 eq) and TsOH (6.98 g, 40.5 mmol, 0.150 eq), and the mixture was stirred at 65°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.35, Rf (product) = 0.60) showed complete consumption of the starting material. The pH was adjusted to 9 by the gradual addition of saturated NaHCO. The mixture was concentrated in vacuo, then added to H2O (200 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (90.0 g, 237 mmol, 87.7% yield) as a yellow solid.

[0252] Step 6: Preparation of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol.

[0253] To a solution of 1-(4-iodo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (45 g, 118 mmol, 1.00 eq) in 2-methyltetrahydrofuran (225 mL) at -65°C was added n-BuLi (2.5 M, 61.5 mL, 1.30 eq). The mixture was stirred at -65°C for 0.5 hour. Then, 7-(benzyloxy)chroman-4-one (22.5 g, 88.9 mmol, 0.750 eq) in 2-methyltetrahydrofuran (100 mL) was added at -65°C, and the mixture was stirred at -65°C for 2.5 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.15) indicated complete consumption of the starting material. The same reaction was repeated once, and the two reactions were combined for workup. The mixture was poured into H2O (300 mL), extracted with EtOAc (50.0 mL x 2), and the combined organic layers were washed with brine (50.0 ml), dried over Na2SO4, filtered and concentrated in vacuo to give 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, crude) as a red solid.

[0254] Step 7: Preparation of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0255] To a solution of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (85.0 g, 165 mmol, 1.00 eq) in MeOH (255 mL) was added TsOH (588 mg, 3.42 mmol, 0.021 eq) at 15°C. The mixture was stirred at 75°C for 0.5 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.30, Rf (product) = 0.60) showed complete consumption of the starting material. The mixture was stirred at 25°C for 30 minutes, filtered, and the filter cake dried under vacuum to afford 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 (400MHz, CDCl3) δ7.30-7.46(m,5H),6.88-7.06(m,4H),6.56(d,J=2.3Hz,1H),6.51(dd,J=8.6,2 .4Hz,1H),5.64(t,J=3.9Hz,1H),5.06(s,2H),4.80(d,J=3.9Hz,2H),4.12(d,J=7.2Hz,1H),3.53(br d,J=11.6Hz,2H),3.40(s,6H),2.68(br t,J=11.2Hz,2H),1.87(br d,J=12.8Hz,2H),1.76(m,1H),1.45-1.65(m,2H).

[0256] Step 8: Preparation of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0257] To 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) under N₂ was added pyridinium tribromide (73.0 g, 245 mmol, 1.60 eq). The mixture was stirred at 15°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.60) showed complete consumption of the starting material. The mixture was poured into H₂O (1.00 L) and extracted twice with EtOAc (300 mL). The organic layer was washed with brine (300 mL), dried over Na₂SO₄, 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 (400MHz, CDCl3) δ7.31-7.49(m,5H),6.85-7.06(m,3H),6.63(m,1H),6.53(d,J=2.20Hz,1H),6.44(dd,J =8.6,2.4Hz,1H),5.03(s,2H),4.98(s,2H),4.13(d,J=7.3Hz,1H),3.50-3.62(m,2H),3.40(s,6H),2.71(br t, J=11.2Hz, 2H), 1.70-1.93 (m, 3H), 1.56 (qd, J=12.0, 3.6Hz, 2H).

[0258] Step 9: Preparation of 1-(4-(7-(benzyloxy)-3-phenyl-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0259] To 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 eq) in DMF (400 mL) and H₂O (40.0 mL) were added phenylboronic acid (25.4 g, 208 mmol, 1.40 eq), K₂CO₃ (45.7 g, 330 mmol, 2.22 eq), and Pd(dppf)Cl₂ (2.50 g, 3.429 mmol, 0.023 eq). The mixture was stirred at 70°C under N₂ for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.55) showed complete consumption of the starting material. The mixture was poured into H₂O (1.50 L) and stirred at 15°C for 30 minutes. The solid was filtered and the filter 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. 1HNMR(400MHz, CDCl3)δ7.30-7.49(m,5H),7.07-7.22(m,3H),6.98(d,2H),6.72-6.88(m,4H),6.65(s,1H),6.50(d,1H),5.06(br s,4H),4.11(br dd,J=5.6,1.2Hz,1H),3.46-3.53(m,2H),3.39(s,6H),2.63(t,J=11Hz,2H),1.87(br d,2H),1.75(m,1H),1.45-1.63(m,2H).

[0260] Step 10: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0261] To 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 Pd / C (3 g, 10% purity) under an N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred at 50°C under H (50 psi) for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf (starting material) = 0.50, Rf (product) = 0.20) showed complete consumption of the starting material. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The hydrogenation reaction was repeated for the same size, and the two reactions were combined for purification. The crude product was triturated with petroleum ether:EtOAc = 10:1 (200 mL) at 25°C for 30 minutes to give cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (50.0 g, 96.8% purity) as an off-white solid. LCMS m / z 478.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.12-7.23 (m, 3H), 6.80 (d, J = 8.3 Hz, 1H), 6.60-6.73 (m, 3H), 6.46 (d, J = 2.4 Hz, 1H), 6.38 (dd, J = 8.3, 2.6 Hz, 1H), 6.22-6.30 (m, 2H), 4.72 (br s,1H),4.41(t,J=11.2Hz,1H),4.25(dd,J=10.8,2.4Hz,1H),4.19(d,J=5. 2Hz, 1H), 4.09 (d, J = 7.4Hz, 1H), 3.54-3.61 (m, 1H), 3.37 (s and m, 8H), 2.54 (br t,J=11.8Hz,2H),1.82(br d,J=12.8Hz,2H),1.65-1.76(m,1H),1.43-1.56(m,2H).

[0262] 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).

[0263] This reaction step was carried out using the same procedure as described in Steps 16-17 of Example 1. LC / MSm / z 758.7[M+H]+; 1H NMR (400MHz, DMSO) δ11.10(s,1H),9.36(s,1H),7.69(d,J=8.2Hz,1H),7.35(s,1H),7.26(d,J=7.7Hz,1H),7.22–7.08(m,3H),6.86–6.64(m,4H),6 .38–6.26(m,3H),6.15(d,J=14.0Hz,1H),5.08(dd,J=13.0,5.4Hz,1H),4 .33(t,J=11Hz,1H),4.26–4.21(m,2H),3.60–3.52(m,1H),3.49–3.39(br s, 4H), 3.27–3.18 (m, 2H), 2.93–2.84 (m, 1H), 2.69–2.48 (m, 8H), 2.20 (br 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); HRMS calculated for C44H44FN5O6 757.3276, observed [M+1] + 758.3336.

[0264] 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).

[0265]

[0266] Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate.

[0267] At 10 ℃, thionyl chloride (130g, 1.09mol) is slowly added to a mixture of 2-bromo-4,5-difluorobenzoic acid (200g, 0.84mol) in MeOH (600mL), and the mixture is stirred at 80 ℃ for 3 hours. TLC shows that the reaction is complete. The mixture is cooled to room temperature, concentrated, and then distributed between ethyl acetate and water. The organic layer is washed twice with saturated Na2CO3 and salt water, dried over Na2SO4 and concentrated to give crude 2-bromo-4,5-difluorobenzoic acid methyl ester (210g, yield: 100%), which is used for the next step without further purification.

[0268] Step 2: Preparation of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0269] 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 KCO (173 g, 1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80° C. for 16 hours. TLC indicated the reaction was complete. The mixture was added to water (2 L) and stirred for 10 minutes, followed by the addition of ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over NaSO, and concentrated to afford tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (315.8 g, 90% yield).

[0270] Step 3: Preparation of tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0271] A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (306g, 0.73mol) and CuCN (98g, 1.09mol) in DMF (1.2L) was stirred at 100°C for 16 hours. TLC showed that the reaction was complete. The mixture was cooled to room temperature. Ethyl acetate (2L) and ammonium hydroxide (2L) were added and the mixture was stirred for 30 minutes. The mixture was filtered. The organic layer was washed with water, dried over Na2SO4 and concentrated to give a crude product (254g). The crude product was taken into refluxing petroleum ether (1L). The mixture was filtered and dried in a 50°C oven to give tert-butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (215g, yield: 81%).

[0272] Step 4: Preparation of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate.

[0273] 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 hours. TLC showed that the reaction was not complete. The mixture was further stirred for 10 hours. 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, dried over Na2SO4 and concentrated under reduced pressure to give a crude product (208 g, crude), which was further purified by silica gel pad to give tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (86.5 g, yield: 43%).

[0274] Step 5: Preparation of (S)-tert-butyl 4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate.

[0275] 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 (S)-tert-butyl 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 the slow addition of sodium cyanoborohydride (27.6 g, 0.44 mol). The mixture was stirred at room temperature for 16 hours. TLC showed 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, brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by passing through a silica gel pad to give (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (80 g, yield: 69%).

[0276] Step 6: Preparation of (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid.

[0277] To a solution of (S)-tert-butyl 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 hours. LCMS showed 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-dionebenzenesulfonic acid (56 g, 86%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ1.94-1.99(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=17.2Hz,1H),4.26(d,J=17.2Hz,1H),5.08(dd,J=13.2,5.2Hz,1H) ,7.29-7.35(m,4H),7.49(d,J=8.7Hz,1H),7.60(m,2H),8.72(s,2H),10.99(s,1H). LCMSm / z 347.3[M+1] + .

[0278] Step 7: Preparation of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol.

[0279] Racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol prepared from step 10 of compound 87 (50.0 g, 104 mmol) was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3H2OMeOH]; B%: 60%-60%).

[0280] The first fraction collected provided (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (15.0 g, 99.4% purity) as an off-white solid. [α] D 25＝ 335.8 (1 g / 100 mL in EtOAc); LCMS m / z 478.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.12-7.23(m,3H),6.65-6.86(m,4H),6.25-6.35(m,3H),6.13(d,1H),4.30(t,1H),4.23(m, 2H), 4.07 (d, J = 6.4Hz, 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).

[0281] The second fraction collected provided (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenylchroman-7-ol (16.0 g, 98.1% purity) 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(400MHz,DMSO-d6)δ9.45(br s,1H),7.16(m,3H),6.65-6.80(m,4H),6.25-6.32(m,3H),6.13(d,J=13.6Hz,1H),4.32(t,1H),4.17-4.27(m,2H),4.07 (d,J=6.4Hz,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).

[0282] 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).

[0283] The (-)-enantiomer isolated 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] + ; 1H NMR (400MHz, DMSO) δ10.99(s,1H),9.35(s,1H),7.43(d,J=11.6Hz,1H),7.27-7.16(m,4H),6.82-6.72(m,3H),6.68(d,J=8.2Hz,1H),6.35 -6.28(m,3H),6.15(d,J=14.1Hz,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); HRMS C44H45F2N5O5 exact mass calculated value 761.3389, observed value [M+1] + 762.3593.

[0284] 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).

[0285]

[0286] Step 1: Preparation of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol.

[0287] Racemic cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol prepared in step 11 of compound 36 (49.2 g, 108 mmol) was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 50%-50%, 5.5 min).

[0288] The first fraction collected provided (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid (19.0 g, 97.8% purity). [α] D 25＝360.4 (1.34 g / 100 mL in EtOAc); LCMS m / z 460.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.11-7.20(m,3H),6.82(d,J=8.3Hz,1H),6.62-6.73(m,4H),6.43-6.51(m,3H),6.35(dd,J=8.2,2.5Hz,1H),4.84(br s,1H,OH),4.43(t,J=11.2Hz,1H),4.17-4.27(m,2H),4.08(d,J=7.4Hz,1H),3.53-3.65(m,3H),3.37(s,6H),2.58(dt,2H),1.82(br d,J=12.8Hz,2H),1.66-1.77(m,1H),1.38-1.49(m,2H).

[0289] The second fraction collected provided (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylchroman-7-ol as an off-white solid (19.0 g, 99.8% purity). [α] D 25＝ -386.8 (0.39 g / 100 mL in EtOAc); LCMS m / z 460.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.11-7.20(m,3H),6.82(d,J=8.3Hz,1H),6.62-6.73(m,4H),6.43-6.51(m,3H),6.35(dd,J=8.2,2.5Hz,1H),4.79(br s,1H,OH),4.43(t,J=11.2Hz,1H),4.17-4.27(m,2H),4.07(d,J=7.4Hz,1H),3.53-3.65(m,3H),3.37(s,6H),2.58(dt,2H),1.82(br d,J=12.8Hz,2H),1.66-1.77(m,1H),1.35-1.49(m,2H).

[0290] 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).

[0291] This compound was prepared under the same conditions as described for the synthesis of compound 41 using the (-)-enantiomer isolated from step 1. LCMS m / z 744.2 [M+H] + ; 1 H NMR (400MHz, DMSO) δ10.99(s,1H),9.29(s,1H),7.43(d,J=11.3Hz,1H),7.27-7.12(m,4H),6.80-6.74(m,2H),6.69-6.59( m,3H),6.38(d,J=8.1Hz,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); HRMSC44H46FN5O5 exact mass calculated value 743.3483, observed value [M+1] + 744.3681.

[0292] 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).

[0293]

[0294] This compound was prepared using the same method as compound 41. After purification, the desired compound was obtained as a neutral white solid. LCMS m / z 743.7 [M+H] + ; 1H NMR (400MHz, DMSO) δ10.97 (s, 1H), 9.37 (s, 1H), 7.52 (d, J = 8.2Hz, 1H), 7.17 (m, 3H), 7.07 (s, 1H) ),7.06(d,J=8.2Hz,1H),6.84-6.71(m,3H),6.69(d,J=8.3Hz,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); HRMS exact mass calculated for C44H46FN5O5 743.3483, observed [M+1] + 744.3567.

[0295] 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).

[0296]

[0297] This compound was prepared using the same method as compound 41. LCMS m / z 743.5 [M+H] + ; 1H NMR (400MHz, DMSO) δ10.97(s,1H),9.37(s,1H),7.53(d,J=7.4Hz,1H),7.20-7.06(m,5H),6.82-6.78(m ,2H),6.78-6.72(m,1H),6.69(d,J=8.3Hz,1H),6.34-6.29(m,3H),6.16(d,J=14.3Hz,1H),5.06(dd,J=1 3.2,4.8Hz,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); HRMS C44H46FN5O5 exact mass calculated value 743.3483, observed value [M+1] + 744.3567.

[0298] 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).

[0299]

[0300] This compound was prepared using the same method as compound 41. LCMS m / z 725.7 [M+H] + ; 1H NMR(400MHz,DMSO)δ10.98(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=8.3Hz,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); HRMS C44H47N5O5 exact mass calculated value 725.3577, observed value [M+1] + 726.3675.

[0301] 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).

[0302]

[0303] This compound was prepared using the same method as compound 41. LCMS m / z 725.5 [M+H] + ; 1H NMR(400MHz,DMSO)δ10.97(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=7.5Hz,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); HRMS C44H47N5O5 exact mass calculated value 725.3577, observed value [M+1] + 726.3702.

[0304] 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).

[0305]

[0306] This compound was prepared using the same method as compound 41. LCMS m / z 725.5 [M+H] + ; 1H NMR(400MHz,DMSO)δ10.97(s,1H),9.31(s,1H),7.62-7.51(m,1H),7.23-7.04(m,5H),6.81 -6.74(m,2H),6.71-6.58(m,3H),6.39(d,J=8.1Hz,2H),6.32(d,J=2.2Hz,1H),6.31-6.26(m ,1H),5.06(dd,J=13.1,4.4Hz,1H),4.34(t,J=11.1Hz,2H),4.28-4.15(m,3H),3.66-3.47(m,3H),3.33-3.26(m,4H),2.96-2.86(m,1H),2.70-2.48(m,7H),2.46-2.31(m,1H),2.20(br s,2H),2.02-1.60(m,4H),1.30-1.15(m,2H); HRMS C44H47N5O5 exact mass calculated value 725.3577, observed value [M+1] + 726.3641.

[0307] Example 10: cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 85).

[0308]

[0309] This compound was prepared using the same method as compound 41. LCMS m / z 744.3 [M+H] + ; 1H NMR (400MHz, DMSO) δ10.96(s,1H),9.37(s,1H),7.57-7.49(m,1H),7.21-7. 04(m,5H),6.83-6.67(m,4H),6.37-6.27(m,3H),6.16(d,J=14.6Hz,1H),5. 06(dd,J=13.3,5.0Hz,1H),4.41-4.16(m,5H),3.59-3.54(m,1H),3.34-3.1 6(m,6H),2.95-2.86(m,1H),2.69-2.48(m,7H),2.44-2.33(m,1H),2.20(br s, 2H), 1.99-1.90 (m, 1H), 1.82-1.74 (m, 2H), 1.72-1.60 (m, 1H), 1.25-1.15 (m, 2H); HRMS C44H46FN5O5 exact mass calculated value 743.3483, observed value [M+H] + 744.3530.

[0310] Example 11: Synthesis of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 60).

[0311]

[0312]

[0313] Step 1: Preparation of 1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine.

[0314] To a solution of 1-{4-[7-(benzyloxy)-3-bromo-2H-chromen-4-yl]-2-fluorophenyl}-4-(dimethoxymethyl)piperidine (200 mg, 0.35 mmol), (4-fluoro-3-methylphenyl)boranediol (80.82 mg, 0.52 mmol), and potassium carbonate (145.12 mg, 1.05 mmol) in DMF and H₂O (10 mL / 10 mL) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (25.60 mg, 0.034 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 90° C. under a nitrogen atmosphere for 12 hours. The resulting mixture was evaporated in vacuo to give a crude product, which was dissolved in DCM (200 mL), washed with water (20 mL), and evaporated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 2:1) to give the desired product as a brown solid (150 mg, 0.29 mmol, 71.3% yield).

[0315] Step 2: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol.

[0316] To a solution of 1-(4-(7-(benzyloxy)-3-(4-fluoro-3-methylphenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (130 mg, 0.26 mmol) in THF (20 mL) stirred at room temperature was added palladium on carbon (553.38 mg, 5.2 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to give the desired product as a yellow solid (130 mg, 0.25 mmol, 85.3% yield). LCMS m / z 509.7 [M+1] + .

[0317] Step 3: Preparation of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 60).

[0318] A solution of 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(4-fluoro-3-methylphenyl)chroman-7-ol (100 mg, 0.2 mmol)) in THF (5 mL) and water (5 ml with 10% H2SO4) was stirred at 70°C for 1 hour. The reaction mixture was dissolved in DCM (200 mL), the pH was adjusted to 10 with aqueous sodium hydroxide solution (2 M), and the organic layer was evaporated in vacuo to give the desired product as a yellow solid (80 mg, 0.17 mmol, 86.3% yield). LCMS m / z 463.7 [M+1] + . To this solid (30 mg, 0.06 mmol) was added (S) -3- (1- oxo-5- (piperazine-1-yl) isoindolin-2-yl) piperidine-2,6-dione benzenesulfonate (29.19 mg, 0.06 mmol) and triethylamine (30.35 mg, 0.3 mmol) in DCM (5 mL). After the addition of MgSO4 (72.00 mg, 0.60 mmol), the mixture was stirred at room temperature. The reaction mixture was further stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (38.15 mg, 0.18 mmol) was added portionwise at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated in vacuo to give a crude product, which was purified by preparative TLC (DCM: MeOH = 10: 1) to give the desired product as a white solid (20 mg, 0.03 mmol, 50.0% yield). LCMS m / z 775.5[M+1] + ; 1HNMR (400MHz, DMSO) δ = 10.95 (s, 1H), 9.36 (s, 1H), 7.52 (d, J = 8.3Hz, 1H), 7.10-7.01 (m, 2H) ,6.93(t,J=9.0Hz,1H),6.77(t,J=8.8Hz,1H),6.68(d,J=8.2Hz,1H),6.64-6.59(m,2H),6.3 6-6.25(m,3H),6.20(d,J=14.1Hz,1H),5.06(dd,1H),4.36-4.12(m,5H),3.59-3.47(m,1H) ,3.30-3.19(m,6H),2.90-2.86(m,1H),2.68-2.48(m,7H),2.38-2.29(m,1H),2.23-2.20(br d, 2H), 2.08 (s, 3H), 2.01-1.92 (m, 1H), 1.79-1.76 (m, 2H), 1.70-1.62 (m, 1H), 1.26-1.15 (m, 2H); HRMS C45H47F2N5O5 exact mass calculated value 775.3545, observed value [M+1] + 776.3584

[0319] Example 12: Synthesis of cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 52).

[0320]

[0321] This compound was synthesized according to the same procedure as described in Example 11. LC / MS: 757.5 [M+1] + ; 1H NMR (400MHz, DMSO) δ = 10.95 (s, 1H), 9.35 (s, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.16-7.02 (m, 3H), 6.98 (d, J = 7.8Hz, 1H), 6.75 (t,J=8.9Hz,1H),6.68(d,J=8.2Hz,1H),6.58(d,J=7.4Hz,1H),6.51(s,1H),6.30-6.24(m,3H),6.16(d,J=13.9Hz,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); HRMS C45H48FN5O5 exact mass calculated value 757.3639, observed value [M+1] + 758.3681.

[0322] Example 13: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 84).

[0323]

[0324] This compound was synthesized according to the same procedure as described in Example 11. LC / MS: m / z 779.4 [M+1] + ; 1HNMR (400MHz, 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); HRMS C44H44F3N5O5 exact mass calculated value 779.3295, observed value [M+1] + 780.3345.

[0325] 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).

[0326]

[0327]

[0328] Step 1: Preparation of 1-(4-(7-(benzyloxy)-3-(3-methoxyphenyl)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine.

[0329] To 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 / H2O (20 mL, DMF / H2O=5:1) was added 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (26.34 mg, 0.036 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 60°C under nitrogen for 5 hours. The reaction mixture was filtered and evaporated in vacuo to give a crude product. The crude product was dissolved in DCM (200 mL), washed with water (20 mL), and the organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo. The resulting residue was purified by preparative TLC (PE:EA=5:1) to give the desired product (80 mg, 0.14 mmol, 76.1% yield) as a yellow solid. LC / MS: 578.1 [M+1] + .

[0330] Step 2: Preparation of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol.

[0331] To 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 on carbon (180 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and evaporated in vacuo to give the desired product (80 mg, 0.16 mmol, 96.1%) as a yellow solid. LC / MS: 489.9 [M+1] + .

[0332] Step 3: Preparation of cis-1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidine-4-carbaldehyde.

[0333] A solution of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-methoxyphenyl)chroman-7-ol (100 mg, 0.2 mmol) in THF / H2SO4 (10% aq) (20 mL, THF / H2SO4 = 1 / 1) was stirred at 70°C for 2 hours. The pH of the reaction mixture was adjusted to approximately 12 with sodium hydroxide solution (2 mol / L), extracted with DCM (200 mL), dried over sodium sulfate, and evaporated in vacuo to give the desired product (80 mg, 0.18 mmol, 88% yield) as a yellow solid. LC / MS: 443.3 [M+1] + .

[0334] 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).

[0335] 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-dionebenzenesulfonic acid (24.32 mg, 0.05 mmol), TEA (0.25 mmol) and MgSO4 (60 mg, 0.5 mmol) in DCM (5 mL) was stirred at room temperature under nitrogen for 30 minutes. Sodium triacetoxyborohydride (31.79 mg, 0.15 mmol) was then 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 give 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] + ; 1H NMR (400MHz, DMSO) δ10.95(s,1H),9.27(s,1H),7.52(d,J=8.6Hz,1H),7.15-6.99(m,3H),6.74-6.59(m,4H),6.42(d,J=8.6Hz, 2H),6.37(d,J=7.6Hz,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); HRMS C45H49N5O6 exact mass calculated value 755.3683, observed value [M+H] + 756.3753.

[0336] Example 15: Synthesis of cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 63).

[0337]

[0338] This compound was prepared using the same method as described in Example 14, except that 4-fluoro-3-methylphenylboronic acid was used. The crude product from the final reductive amination step was purified by preparative TLC to give the desired compound (65 mg, 0.084 mmol, 38.9% yield) as a white solid. LC / MS: 773.6 [M+1] + ; 1H NMR (400MHz, DMSO) δ10.95 (s, 1H), 9.29 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.12-7.0 3(m,2H),6.98(dd,J=11.5,8.3Hz,1H),6.68(dd,J=8.5,2.5Hz,3H),6.44(d,J=8. 5Hz,2H),6.41-6.33(m,2H),6.33-6.25(m,2H),5.05(dd,J=13.2,5.0Hz,1H),4.3 7-4.25(m,2H),4.24-4.18(m,1H),4.18-4.10(m,2H),3.61-3.48(m,6H),3.28(br s, 4H), 2.96-2.83 (m, 1H), 2.64-2.51 (m, 7H), 2.46-2.29 (m, 1H), 2.20 (br s, 2H), 2.01-1.93 (m, 1H), 1.83-1.74 (m, 2H), 1.73-1.63 (br, 1H), 1.27-1.12 (m, 2H); HRMS C45H48FN5O6 exact mass calculated value 773.3589, observed value [M+1] + 774.3818.

[0339] Example 16: Synthesis of cis-(S)-3-(6-fluoro-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 74).

[0340]

[0341] This compound was prepared using the same method as described in Example 14, except that (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate was used in the final reductive amination step. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to give the desired product (25 mg, 48% yield) as a white solid. LC / MS: 774.1 [M+1] + ; 1HNMR (400MHz, DMSO) δ10.97(s,1H),9.28(s,1H),7.42(d,J=11.6Hz,1H),7.22(d,J=7. 3Hz,1H),7.05(t,J=7.9Hz,1H),6.75-6.58(m,4H),6.45-6.33(m,3H),6.30-6.15(m,3 H), 5.08 (dd, 1H), 4.38-4.09 (m, 5H), 3.58 (s, 3H), 3.57-3.52 (m, 2H), 3.52-3.43 (m, 1H), 3.21-3.04 (m, 4H), 2.99-2.85 (m, 1H), 2.69-2.53 (m, 7H), 2.49-2.28 (m, 1H), 2.20 (br d, 2H), 2.02-1.94 (m, 1H), 1.80-1.60 (m, 3H), 1.30-1.10 (m, 2H); HRMSC45H48FN5O6 exact mass calculated value 773.3589, observed value [M+1] + 774.3688.

[0342] Example 17: Synthesis of cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 89).

[0343]

[0344] This compound was prepared using the same method as described in Example 14, except that 4-methoxyphenylboronic acid was used. The crude product from the final reductive amination step was purified by preparative TLC (DCM:MeOH=5:1) to give the desired compound as a white solid. LC / MS: 756.2 [M+1] + ; 1H NMR (400MHz, DMSO) δ = 10.94 (s, 1H), 9.26 (s, 1H), 7.52 (d, J = 8.5, 1H), 7.05 (m, 2 H),6.79-6.56(m,7H),6.40(d,J=8.6,2H),6.33-6.23(m,2H),5.08-5.01(m,1H ),4.36-4.11(m,5H),3.68(s,3H),3.60-3.52(m,2H),3.48-3.42(m,1H),3.31- 3.25(m,4H),2.95-2.84(m,1H),2.67-2.42(m,7H),2.46-2.28(m,1H),2.19(br d, 2H), 2.00-1.92 (m, 1H), 1.77 (m, 2H), 1.69-1.63 (m, 1H), 1.27-1.10 (m, 2H); HRMSC45H49N5O6 exact mass calculated value 755.3683, observed value [M+1] + 756.3763.

[0345] Example 18: Synthesis of cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 90).

[0346]

[0347] This compound was prepared using the same method as described in Example 17, except that (S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate was used in the final reductive amination step. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to give the desired compound as a white solid. LC / MS: 774.2 [M+1] + ; 1H NMR (400MHz, DMSO) δ10.98(s,1H),9.30(s,1H),7.43(d,J=11.5Hz,1H),7.24(d,J=7.3Hz,1H),6.77-6. 57(m,7H),6.40(d,J=8.5Hz,2H),6.34-6.20(m,2H),5.05(dd,1H),4.45-4.12(m,5H),3.68(s,3H),3.58 -3.48 (m, 3H), 3.26-3.05 (m, 4H), 2.95-2.87 (m, 1H), 2.69-2.46 (m, 7H), 2.45-2.28 (m, 1H), 2.22 (br, 2H), 2.03-1.95 (m, 1H), 1.79-1.65 (m, 3H), 1.30-1.16 (m, 2H); HRMS C45H48FN5O6 exact mass calculated value 773.3589, observed value [M+1] + 774.3648.

[0348] Example 19: ERa degradation activity of compounds of the present disclosure in T47D, MCF7 and CaMA1 cells.

[0349] T47D cells were cultured at 1.5 × 10 5 MCF7 cells were seeded at 1.5 × 10 cells / well in RPMI growth medium containing 10% FBS and 1x penicillin-streptomycin in a 24-well plate. 5 CAMA1 cells were seeded at 2×10 cells / well in a 24-well plate in DMEM growth medium containing 10% FBS and 1× penicillin-streptomycin. 5 Cells were seeded per well in 24-well plates in RPMI growth medium supplemented with 20% FBS and 1x penicillin-streptomycin. They were then incubated overnight at 37°C. The following day, test compounds were administered to the cells using various concentrations of 1000x compound stock solutions prepared in DMSO. Following compound administration, the cells were then incubated at 37°C for 6 hours.

[0350] Upon completion, cells were washed with PBS and proteins were collected in Laemmli sample buffer (1×; VWR International). Proteins in cell lysates were separated by SDS-PAGE and analyzed using The membrane was transferred to an Odyssey nitrocellulose membrane (Licor) using a dry blot transfer system (ThermoFisher). Nonspecific binding was blocked by incubating the membrane with Intercept blocking buffer (Licor) at room temperature for 1 hour with gentle shaking. The membrane was then incubated 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 at 4°C overnight. After washing three times with TBS-T, the membrane was incubated with 800CW goat anti-mouse IgG (1:20,000, Licor) or Incubate with 800CW goat anti-rabbit IgG (1:20,000, Licor) for 1 hour. After washing with TBS-T, rinse the membrane in TBS and Scanned on a CLx imaging system (Licor). TM The bands were quantified using Licor software (Licor).

[0351] Figures 1A to 1D The ERa degradation activity of exemplary compounds 85, 60, 32, and 52 of the present disclosure in the T47D cell line is illustrated 6 hours after administration. Figure 2A and 2B The ERa degradation activity of exemplary compounds 87 and 84 of the present disclosure in the T47D cell line is demonstrated 6 hours after administration. Figure 4A and 4B The ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the T47D cell line 6 hours after administration is illustrated. Figures 6A to 6C The ERa degradation activity of exemplary compounds 41, 42, and 63 of the present disclosure in the T47D cell line 6 hours after administration is illustrated. Figures 7A to 7D The ERa degradation activity of exemplary compounds 89, 56, 90, and 74 of the present disclosure in the T47D cell line is illustrated 6 hours after administration.

[0352] Table 3 illustrates the ERa degradation activity of exemplary compounds of the present disclosure in the T47D cell line 6 hours after administration.

[0353] Table 3. ERα degradation activity of exemplary compounds in T47D cell line

[0354]

[0355] Figure 3A and 3BThe ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the MCF7 cell line after 6 hours of administration is illustrated.

[0356] Figure 5A and 5B The ERa degradation activity of exemplary compounds 86 and 33 of the present disclosure in the CAMA-1 cell line 6 hours after administration is illustrated.

[0357] In summary, the present invention relates to the following aspects:

[0358] 1. A compound of formula (I), a stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt or hydrate thereof:

[0359]

[0360] in:

[0361] R 1 Selected from H, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0362] R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0363] Each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 4 The groups together form an oxo group;

[0364] R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0365] X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0366] X 3 and X 4 are each independently selected from H or halogen;

[0367] L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 6 replace;

[0368] Each R 6 independently selected from C1-C6 alkyl, halogen, cyano and hydroxy,

[0369] Each R 7 independently selected from hydrogen, C1-C6 alkyl and acyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 7 The groups together form a 3- to 6-membered heterocyclic ring or a heteroaryl group.

[0370] 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0371] 3. The compound according to item 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H or methyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0372] 4. The compound according to item 3 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H or methyl.

[0373] 5. The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 It’s H.

[0374] 6. The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 It's methyl.

[0375] 7. The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0376] 8. The compound according to any one of items 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each independently selected from H and methyl, each of which is replaced by 0, 1, 2 or 3 R6 replace.

[0377] 9. The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from H and methyl.

[0378] 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is H.

[0379] 11. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is a methyl group.

[0380] 12. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 H and methyl respectively.

[0381] 13. A compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 4 The groups are taken together to form an oxo group.

[0382] 14. A compound according to any one of items 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, or two R 4 The groups are taken together to form an oxo group.

[0383] 15. The compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 4 It’s H.

[0384] 16. The compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein both R 4 The groups are taken together to form an oxo group.

[0385] 17. The compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7)2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0386] 18. A compound according to any one of items 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN.

[0387] 19. A compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen.

[0388] 20. The compound according to any one of items 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 5 It's F.

[0389] 21. The compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0390] 22. The compound according to any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0391] 23. The compound according to any one of items 1 to 22, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is independently selected from H, F, CN, methyl, methoxy, and trifluoromethyl.

[0392] 24. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is H.

[0393] 25. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is F.

[0394] 26. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2H and methyl respectively.

[0395] 27. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 H and F respectively.

[0396] 28. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 H and methoxy respectively.

[0397] 29. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 F and methyl respectively.

[0398] 30. A compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 F and methoxy respectively.

[0399] 31. A compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 F and trifluoromethyl respectively.

[0400] 32. A compound according to any one of items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 are each independently selected from H or halogen.

[0401] 33. A compound according to any one of items 1 to 32, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 are each independently selected from H or F.

[0402] 34. A compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each is H.

[0403] 35. A compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each is F.

[0404] 36. A compound according to any one of items 1 to 33, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 H and F respectively.

[0405] 37. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is a linker having a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0406] 38. A compound according to any one of items 1 to 37, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 20 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0407] 39. A compound according to any one of items 1 to 38, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 18 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0408] 40. A compound according to any one of items 1 to 39, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0409] 41. A compound according to any one of items 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 14 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0410] 42. A compound according to any one of items 1 to 41, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 12 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0411] 43. A compound according to any one of items 1 to 42, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0412] 44. A compound according to any one of items 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of: O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0413] 45. A compound according to any one of items 1 to 44, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0414] 46. ​​A compound according to any one of items 1 to 45, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 6 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0415] 47. A compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, wherein L is a linker of 1 to 4 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is independently substituted by 0, 1, 2 or 3 R 6 replace.

[0416] 48. A compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, wherein L is a linker, wherein two carbon atoms are each independently replaced by a heterocycle, each heterocycle is each independently replaced by 0, 1, 2 or 3 R 6 replace.

[0417] 49. A compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, wherein L is a linker in which one carbon atom is replaced by a heterocycle, one carbon atom is replaced by a cycloalkyl, each of which is independently replaced by 0, 1, 2 or 3 R 6 replace.

[0418] 50. A compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, wherein L is a linker in which more than one carbon atom is independently replaced by a group selected from the group consisting of C(O), O, NR 4 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

[0419] 51. A compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, wherein L is a linker in which more than one carbon atom is independently replaced by a group selected from the group consisting of C(O), O, and NR 4 , each of which is represented by 0, 1, 2 or 3 R 6 replace.

[0420] 52. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0421] 53. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0422] 54. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0423] 55. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0424] 56. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0425] 57. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0426] 58. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0427] 59. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0428] 60. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0429] 61. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0430] 62. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0431] 63. A compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, wherein L is

[0432] 64. The compound according to any one of items 1 to 63, or a pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer.

[0433] 65. The compound according to item 64, wherein the compound is a cis-isomer.

[0434] 66. The compound according to item 64, wherein the compound has formula (I)*:

[0435]

[0436] 67. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0437] cis-3-(5-(2-(2-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethoxy)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0438] cis-3-(5-(2-(2-((2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0439] cis-3-(5-(2-(4-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0440] cis-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-N-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)-N-methylpentanamide;

[0441] cis-3-(5-((5-(4-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0442] cis-3-(5-(6-(4-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0443] cis-3-(4-(6-(4-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0444] cis-2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)pentyl)amino)isoindoline-1,3-dione;

[0445] cis-3-(5-(3-(1-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)propoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0446] cis-3-(5-(4-(1-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0447] cis-3-(4-(4-(1-(2-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)ethyl)azetidin-3-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0448] cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione;

[0449] cis-3-(5-(4-(5-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0450] cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0451] cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluorophenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0452] cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0453] cis-3-(5-(4-(5-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0454] cis-3-(5-(4-(5-(2-fluoro-4-(3-(4-fluoro-2-methylphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0455] cis-3-(5-(4-(5-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0456] cis-3-(5-(4-(5-(4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0457] cis-3-(5-(4-(5-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0458] cis-3-(5-(4-(5-(4-(3-(4-fluoro-2-(trifluoromethyl)phenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0459] cis-3-(5-(4-(5-(4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0460] cis-3-(5-(4-(5-(4-(7-hydroxy-3-(o-tolyl)chroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0461] cis-3-(5-(4-(4-(4-(7-hydroxy-3-phenylchroman-4-yl)phenoxy)butyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0462] cis-3-(5-(4-(5-(4-(7-hydroxy-2,2-dimethyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0463] cis-3-(5-(4-(5-(4-(7-methoxy-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0464] 3-(5-(4-(5-(4-((2R,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0465] 3-(5-(4-(5-(4-((2S,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0466] 3-(5-(4-(5-(4-((2R,3R,4S)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0467] 3-(5-(4-(5-(4-((2S,3R,4S)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0468] 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;

[0469] (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;

[0470] (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;

[0471] cis-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;

[0472] 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;

[0473] cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione;

[0474] cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0475] cis-(S)-3-(6-fluoro-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;

[0476] cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0477] (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;

[0478] (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;

[0479] (S)-3-(6-fluoro-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;

[0480] cis-(S)-3-(5-(4-(2-(1-(4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0481] (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;

[0482] (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-2,2-dimethyl-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0483] (S)-3-(5-(4-((1-(2-fluoro-4-((2R,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0484] (S)-3-(5-(4-((1-(2-fluoro-4-((2S,3S,4R)-7-hydroxy-2-methyl-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0485] (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-methoxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0486] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0487] cis-(S)-3-(5-(4-((1-(4-(3-(4-fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0488] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0489] cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0490] cis-(S)-3-(5-(4-((1-(2-fluoro-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;

[0491] (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0492] 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;

[0493] cis-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;

[0494] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(3-methoxyphenyl)-2,2-dimethylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0495] cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)-2,2-dimethylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0496] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0497] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0498] cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0499] cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0500] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-2-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0501] cis-(S)-3-(5-(4-((1-(4-(3-(4-fluoro-2-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0502] cis-(S)-3-(5-(4-((1-(4-((2R)-7-hydroxy-3-(3-methoxyphenyl)-2-methylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0503] cis-(S)-3-(5-(4-((1-(4-((2S)-7-hydroxy-3-(3-methoxyphenyl)-2-methylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0504] cis-3-(5-(3-(((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0505] cis-3-(5-(3-(((1-(2-fluoro-4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0506] cis-3-(5-(3-(((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0507] cis-3-(5-(3-(((1-(4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0508] cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-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;

[0509] cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-(2-fluoro-4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0510] cis-(S)-3-(6-fluoro-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;

[0511] cis-2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-(4-(7-hydroxy-3-(3-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0512] cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0513] cis-(S)-3-(6-fluoro-5-(4-((1-(4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0514] cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0515] cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0516] cis-(S)-3-(6-fluoro-5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0517] cis-(S)-3-(5-(4-((1-(2,6-difluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0518] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-methoxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0519] cis-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-fluoro-4-(7-methoxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione;

[0520] cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0521] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0522] (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;

[0523] 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;

[0524] cis-(S)-3-(5-(4-((1-(2,6-difluoro-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;

[0525] cis-(S)-3-(5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and

[0526] cis-(S)-3-(6-fluoro-5-(4-((1-(4-(7-hydroxy-3-(4-methoxyphenyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0527] 68. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0528] 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;

[0529] (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;

[0530] (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;

[0531] 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;

[0532] (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;

[0533] (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;

[0534] (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;

[0535] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0536] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0537] cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0538] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0539] (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; and

[0540] 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.

[0541] 69. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0542] (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;

[0543] 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;

[0544] (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;

[0545] (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;

[0546] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(7-hydroxy-3-(m-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0547] cis-(S)-3-(5-(4-((1-(2-fluoro-4-(3-(4-fluoro-3-methylphenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0548] cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0549] (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; and

[0550] 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.

[0551] 70. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0552] (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;

[0553] 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;

[0554] (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;

[0555] (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;

[0556] cis-(S)-3-(5-(4-((1-(4-(3-(3,4-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0557] (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; and

[0558] 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.

[0559] 71. A pharmaceutical composition comprising a compound according to any one of items 1 to 70 and at least one additional component selected from a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle and a pharmaceutically acceptable excipient.

[0560] 72. A pharmaceutical composition according to item 71, wherein the compound is present in a therapeutically effective amount.

[0561] 73. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 70 or a pharmaceutical composition according to item 66 or 67, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer and esophageal cancer.

[0562] 74. A method according to claim 73, wherein the cancer is breast cancer.

[0563] 75. The method of claim 74, wherein the cancer is ovarian cancer.

[0564] 76. A method according to any one of items 73 to 75, wherein the cancer is positive for ERa.

[0565] 77. A method according to any one of items 74 to 76, wherein the subject has previously been treated with an anti-cancer agent.

[0566] 78. A method according to claim 77, wherein the anticancer agent is tamoxifen.

[0567] 79. The method of claim 77, wherein the anticancer agent is fulvestrant.

[0568] 80. Use of a compound according to any one of items 1 to 70 in a therapeutic treatment method, wherein the therapeutic treatment is selected from the treatment of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, esophageal cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-related gynecomastia, dyspareunia caused by menopause, retroperitoneal fibrosis and idiopathic sclerosing mesenteritis.

[0569] 81. Use of a compound according to any one of items 1 to 70 in the preparation of a medicament.

[0570] 82. The method of claim 81 , wherein the medicament is used to treat breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, esophageal cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-related gynecomastia, dyspareunia caused by menopause, retroperitoneal fibrosis, and idiopathic sclerosing mesenteritis.

[0571] 83. A method of inhibiting cell growth, comprising contacting a cell with a compound according to any one of items 1 to 70 or a pharmaceutical composition according to item 71 or 72.

[0572] 84. A method according to claim 83, wherein the cell is a cancer cell.

[0573] 85. A method according to item 83 or 84, wherein the cell expresses ERα.

[0574] The many features and advantages of the present disclosure are apparent from the detailed description, and thus, the appended claims are intended to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation shown and described, and thus all suitable modifications and equivalents may be employed, which fall within the scope of the present disclosure.

[0575] Furthermore, those skilled in the art will appreciate that the concepts upon which this disclosure is based can readily be used as a basis for designing other structures, methods, and systems for carrying out the several purposes of this disclosure.Accordingly, the claims are not to be considered limited by the foregoing description or examples.

Claims

1. A compound of formula (I), a stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt or hydrate thereof: in: R 1 Selected from H, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace; R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace; Each R 4 independently selected from H, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 4 The groups together form an oxo group; R 5 Selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -N(R 7 )2 and -CN, each of which is replaced by 0, 1, 2 or 3 R 6 replace; X 1 and X 2 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace; X 3 and X 4 are each independently selected from H or halogen; L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from the group consisting of C(O), O, NR 7 , S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 0, 1, 2 or 3 R 6 replace; Each R 6 independently selected from C1-C6 alkyl, halogen, cyano and hydroxy, Each R 7 independently selected from hydrogen, C1-C6 alkyl and acyl, each of which is replaced by 0, 1, 2 or 3 R 6 Replace, or two R 7 The groups together form a 3- to 6-membered heterocyclic ring or a heteroaryl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, or C1-C6 alkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H or methyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H or methyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 It’s H.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 It's methyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each independently selected from H and methyl, each of which is replaced by 0, 1, 2 or 3 R 6 replace.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from H and methyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is H.

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