Combination of an estrogen receptor degrader and a cyclin-dependent kinase inhibitor for the treatment of cancer

Abstract

This document provides pharmaceutical combinations, compositions, and methods using compounds with estrogen receptor (ER) degradation activity and cyclin-dependent kinase (CDK) inhibitors, wherein the compounds are such as compounds of formula (I) or their tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates, wherein R1, Y, R 22 R 33 R2, p, X3, X4 and Z are defined in this paper.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 952,695, filed December 23, 2019, the contents of which are hereby incorporated in their entirety for all purposes. Background Technology

[0003] Estrogen is a female sex hormone that regulates a wide range of physiological processes through its homologous estrogen receptors ERα and ERβ, such as the development of the female reproductive system, bone mass maintenance, and the protection of cardiovascular tissue and the central nervous system. Once estrogen binds to its estrogen receptor ("ER"), the receptor undergoes a conformational change that causes it to homodimerize. The ER homodimer then binds to estrogen response elements ("EREs") located in the promoters of a specific set of target genes, and their expression is regulated with the help of transcriptional co-regulatory factors.

[0004] Because ER signaling is involved in many pathways, it is well known that dysregulation of ER signaling (especially through ERα) leads to uncontrolled cell proliferation, which ultimately results in cancer. ER+ breast cancer accounts for approximately 75% of all diagnosed breast cancers, as well as some ovarian and endometrial cancers.

[0005] The prevalence of ER+ cancer has led to decades of investigation and development of anti-estrogens as therapeutic agents. Anti-estrogens (i.e., hormones) therapy is the first-line treatment for most ER+ breast cancers. There are three main classes of anti-estrogens: aromatase inhibitors (e.g., letrozole and anastrozole), selective estrogen modulators (e.g., tamoxifen, toremifene, and raloxifene), and selective estrogen receptor degraders (e.g., fulvestrant). These classes of anti-estrogens work through different mechanisms of action, such as inhibiting aromatase, competitively binding to ERα, and / or causing ERα degradation.

[0006] The aforementioned therapies may have adverse effects. For example, administration of aromatase inhibitors can lead to decreased bone mineral density, which can increase the risk of fractures. Administration of selective estrogen modulators can cause the development of endometrial cancer and / or cardiovascular problems such as deep blood clots and pulmonary embolism. Furthermore, the aforementioned therapies may suffer from insufficient clinical efficacy.

[0007] Recently, novel small molecules (referred to in this paper as "ER degraders") that selectively target and degrade ER have been developed. These small molecules downregulate ER activity, thereby improving cell proliferation, which would otherwise lead to cancer. Although ER degraders can effectively downregulate ER signaling, cancer cell proliferation can proceed through other pathways.

[0008] Cyclin-dependent kinases (CDKs) and their associated proteins play a crucial role in coordinating and driving the cell cycle of proliferating cells. Progression throughout the cell cycle is regulated by a series of checkpoints, also known as restriction points, which are regulated CDKs. CDKs are subsequently regulated at many levels, such as through binding to cyclins. Tumor development is closely associated with genetic alterations and dysregulation of CDKs and their regulators, suggesting that CDK inhibitors may be a useful anticancer therapy.

[0009] There remains a need for effective and safe therapeutic agents, as well as their use in combination therapies. In particular, there is a need for effective methods to treat or prevent cancers such as ER+ cancers. Summary of the Invention

[0010] This article describes a method for treating cancer in patients in need, which involves administering estrogen receptor (ER) degraders and cyclin-dependent kinase (CDK) inhibitors.

[0011] This article also provides drug combinations and formulations containing estrogen receptor (ER) degraders and cyclin-dependent kinase (CDK) inhibitors.

[0012] In some implementations, the estrogen receptor (ER) degrader is a compound of formula (I):

[0013]

[0014] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates;

[0015] in:

[0016] Is it a single bond or a double bond?

[0017] --- indicates a single key or that the key does not exist;

[0018] Y is either -CH3 or -O-;

[0019] When Y is -CH3, --- does not exist and It is a double bond; and when Y is -O-, --- and Both are single bonds;

[0020] Z is

[0021] X 3 and X 4 Each is independently selected from H or halogen;

[0022] X 1 and X 2Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0023] A is selected from:

[0024]

[0025] Each of them is R 55 Or 0, 1, 2 or 3 Rs 5 replace;

[0026] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0027] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0028] R 1 and R 2 Each is independently selected from H, C1-C6 acyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0029] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0030] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 replace;

[0031] Each R 55 Independently selected from halogens, hydroxyl groups, C1-C3 alkyl groups, C1-C3 alkyl groups, C1-C3 haloalkyl groups, and -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 5 replace;

[0032] Each R 7 Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups;

[0033] Each R 5 Independently selected from C1-C6 alkyl, C1-C6 alkyl group, C1-C6 haloalkyl group, oxo group, halogen group, cyano group, and hydroxyl group;

[0034] R 22 and R 33 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 5 replace;

[0035] in Represents A and X 2 The connection points; and

[0036] p is 1 or 2.

[0037] In some implementations, the estrogen receptor (ER) degrader is a compound of formula (IA):

[0038]

[0039] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[0040] In some implementations, the estrogen receptor (ER) degrader is a compound of formula (IB):

[0041]

[0042] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[0043] In some implementations, the estrogen receptor (ER) degrader is a compound of formula (IB)*:

[0044]

[0045] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[0046] In some implementations, the CDK inhibitor is a CDK1 inhibitor. In some implementations, the CDK inhibitor is a CDK4 / 6 inhibitor.

[0047] In some implementations, CDK inhibitors have a structure according to formula (II):

[0048]

[0049] Or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates.

[0050] in:

[0051] M is a bond, -NH- or -C(O)-;

[0052] L is hydrogen, alkyl, carbocycloyl, arylalkyl, heteroarylalkyl, or heterocyclic, each of which is optionally substituted by one or more substituents;

[0053] Q is CH2, O, S, or a bond;

[0054] W and Y are independently CH or N, provided that at least one of W or Y is N, and Q is O or S when W is CH; and

[0055] R1 and R2 are independently selected from hydrogen, halogen, alkyl, and heterocyclic, wherein each of the alkyl and heterocyclic groups is optionally substituted by one or more substituents; or

[0056] R1 and R2, together with the atoms they are attached to, form a carbocyclic or heterocyclic group, each of which is optionally substituted by one or more substituents; and

[0057] R9 is hydrogen, halogen, or alkyl, wherein the alkyl group is optionally substituted.

[0058] In some implementations, CDK inhibitors have a structure according to formula (III):

[0059]

[0060] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[0061] In some implementations, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib, or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. Attached Figure Description

[0062] Figure 1 This is a cell growth inhibition curve describing the percentage of cell growth in ER-positive T47D cells treated with palbociclib alone at 10 nM, 30 nM, and 100 nM, and with ER degrader 160a alone or in combination with palbociclib at 10 nM, 30 nM, and 100 nM.

[0063] Figure 2The cell growth inhibition curves describe the percentage of cell growth in ER-positive T47D cells treated with abexinib alone at 10 nM, 30 nM and 100 nM, and alone or in combination with abexinib at 10 nM, 30 nM and 100 nM, as listed in Table 1A, of the ER degrader 160a.

[0064] Figure 3 The cell growth inhibition curves describe the percentage of cell growth in ER-positive T47D cells treated with palbociclib alone at 10 nM, 30 nM, and 100 nM, and with ER degraders 86 in Table 1B, alone or in combination with palbociclib at 10 nM, 30 nM, and 100 nM.

[0065] Figure 4 The cell growth inhibition curves describe the percentage of cell growth in ER-positive T47D cells treated with abexinib alone at 10 nM, 30 nM, and 100 nM, and with ER degrader 86 from Table 1B, alone or in combination with abexinib at 10 nM, 30 nM, and 100 nM.

[0066] Figure 5 This describes the antitumor activity of 160a and palbociclib or their combination from Table 1A at the indicated dose alone in the MCF7 human tumor xenograft model.

[0067] Figure 6 This demonstrates the antitumor activity of 86 and palbociclib or combinations thereof from Table 1B at individual indicated doses in the MCF7 human tumor xenograft model.

[0068] Figure 7 This study describes the antitumor activity of 160b from Table 1A and palbociclib or their combination at the indicated dose in the netamoxifen MCF7 human tumor xenograft model.

[0069] definition

[0070] While it is believed that the following terms will be well understood by those skilled in the art, the following definitions are set forth in order to illustrate the subject matter of this disclosure.

[0071] Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety to more fully describe the prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0072] When immediately preceding a numerical value, the term "about" means a range of variations that are acceptable in the art, plus or minus. In some embodiments, unless the context of this disclosure otherwise indicates, or is inconsistent with such interpretation, the term "about" includes 10% of the value, for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55…", "about 50" means a range extending to less than half the interval between the preceding and following values, for example, greater than 49.5 to less than 52.5. Furthermore, the phrase "less than about" or "greater than about" a value should be understood in light of the definition of the term "about" provided herein.

[0073] "Subject" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experimentation. The methods described herein are useful for both human therapeutics and veterinary applications. In one implementation, the subject is a human.

[0074] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation will occur and the possibility that it will not occur. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl" as defined below. Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any spatially impractical, synthetically infeasible, and / or inherently unstable substitution or substitution pattern.

[0075] It is further noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a preliminary basis for the use of exclusive terms such as "only" or "merely" or for the use of negative restrictions in relation to the statement of elements of the claims.

[0076] The term "pharmaceutically acceptable salt" includes those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by any of many known methods through the reaction of a compound with a suitable inorganic or organic acid.

[0077] The term "pharmaceutically acceptable ester" includes those obtained by replacing hydrogen on an acidic group with an alkyl group, for example by reacting the acid group with an alcohol or a haloalkyl group. Examples of esters include, but are not limited to, replacing hydrogen on a -C(O)OH group with an alkyl group to form a -C(O)O alkyl group.

[0078] The term "pharmaceutically acceptable solvate" refers to a complex of a solute (e.g., an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may be called a hydrate, such as a monohydrate, dihydrate, trihydrate, etc.

[0079] As used herein, the terms "drug combination," "treatment combination," or "combination" refer to a single dosage form containing at least two therapeutic agents, or a separate dosage form containing at least two therapeutic agents, used together or separately in a combination therapy. For example, one therapeutic agent may be formulated into one dosage form, and another therapeutic agent may be formulated into a single dosage form or different dosage forms. For example, one therapeutic agent may be formulated into a solid oral dosage form, while the second therapeutic agent may be formulated into a solution dosage form for parenteral administration.

[0080] The term "treatment" means one or more of the relief, mitigation, delay, reduction, reversal, improvement, or control of at least one symptom of a subject's condition. The term "treatment" may also mean one or more of the prevention, delay of onset (i.e., the period prior to the clinical manifestation of the condition), or reduction of the risk of the condition developing or worsening.

[0081] The term "therapeuticly effective" when applied to dosage or amount refers to an amount of a compound or pharmaceutical preparation that, when administered to a patient in need, is sufficient to produce the desired clinical benefit.

[0082] Unless otherwise indicated, all weight percentages (i.e., "weight %" and "wt.%" and w / w) cited herein are measured relative to the total weight of the pharmaceutical composition.

[0083] When listing a range of values, it is intended to include every value within that range and its subranges. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6 ... 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0084] As used herein, the term "acyl" refers to an R-C(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 (heterocyclic)-C(O)-, wherein the group is attached to the parent molecule structure via a carbonyl functional group. In some embodiments, it is C 1-10 An acyl group refers to the total number of chain atoms or ring atoms plus carbonyl carbons in an acyl group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety. For example, a C4-acyl group has three other ring atoms or chain atoms plus a carbonyl group.

[0085] As used interchangeably herein, "alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain having one to twelve carbon atoms, connected to the remainder of the molecule by single bonds. This includes alkyl groups containing any number of carbon atoms from one to twelve. Alkyl groups containing up to twelve carbon atoms are C1-C1. 12 Alkyl groups, which contain up to 10 carbon atoms, are C1-C64. 10 Alkyl groups, specifically C1-C6 alkyl groups containing up to 6 carbon atoms and C1-C5 alkyl groups containing up to 5 carbon atoms, are further categorized as follows: C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all of the aforementioned portions of C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C... 10 Alkyl groups include all of the above-described portions of C1-C5 alkyl and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all the preceding parts, but also include C. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. In some embodiments, "alkyl" is a straight-chain hydrocarbon. In some embodiments, "alkyl" is a branched hydrocarbon. Unless otherwise specifically specified in the specification, the alkyl group may optionally be substituted.

[0086] "Hydrocarbonyl group" refers to the formula -OR a The group, wherein R a It is an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkyl group may optionally be substituted.

[0087] As used interchangeably in this article, "alkane" or "alkane chain" refers to a fully saturated straight divalent hydrocarbon chain or branched divalent hydrocarbon chain having one to twelve carbon atoms. C1-C 12 Non-limiting examples of alkylenes include methylene, ethylene, propane, n-butane, ethylene, propylene, n-butene, propyne, and n-butyne. The alkylene chain is attached to the rest of the molecule and to a group via single bonds. The connection points between the alkylene chain and the rest of the molecule, and with the group, can be through one or any two carbons within the chain. Unless otherwise specifically specified in the specification, the alkylene chain may optionally be substituted.

[0088] As used interchangeably in this document, "alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 12. Alkenyl groups containing up to 12 carbon atoms are C2-C. 12 Alkenyl groups, which contain up to 10 carbon atoms, are C2-C. 10 Alkenyl groups, comprising up to 6 carbon atoms, are C2-C6 alkenyl groups, and alkenyl groups comprising up to 5 carbon atoms are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl groups. C2-C6 alkenyl groups include all of the above-described portions of the C2-C5 alkenyl group, but also include C6 alkenyl groups. C2-C 10 Alkenyl groups include all of the above-described portions of C2-C5 alkenyl and C2-C6 alkenyl groups, but also include C7, C8, C9, and C6 alkenyl groups. 10 Alkenyl. Similarly, C2-C 12 The alkenyl group includes all the preceding parts, but also includes C. 11 and C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl... Alkenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl. Unless otherwise specifically specified in the specification, the hydrocarbon group may optionally be substituted.

[0089] As used interchangeably in this document, "alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. This includes alkynyl groups containing any number of carbon atoms from 2 to 12. Alkynyl groups containing up to 12 carbon atoms are C2-C. 12 The alkynyl group, which contains up to 10 carbon atoms, is C2-C. 10 The ynyl group includes C2-C6 ynyl groups containing up to 6 carbon atoms and C2-C5 ynyl groups containing up to 5 carbon atoms. C2-C5 ynyl groups include C5, C4, C3, and C2 ynyl groups. C2-C6 ynyl groups include all of the above-described portions of the C2-C5 ynyl group, but also include C6 ynyl groups. 10 The alkynyl group includes all of the above-described portions of C2-C5 alkynyl and C2-C6 alkynyl groups, but also includes C7, C8, C9, and C6 alkynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the preceding parts, but also includes the C group. 11 and C 12 Alkyne group. C2-C 12Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentyyn, etc. Unless otherwise specified in the specification, the alkynyl group may optionally be substituted.

[0090] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is linked to the remaining molecules by a single bond. For the purposes of this invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused-ring or bridged-ring systems. Aryl groups include, but are not limited to, those derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, etc. Aryl groups of fluoranthene, fluorene, asymmetric benzodiindene, symmetric benzodiindene, indene, indene, naphthalene, fentanyl, pleiadene, pyrene, and benzo[a]phenanthrene. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0091] As used interchangeably in this article, "arylalkyl" or "arylalkyl" refers to formula -R b -R c The group, wherein R b It is the alkyl group as defined above and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0092] "Carbocyclic group," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon and is connected to the rest of the molecule by a single bond. A carbocyclic ring can contain from 3 to 20 carbon atoms. Carbocyclic rings include aryl and cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specifically specified in the specification, the carbocyclic group may optionally be substituted.

[0093] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon consisting only of carbon and hydrogen atoms. It can include fused rings, spirochetes, or bridged ring systems (e.g., fused or bridged ring systems), having three to twenty carbon atoms connected to the rest of the molecule by single bonds. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Unless otherwise specifically specified in the specification, the cycloalkyl group may optionally be substituted.

[0094] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds. It can include fused ring or bridged ring systems, having three to twenty carbon atoms, preferably three to ten, and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0095] Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl groups. Unless otherwise specified in the specification, the cycloalkenyl groups may optionally be substituted.

[0096] "Cycloynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having 3 to 20 carbon atoms and one or more carbon-carbon triple bonds. It can include fused ring or bridged ring systems, and is connected to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise specified in the specification, the cycloynyl group may optionally be substituted.

[0097] "Halogenated alkyl" refers to an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified in the specification, the halogenated alkyl group may optionally be substituted.

[0098] As used interchangeably herein, "heterocyclic group," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered aromatic or non-aromatic ring consisting of 2 to 12 carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur, connected to the remainder of the molecule by single bonds. Heterocyclic groups or heterocycles include heteroaryl groups as defined below. Unless otherwise specifically specified in the specification, heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring, spirocyclic, or bridged ring systems (e.g., fused ring or bridged ring systems); and the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiohexacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolylyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiohexacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. For example, biotinyl, dihydrofuranyl, dihydroindolyl, dihydropyranyl, dihydrothiophenyl, dithiazolyl, homopiperidinyl, pyranyl, pyrazolinyl, thiaranyl, pyrrolidine-2-oneyl, or tetrahydroisoquinolinyl. Unless otherwise specified in the specification, heterocyclic groups may optionally be substituted.

[0099] "Heteroaryl" refers to a 5- to 20-membered ring system comprising a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring, which is connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; heteroaryl may contain one or more non-aromatic rings (e.g., cycloalkyl or heterocyclic groups) fused to the aromatic ring. The nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azaheptatrienyl, acridineyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzo-m-dioxacyclopentenyl, benzodioxenyl, and benzo[b][1,4]dioxacyclopentenyl. Pyranyl, benzopyranone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, isothiazolyl, imidazoyl, indazole Indole, inzolyl, isoindole, dihydroindole, isodihydroindole, isoquinolyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazacycloheptatrienyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl groups may be optionally substituted.

[0100] "Heteroarylalkyl" refers to the formula -R b -R f The group, wherein R b It is an alkyl chain as defined above and R f It is a heteroaryl group as defined above. Unless otherwise specified in the specification, the heteroaryl alkyl group may optionally be substituted.

[0101] As used herein, the term "substitution" means that at least one hydrogen atom is replaced by a bond with a non-hydrogen atom in any of the above groups (i.e., alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, N-heterocyclic, heteroaryl, etc.), wherein the non-hydrogen atom is such as, but not limited to: halogen atoms such as F, Cl, Br and I; oxygen atoms in groups such as hydroxyl groups, alkyloxy groups and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; and other heteroatoms in various other groups. "Substitution" also means that one or more hydrogen atoms are replaced by any of the above groups with a higher-order bond (e.g., double or triple bond) of a heteroatom (such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups). For example, "substitution" includes one or more hydrogen atoms replaced by NR. g R h NR g C(=O)R h NR g C(=O)NR g R h NR g C(=O)OR h NR g SO2R h OC (=O)NR g R h OR g SR g SOR g SO2R g OSO2R g SO2OR g =NSO2R g and SO2NR g R h The substitution of any of the above groups. "Substitution" also means one or more hydrogen atoms replaced by C(=O)R g C(=O)OR g C(=O)NR g R h CH2SO2R g CH2SO2NR g R h Any of the above-mentioned groups that have been substituted. In the foregoing, R g and R h"Substitution" refers to any of the following groups, whether identical or different, and independently consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substitution" further means that one or more hydrogen atoms are substituted with a bond of an amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. Furthermore, "substitution" means that each of the above groups is bonded to form a fused ring system containing hydrogen-linked atoms. Additionally, each of the aforementioned substituents may optionally be substituted by one or more substituents. In some embodiments, any one of the above groups (i.e., alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, N-heterocyclic, heteroaryl, etc.) is substituted with an alkyloxy group, aryloxy group, alkyl group, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, ketone, nitro, phosphate, thioether, thionyl, sulfonyl, sulfonic acid, sulfonamide, or thione.

[0102] The term "bond" is used herein to refer to the direct coupling of two adjacent groups without any intermediate atoms or groups. For example, when the group in Formula I is a bond, the group does not actually exist and is described as the portion connected to the group being bonded together.

[0103] The term "ring" can refer to monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused ring or bridged ring systems.

[0104] The compounds disclosed herein may contain one or more chiral centers and / or double bonds, and thus exist as stereoisomers (such as geometric isomers, enantiomers, or diastereomers). When used herein, the term "stereoisomer" comprises all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbol "R" or "S," depending on the configuration of the substituents surrounding the stereocarbon atom. This disclosure includes various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers are designated in nomenclature as "(±)", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. In some embodiments, enantiomers or stereoisomers substantially free of the corresponding enantiomers are provided.

[0105] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, what is provided herein is a mixture of compounds in which individual compounds of the mixture are present primarily in the (S)- or (R)- isomer configuration. For example, the compound mixture has an excess of (S)-enantiomers of more 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 excess of (S)-enantiomers of more than about 55% to about 99.5%, more than about 60% to about 99.5%, more than about 65% to about 99.5%, more than about 70% to about 99.5%, more than about 75% to about 99.5%, more than about 80% to about 99.5%, more than about 85% to about 99.5%, more than about 90% to about 99.5%, more than about 95% to about 99.5%, more than about 96% to about 99.5%, more than about 97% to about 99.5%, more than about 98% to more than about 99.5%, more than about 99% to about 99.5% or more. In other embodiments, the compound mixture has a purity of (R)-enantiomer 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 excess of (R)-enantiomers of more than about 55% to about 99.5%, more than about 60% to about 99.5%, more than about 65% to about 99.5%, more than about 70% to about 99.5%, more than about 75% to about 99.5%, more than about 80% to about 99.5%, more than about 85% to about 99.5%, more than about 90% to about 99.5%, more than about 95% to about 99.5%, more than about 96% to about 99.5%, more than about 97% to about 99.5%, more than about 98% to more than about 99.5%, more than about 99% to about 99.5% or more.

[0106] Individual stereoisomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; or (3) directly separating the optically enantiomer mixture on a chiral chromatographic column. The stereoisomer mixture can also be resolved into its component stereoisomers by well-known methods such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0107] Geometric isomers may also be present in the compounds disclosed herein. The invention includes various geometric isomers and mixtures thereof resulting from the arrangement of substituents around the carbon-carbon double bond or the arrangement of substituents around the carbon ring. Substituents around the carbon-carbon double bond are designated as being in the "Z" or "E" configuration, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, the description of the double bond includes both E and Z isomers.

[0108] Alternatively, substituents around the carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" indicates a substituent on the same side of the double bond and "trans" indicates a substituent on the opposite side of the double bond. The arrangement of substituents around the carbon ring is indicated as "cis" or "trans." The term "cis" indicates a substituent on the same side of the ring plane and the term "trans" indicates a substituent on the opposite side of the ring plane. A mixture of compounds in which substituents are distributed on both the same and opposite sides of the ring plane is called "cis / trans."

[0109] The compounds disclosed herein may exist as tautomers, and both tautomer forms are intended to be included within the scope of this disclosure, even if only one tautomer structure is described.

[0110] Furthermore, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of atoms enriched by one or more isotopes. For example, in addition to hydrogen enriched by deuterium (… 2 H) or tritium ( 3 H) Replacement or carbonization 13 C-carbon atom or 14 Compounds having the structure of this invention, other than those involving C-carbon substitution, are within the scope of this disclosure. Such compounds are useful as, for example, analytical tools, probes in bioassays, or therapeutic agents.

[0111] As used in this article, "cancer" refers to a disease, condition, or illness involving the growth of abnormal cells that have the potential to invade or spread to other parts of the body. Detailed Implementation

[0112] This document describes a pharmaceutical combination comprising an estrogen receptor (ER) degrader and a cyclin-dependent kinase (CDK) inhibitor. It also describes a method of treating a patient with a form of cancer disclosed herein or of treating one or more symptoms of the cancer disclosed herein, comprising administering an estrogen receptor (ER) degrader and a cyclin-dependent kinase (CDK) inhibitor. Suitable ER degraders include one or more of the ER degraders disclosed herein, such as compounds of formulas (I), (IA), (II-A), (IB), (IB*), (IC), (III-C), compounds of Table 1A, or compounds of Table 1B). In some embodiments, the ER degrader is one or more compounds of formulas (I), (IA), (II-A), (IB), (IB*), (IC), (III-C), compounds of Table 1A, or compounds of Table 1B), or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof. In some embodiments, the ER degrader is one or more compounds of formula (I), (IA), (II-A), (IB), (IB*), (IC), (III-C), compounds of Table 1A, or compounds of Table 1B), or tautomers, stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts or hydrates thereof. Suitable (CDK) inhibitors include one or more (CDK) inhibitors of this disclosure, such as one or more compounds of formula (II) or (III). In some embodiments, the CDK inhibitor is one or more compounds of formula (II) or (III), or pharmaceutically acceptable salts, solvates, esters, or tautomers thereof. In some embodiments, the CDK inhibitor is one or more compounds of formula (II) or (III), or tautomers, stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts or hydrates thereof. In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, rebociclib, or abeciclib, or a pharmaceutically acceptable salt.

[0113] Not bound by theory, administration of a combination of one or more ER-degrading agents and one or more CDK inhibitors of this disclosure provides greater therapeutic effect compared to each agent alone (e.g., ER-degrading agents and CDK inhibitors, respectively). In some embodiments, the combination of this disclosure provides more than just additive therapeutic effect compared to each agent alone. In some embodiments, the combination of this disclosure provides synergistic therapeutic effect compared to each agent alone. In some embodiments, the combination of this disclosure provides therapeutic effect over a longer period of time compared to each agent alone.

[0114] The administration of the drug combinations disclosed herein can produce not only beneficial effects, such as synergistic therapeutic effects (e.g., regarding the reduction or delay of the progression of a disease or condition (e.g., cancer) or the suppression of its symptoms), but also further surprising beneficial effects, such as fewer side effects, more durable responses, improved quality of life, or reduced morbidity compared to monotherapy containing one of the individual combination partners.

[0115] In some embodiments, a further benefit is that lower doses of the therapeutic agents of the drug combination of this disclosure can be used, for example, so that the dosage can be applied not only more frequently but also at a lower frequency, or it can be used to reduce the incidence of side effects observed with one of the individual combination partners.

[0116] As discussed herein, in some embodiments, the drug combinations or compositions or both provided herein exhibit a synergistic effect. As used herein, the term "synergistic effect" refers to an effect that causes the ER degrader and the CDK inhibitor of this disclosure to act to produce, for example, a symptom progression of cancer or its symptoms, which is greater than the simple sum of the effects of each drug when administered alone.

[0117] The beneficial effects described herein can be demonstrated using established testing models. Relevant testing models for demonstrating such beneficial effects are known to those skilled in the art. The pharmacological activity of the combinations disclosed herein can be demonstrated, for example, in clinical studies or animal models.

[0118] For example, synergistic effects can be calculated using appropriate methods such as the Sigmoid-Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)) and the median effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each of these equations can be applied to experimental data to generate corresponding graphs to help assess the effects of drug combinations. The corresponding graphs associated with the equations mentioned above are concentration-action curves, equivalence curves, and combination exponent curves. Another method to demonstrate synergistic effects is the highest single-reagent model (HSA) with a null hypothesis (Berenbaum 1989). The functional association between targets that exceed the over-predictive suppression of the HSA model (Lehar, Zimmermann et al. 2007; Lehar, Krueger et al. 2009). This method results in the index z.sub.c of combined strength.

[0119] In some embodiments, this disclosure provides synergistic combinations (e.g., comprising the ER degrader and CDK inhibitor disclosed herein) for administration to subjects in need, wherein the dose range of each component corresponds to the synergistic range suggested in a suitable tumor model or clinical study.

[0120] ■ ER degradation agent

[0121] In some implementations, compounds with ER-degrading activity degrade ERα (also known as ER degrading agents).

[0122] Unbound by any theory, it is believed that ERα degradation may occur when both ERα and ubiquitin ligases bind and come into close proximity. Cereblon ("CRBN") E3 ubiquitin ligase is a ubiquitin ligase that forms an E3 ubiquitin ligase complex with CRBN, along with damaged DNA-binding protein 1 and Cullin 4. It functions as a substrate acceptor by bringing the substrate into close proximity for ubiquitination and subsequent degradation via the proteasome. Recently, small molecule drugs (such as thalidomide and its close analogues lenalidomide and pomalidomide) have been found to interact simultaneously with CRBN and several other proteins. In doing so, CRBN is used for the degradation of target proteins, such as IKZF1 and IKZF3. This is thought to contribute to the antimyeloma effects of thalidomide and related compounds.

[0123] In some embodiments, ER degrading agents are described in U.S. Patent Nos. 9,944,632 or 10,800,770, the contents of which are hereby incorporated herein by reference in their entirety for all purposes.

[0124] In one respect, estrogen receptor (ER) degraders are compounds of formula (I):

[0125]

[0126] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates;

[0127] in:

[0128] Is it a single bond or a double bond?

[0129] --- indicates a single key or that the key does not exist;

[0130] Y is either -CH3 or -O-;

[0131] When Y is -CH3, --- does not exist and It is a double bond; and when Y is -O-, --- and Both are single bonds;

[0132] Z is

[0133] X 3 and X 4 Each is independently selected from H or halogen;

[0134] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0135] A is selected from:

[0136]

[0137]

[0138] Each of them is R 55 Or 0, 1, 2 or 3 Rs 5 replace;

[0139] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0140] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0141] R 1 and R 2 Each is independently selected from H, C1-C6 acyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0142] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0143] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 replace;

[0144] Each R 55 Independently selected from halogens, hydroxyl groups, C1-C3 alkyl groups, C1-C3 alkyl groups, C1-C3 haloalkyl groups, and -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 5 replace;

[0145] Each R 7 Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs 7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups;

[0146] Each R 5 Independently selected from C1-C6 alkyl, C1-C6 alkyl group, C1-C6 haloalkyl group, halogen, cyano group and hydroxyl group;

[0147] R 22 and R 33 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 5 replace;

[0148] in Represents A and X 2 The connection points; and

[0149] p is 1 or 2.

[0150] In one respect, the estrogen receptor (ER) degrader presented herein is a compound of formula (IA):

[0151]

[0152] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates;

[0153] in:

[0154] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0155] A is selected from:

[0156] Each of them is composed of 0, 1, 2 or 3 Rs. 5 replace;

[0157] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0158] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0159] R 1 and R 2 Each is independently selected from H, C1-C6 alkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto groups, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0160] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0161] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 Replace; and

[0162] Each R5 Independently selected from C1-C6 alkyl, halogen, cyano, and hydroxyl groups;

[0163] in Represents A and X 2 The connection point.

[0164] In some embodiments, the compound of formula (I) or (IA) may include both E and Z isomers. In some embodiments, the compound of formula (I) or (IA) is a mixture of trans-olefins and cis-olefins.

[0165] In some embodiments of compounds of formula (I) or formula (IA), A is In some implementation schemes, A is In some implementation schemes, A is In some implementation schemes, A is In some implementation schemes, A is In some implementation schemes, A is In some implementation schemes, A is In some implementation schemes, A is

[0166] In some embodiments, the estrogen receptor (ER) degrader is a compound of formula (II-A), or a tautomer, stereoisomer, pharmaceutical salt, or hydrate thereof:

[0167]

[0168] in:

[0169] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0170] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0171] C is selected from:

[0172] Each of them is composed of 0, 1, 2 or 3 Rs. 5 replace;

[0173] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0174] R 1 and R 2 Each is independently selected from H, C1-C6 alkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto groups, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0175] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0176] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 Replace; and

[0177] Each R 5 Independently selected from C1-C6 alkyl, halogen, cyano, and hydroxyl groups;

[0178] in Representing C and X 2 The connection point.

[0179] In some embodiments of compounds of formula (II-A), C is In some implementations, C is In some implementations, C is In some implementations, C is In some implementations, C is

[0180] In some embodiments of compounds of formula (I), (IA) and / or (II-A), B is composed of 0, 1, 2 or 3 Rs. 5 The 5-membered heterocycle is replaced. In some embodiments, B is a 5-membered heterocycle. In some embodiments, B is replaced by one R 5 The replaced 5-membered heterocyclic ring. In some implementations, R 5 It is a C1 alkyl group.

[0181] In some embodiments of compounds of formula (I), (IA) and / or (II-A), B is composed of 0, 1, 2 or 3 Rs. 5 The substituted 6-membered heterocycle. In some embodiments, B is a 6-membered heterocycle. In some embodiments, B is replaced by one R 5The substituted 6-membered heterocycle. In some implementations, R 5 It is a C1 alkyl group.

[0182] In some embodiments of compounds of formula (I), (IA) and / or (II-A), B is selected from:

[0183] in This represents the connection point between B and A. In some implementations, B is...

[0184] In some embodiments of compounds of formula (I), (IA) and / or (II-A), R 1 and R 2 Each is independently selected from H, C1-C3 alkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto groups, each marked with 0, 1, 2, or 3 R groups. 5 Replacement. In some implementations, R 1 and R 2 Each is independently selected from H, C1 alkyl, halogen, and hydroxyl groups, each marked with 0, 1, 2, or 3 R groups. 5 Replacement. In some implementations, R 1 and R 2 Each is independently H or OH. In some implementations, R 1 It is H. In some implementations, R 1 It is OH. In some implementations, R 2 It is H. In some implementations, R 2 It is OH. In some implementations, R 1 It is OH and R 2 It is H. In some implementations, R 1 It is H and R 2 It is H. In some implementations, R 1 It is H and R 2 It is OH. In some implementations, R 1 It is OH and R 2 It is OH.

[0185] In some embodiments of compounds of formula (I), (IA) and / or (II-A), X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Replacement. In some implementations, where X 1 and X2 Each is independently selected from CH2 and NR 4 O, S, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Replacement. In some implementations, X 1 It is O. In some embodiments, X 1 It is C(R) 3 2. In some implementation schemes, R 3 It is H or a halogen. In some embodiments, the halogen is fluorine. In some embodiments, R 3 It is H. In some implementations, X 1 It is NR 4 In some implementations, R 4 Selected from H, C1-C3 alkyl and acyl groups, each of which is surrounded by 0, 1, 2 or 3 R groups. 5 Replacement. In some implementations, R 4 It is H. In some implementations, R 4 Is it 0, 1, 2 or 3 Rs? 5 Substituted C1-C3 alkyl groups. In some embodiments, R 4 Is it 0, 1, 2 or 3 Rs? 5 Substituted C1 alkyl group. In some embodiments, R 4 It is a C1 alkyl group. In some embodiments, R 4 Is it 0, 1, 2 or 3 Rs? 5 Substituted acyl group.

[0186] In some embodiments of compounds of formula (I), (IA) and / or (II-A), X 1 It is a 5- or 6-membered cycloalkyl group. In some embodiments, X 1 It is a 5- or 6-aryl group. In some implementations, X 1 It is a 5- or 6-membered heterocyclic ring. In some implementations, X 1 It is a 5- or 6-membered heteroaryl group. In some implementations, X 1 Is it 0, 1, 2 or 3 Rs? 5 Substituted 5- or 6-membered cycloalkyl groups. In some embodiments, X 1 Is it 0, 1, 2 or 3 Rs? 5 The 5- or 6-membered aryl group is replaced. In some embodiments, X 1 Is it 0, 1, 2 or 3 Rs? 5 The substituted 5- or 6-membered heterocyclic ring. In some implementations, X 1 Is it 0, 1, 2 or 3 Rs? 5 Replacement of 5- or 6-membered heteroaryl groups.

[0187] In some embodiments of compounds of formula (I), (IA) and / or (II-A), X 1 Selected from acridine, aziridine, pyrrolidine, piperidinyl, piperazinyl, pyrrolyl, pyridinyl, pyrimidinyl, ethylene oxide, oxadiazine, tetrahydrofuranyl, furanyl, pyranyl, tetrahydropyranyl, dioxidine, imidazolyl, pyrazolyl, oxazole, isoxazole, thiazole, isothiazole, triazole, tetraazole, indole, benzimidazole, benzofuran, benzoxazole, benzothiazole, quinoline, isoquinoline, and quinazoline, each independently bound by 0, 1, 2, or 3 R groups. 5 Replacement. In some implementations, X 1 Selected from:

[0188] In some implementation schemes, X 1 Selected from:

[0189]

[0190] In some embodiments of compounds of formula (I), (IA) and / or (II-A), X 2 Selected from:

[0191]

[0192]

[0193] In some embodiments of the compounds of formula (I), (IA) and / or (II-A), L* is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L* is a linker with a length of 1 to 14 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L* is a linker with a length of 1 to 12 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5Substitution. In some embodiments, L* is a linker with a length of 1 to 10 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0194] In some embodiments of the compounds of formula (I), (IA) and / or (II-A), L* is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L* is a linker with a length of 1 to 6 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0195] In some embodiments of the compounds of formula (I), (IA) and / or (II-A), L* is a linker in which two carbon atoms are each independently substituted by a heterocycle, each independently substituted by 0, 1, 2 or 3 R atoms. 5 Replacement. In some embodiments, L* is a connector in which one carbon atom is replaced by a heterocyclic ring and another carbon atom is replaced by a cycloalkyl ring, each independently replaced by 0, 1, 2, or 3 R atoms. 5 Substitution. In some embodiments, L* is a linker in which more than one carbon atom is independently substituted by a group selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L* is a linker in which more than one carbon atom is independently substituted by a group selected from: C(O), O, and NR. 4 Each of them is composed of 0, 1, 2 or 3 R. 5 replace.

[0196] In some embodiments of compounds of formula (I), (IA) and / or (II-A), L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is In some implementations, L* is

[0197] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0198] (Z)-3-(4-(3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)propoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0199] (Z)-3-(4-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0200] (Z)-3-(5-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0201] (Z)-3-(5-(2-(5-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0202] (Z)-3-(5-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0203] (Z)-3-(5-((3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0204] (Z)-3-(5-((3-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0205] (Z)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0206] (Z)-3-(4-(2-(6-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0207] (Z)-3-(5-(5-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)-5-oxopentyl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0208] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0209] (Z)-3-(5-((4-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)butyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0210] (Z)-3-(5-(3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)-3-oxopropyl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0211] (Z)-3-(5-((3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0212] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0213] (E) / (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0214] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0215] (E) / (Z)-(S)-3-(5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0216] (Z)-3-(5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0217] (Z)-3-(5-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0218] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((2-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)ethyl)amino)isodihydroindole-1,3-dione;

[0219] (Z)-3-(5-((2-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0220] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)propyl)amino)isodihydroindole-1,3-dione;

[0221] (Z)-3-(5-((3-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0222] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)amino)isodihydroindole-1,3-dione;

[0223] (Z)-3-(5-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0224] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0225] (Z)-3-(5-(3-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)oxy)propyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0226] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)oxy)propyl)isodihydroindole-1,3-dione;

[0227] (E) / (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0228] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0229] (E) / (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0230] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0231] (Z)-3-(5-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0232] (E) / (Z)-(S)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0233] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0234] (E) / (Z)-(S)-3-(5-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0235] (Z)-3-(5-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0236] (Z)-3-(5-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)butoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0237] (Z)-3-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0238] (Z)-3-(5-((6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hex-2,4-diyn-1-yl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0239] (Z)-3-(5-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0240] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0241] (Z)-3-(5-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-1,4-diazacycloheptane-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0242] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)pentyl)oxy)isodihydroindole-1,3-dione;

[0243] (E)-3-(5-((5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)pentyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0244] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)butoxy)isodihydroindole-1,3-dione;

[0245] (E)-3-(5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)butoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0246] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)pentyl)amino)isodihydroindole-1,3-dione;

[0247] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)butyl)amino)isodihydroindole-1,3-dione;

[0248] (Z)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-5-yl)methyl)-2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)acetamide;

[0249] (Z)-3-(5-(3-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0250] (Z)-3-(5-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0251] (Z)-3-(5-(3-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0252] (Z)-3-(5-(2-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-3-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0253] (Z)-3-(5-(4-((4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)amino)phenyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0254] (Z)-3-(5-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0255] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)isodihydroindole-1,3-dione;

[0256] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-2,5-dimethylpiperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,5-dione;

[0257] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide;

[0258] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,5-dione;

[0259] (Z)-2-(2,5-dioxopiperidin-3-yl)-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0260] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclohexyl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0261] (Z)-3-(5-(4-((4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0262] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-((4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclohexyl)oxy)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0263] (Z)-3-(5-(4-(2-((4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclohexyl)oxy)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0264] (Z)-3-(5-(2-((2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2-azaspiro[3.3]hept-6-yl)oxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0265] (E)-3-(6-((4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)butyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0266] (Z)-3-(5-((2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0267] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide;

[0268] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0269] (Z)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-5-yl)methyl)-2-(4-(1-(4-(1-(4-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)prop-2-yl)piperazin-1-yl)acetamide;

[0270] (Z)-3-(5-(3-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)-1,4-diazacycloheptane-1-yl)propyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0271] (E)-3-(5-((5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)pentyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0272] (Z)-3-(5-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0273] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)isodihydroindole-1,3-dione;

[0274] (Z)-3-(5-(3-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0275] (Z)-3-(5-(2-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-1,4-diazacycloheptane-1-yl)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0276] (Z)-3-(5-(4-amino-3-((5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)oxy)phenyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0277] (Z)-3-(5-(4-amino-3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butoxy)phenyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0278] (Z)-3-(5-((3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0279] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propyl)amino)isodihydroindole-1,3-dione;

[0280] (Z)-3-(5-(3-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0281] (Z)-3-(5-(3-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-3-yl)propyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0282] (Z)-3-(5-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-1,4-diazacycloheptane-1-yl)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0283] (Z)-3-(5-(2-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)-1H-indol-5-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0284] (Z)-3-(5-(2-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-1H-indol-5-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0285] (Z)-3-(5-(2-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-1H-indol-5-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0286] (Z)-3-(5-(2-((1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)piperidin-3-yl)oxy)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0287] (Z)-3-(5-(2-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-3-yl)oxy)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0288] (E)-3-(5-(4-((2-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)benzyl)oxy)ethyl)(methyl)amino)cyclohexyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0289] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-1,4-diazacycloheptane-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0290] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-1,4-diazacycloheptane-1-yl)isodihydroindole-1,3-dione;

[0291] (Z)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylacetamide;

[0292] (Z)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0293] (Z)-3-(5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-1,4-diazacycloheptane-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0294] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-1,4-diazacycloheptane-1-yl)isodihydroindole-1,3-dione;

[0295] (Z)-3-(5-(4-(2-(2-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)cyclopropyl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0296] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)cyclopropyl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0297] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)piperidin-1-yl)methyl)piperidin-1-yl)isodihydroindole-1,3-dione;

[0298] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0299] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0300] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0301] (Z)-3-(5-(4-(4,4-difluoro-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0302] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)azacyclobutane-3-yl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0303] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)-1-methylpiperidin-2,6-dione;

[0304] (Z)-3-(5-(6-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)oxy)pyridin-3-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0305] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0306] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)isodihydroindole-1,3-dione;

[0307] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)isodihydroindole-1,3-dione;

[0308] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)isodihydroindole-1,3-dione;

[0309] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-3,5-dimethylpiperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0310] (Z)-3-(5-(4-((4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0311] (Z)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylbutyramide;

[0312] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(7-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-2,7-diazaspiro[3.5]non-2-yl)isodihydroindole-1,3-dione;

[0313] (Z)-2-(2,6-dioxopiperidin-3-yl)-6-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione;

[0314] (Z)-3-(5-(7-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0315] (Z)-3-(5-(4-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0316] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(6-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-2,6-diazaspiro[3.3]hept-2-yl)isodihydroindole-1,3-dione;

[0317] (Z)-3-(5-(2-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pyridin-3-yl)piperazin-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0318] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pyridin-3-yl)piperazin-1-yl)ethoxy)isodihydroindole-1,3-dione;

[0319] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pyridin-3-yl)piperazin-1-yl)propoxy)isodihydroindole-1,3-dione;

[0320] (Z)-3-(5-(3-(4-(6-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pyridin-3-yl)piperazin-1-yl)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0321] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)isodihydroindole-1,3-dione;

[0322] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)-2,5-dimethylpiperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0323] (Z)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylhexanoamide;

[0324] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)oxy)pyrazin-2-yl)isodihydroindole-1,3-dione;

[0325] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)pyrazin-2-yl)isodihydroindole-1,3-dione;

[0326] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)azacyclobutane-3-yl)methoxy)pyrazin-2-yl)isodihydroindole-1,3-dione;

[0327] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)isodihydroindole-1,3-dione;

[0328] (Z)-6-(2,6-dioxopiperidin-3-yl)-2-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-5H-pyrrolo[3,4-b]pyrazin-5,7(6H)-dione;

[0329] (Z)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylheptamide;

[0330] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(1'-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-[1,4'-bipiperidin]-4-yl)isodihydroindole-1,3-dione;

[0331] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)isodihydroindole-1,3-dione;

[0332] (E)-3-(5-(4-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-1H-pyrazol-1-yl)propyl)piperazin-1-yl)-1-oxoisodihydroindole-2-yl)piperidine-2,6-dione;

[0333] (Z)-6-(2,6-dioxopiperidin-3-yl)-2-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-5H-pyrrolo[3,4-d]pyrimidine-5,7(6H)-dione;

[0334] (Z)-3-(5-(1'-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-[1,4'-piperidin]-4-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0335] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)piperidin-1-yl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0336] (E)-3-(5-(4-(1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)pyrrolidine-3-yl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0337] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0338] (E)-3-(5-(4-((1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0339] (Z)-3-(5-((6-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)pyridin-3-yl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0340] (E)-3-(5-(4-(2-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0341] (E)-3-(5-(4-(2-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0342] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0343] (Z)-3-(5-(4-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2-azaspiro[3.3]hept-6-yl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0344] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-1H-pyrazol-1-yl)propyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0345] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-2H-tetrazol-2-yl)propyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0346] (Z)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyloctylamide;

[0347] (Z)-3-(5-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0348] (E)-3-(5-(4-((1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0349] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperidin-4-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0350] (E)-3-(5-(4-(1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperidin-4-yl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0351] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperidin-4-yl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0352] (E)-3-(5-(4-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)propyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0353] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)propyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0354] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0355] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0356] (Z)-3-(4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0357] (Z)-3-(4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0358] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0359] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadecane-18-amide;

[0360] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide;

[0361] (Z)-3-(5-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0362] (Z)-3-(7-chloro-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0363] (E) / (Z)-(S)-3-(5-(4-((1-(4-(1-((1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0364] (E)-3-(5-(4-((1-(4-(1-((4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0365] (E)-(S)-3-(5-(4-((1-(4-(1-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0366] (E) / (Z)-(S)-3-(5-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0367] (E)-3-(5-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0368] (Z)-3-(5-fluoro-6-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0369] (Z)-3-(4-fluoro-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0370] (E)-3-(5-(2-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)-1,4-diazacycloheptane-1-yl)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0371] (Z)-3-(5-(6-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0372] (Z)-3-(5-(8-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0373] (Z)-3-(5-(4-(2-hydroxy-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0374] (Z)-3-(7-fluoro-5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0375] (Z)-3-(5-(4-(3-hydroxy-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-3-methylpentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0376] (Z)-3-(5-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-2-oxopentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0377] (Z)-3-(4-fluoro-5-(4-(2-hydroxy-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0378] (Z)-3-(4,6-difluoro-5-(4-(2-hydroxy-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0379] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)isodihydroindole-1,3-dione;

[0380] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)isodihydroindole-1,3-dione;

[0381] (Z)-3-(5-(4-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0382] (Z)-3-(5-(4-(2-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclobutoxy)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0383] (Z)-5-(4-(4,4-difluoro-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione;

[0384] (Z)-3-(5-(4-(3-hydroxy-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0385] (Z)-3-(5-(5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0386] (Z)-3-(5-(5-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0387] (Z)-3-(5-(4-(5-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)sulfonyl)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0388] (E)-3-(5-(2-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)azacyclobutane-3-yl)methyl)-1,4-diazacycloheptane-1-yl)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0389] (Z)-3-(5-(4-(2-((2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0390] (E) / (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0391] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0392] (E) / (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0393] (E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0394] (Z)-3-(5-(4-(5-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)thio)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0395] (Z)-3-(5-(4-((5-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)tetrahydrofuran-2-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0396] (Z)-3-(5-(4-(2-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclobutyl)ethyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0397] (Z)-3-(6-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0398] (Z)-3-(2-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione;

[0399] (Z)-3-(2-(4-(4,4-difluoro-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione;

[0400] (Z)-3-(6-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)pentyl)piperazin-1-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidin-2,6-dione;

[0401] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)butyl)isodihydroindole-1,3-dione;

[0402] (Z)-3-(5-(4-((3-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)cyclobutyl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0403] (Z)-3-(2-(4-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)butyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione;

[0404] (E)-3-(5-((1-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0405] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-(4-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)pyrrolidine-3-yl)butyl)isodihydroindole-1,3-dione;

[0406] (E)-3-(2-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione;

[0407] (E)-3-(2-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione;

[0408] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((1-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)isodihydroindole-1,3-dione;

[0409] (Z)-3-(5-(4-((6-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)pyridazine-3-yl)methyl)piperazine-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0410] (E)-3-(5-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindole-2-yl)-3-methylpiperidin-2,6-dione;

[0411] (E)-3-(5-(7-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0412] (Z)-3-(6-(2-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)cyclobutoxy)piperidin-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0413] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6,6,6-trifluoro-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0414] (Z)-3-(1-oxo-5-(4-(6,6,6-trifluoro-5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)hexyl)piperazin-1-yl)isodihydroindol-2-yl)piperidine-2,6-dione;

[0415] (Z)-3-(5-(4-((5-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0416] (E)-3-(6-(4-((1-(4-(1-((4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidin-2,6-dione;

[0417] (E)-3-(5-(4-(7-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0418] (E)-3-(2-(4-(7-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione;

[0419] (E)-3-(6-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)piperidin-2,6-dione;

[0420] (E)-3-(5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)-4-methylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0421] (E)-3-(4,6-difluoro-5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0422] (E)-3-(5-((1-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0423] (E)-3-(2-(3-(((1-(4-(1-((4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)amino)pyrrolidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidin-2,6-dione;

[0424] (E)-3-(4-fluoro-5-(4-((1-(4-(1-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0425] (E)-3-(6-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0426] (E)-3-(5-(3-(((1-(4-(1-((4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)amino)pyrrolidin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0427] (E)-3-(5-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)-1-methylpiperidin-2,6-dione;

[0428] (E)-3-(5-(4-((4-hydroxy-1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0429] (E)-3-(5-(4-(((1-(4-(1-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)amino)piperidin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0430] (E)-3-(5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)amino)piperidin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0431] (E)-3-(5-(4-((4-fluoro-1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0432] (Z)-3-(4-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0433] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethyl)amino)isodihydroindole-1,3-dione;

[0434] (Z)-3-(5-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)-2-oxoethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0435] (Z)-3-(4-((6-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)pyridin-3-yl)methoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0436] (Z)-3-(4-(2-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)prop-2-yl)piperazin-1-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0437] (Z)-3-(4-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0438] (Z)-3-(4-((14-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0439] (Z)-3-(4-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0440] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((14-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)isodihydroindole-1,3-dione;

[0441] (Z)-3-(4-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0442] (Z)-3-(4-((2-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0443] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0444] (Z)-3-(4-((2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0445] (Z)-3-(4-((14-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0446] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0447] (Z)-3-(4-((2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0448] (Z)-3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0449] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0450] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0451] (Z)-3-(4-((2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0452] (Z)-3-(4-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0453] (Z)-3-(4-(3-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)propoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0454] (Z)-3-(4-(2-(5-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0455] (Z)-3-(5-(2-(6-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-2,6-diazaspiro[3.3]hept-2-yl)ethoxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0456] (Z)-3-(5-(2-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)oxy)ethoxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0457] (Z)-3-(5-((7-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-7-azaspiro[3.5]non-2-yl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0458] (Z)-3-(5-(4-(4-(1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)prop-2-yl)piperazin-1-yl)butyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0459] (Z)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-5-yl)methyl)-1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-carboxamide;

[0460] (Z)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-5-yl)methyl)-2-(1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)acetamide;

[0461] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)isodihydroindole-1,3-dione;

[0462] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(7-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)heptyl)piperazin-1-yl)isodihydroindole-1,3-dione;

[0463] (Z)-3-(5-((3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-1,4-diazacycloheptane-1-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0464] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)isodihydroindole-1,3-dione;

[0465] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)isodihydroindole-1,3-dione;

[0466] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)propoxy)isodihydroindole-1,3-dione;

[0467] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)propoxy)isodihydroindole-1,3-dione;

[0468] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propyl)amino)isodihydroindole-1,3-dione;

[0469] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)propyl)amino)isodihydroindole-1,3-dione;

[0470] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)propyl)amino)isodihydroindole-1,3-dione;

[0471] (Z)-3-(5-((2-(2-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0472] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)propoxy)isodihydroindole-1,3-dione;

[0473] (Z)-3-(5-((3-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0474] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butoxy)propoxy)propoxy)isodihydroindole-1,3-dione;

[0475] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethoxy)propoxy)propyl)amino)isodihydroindole-1,3-dione;

[0476] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butoxy)propoxy)propyl)amino)isodihydroindole-1,3-dione;

[0477] (Z)-3-(5-((3-(3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)butoxy)propoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0478] (Z)-3-(5-((3-(3-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)propoxy)propoxy)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0479] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)propyl)amino)isodihydroindole-1,3-dione;

[0480] (Z)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-1,4-diazacycloheptane-1-yl)propyl)amino)isodihydroindole-1,3-dione;

[0481] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperazin-1-yl)propyl)amino)isodihydroindole-1,3-dione;

[0482] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)-1,4-diazacycloheptane-1-yl)propyl)amino)isodihydroindole-1,3-dione;

[0483] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)propyl)amino)isodihydroindole-1,3-dione;

[0484] (E)-2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)butyl)amino)isodihydroindole-1,3-dione;

[0485] (E)-3-(5-((3-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)piperazin-1-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione;

[0486] (E)-3-(5-((3-(4-(3-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)propyl)-1,4-diazacycloheptane-1-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0487] (E)-3-(5-((3-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)propyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0488] (E)-3-(5-((5-(4-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-1-yl)pentyl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione; and

[0489] (E)-3-(5-(2-(4-(5-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)pentyl)-1,4-diazacycloheptane-1-yl)ethyl)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione.

[0490] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0491] (Z)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0492] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0493] (Z)-3-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0494] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide;

[0495] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide;

[0496] (Z)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylacetamide;

[0497] (Z)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0498] (Z)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylbutyramide;

[0499] (Z)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylhexanoamide;

[0500] (Z)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylheptamide;

[0501] (Z)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyloctylamide;

[0502] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0503] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0504] (Z)-3-(4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0505] (Z)-3-(4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0506] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0507] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0508] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadecane-18-amide;

[0509] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide; and

[0510] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide).

[0511] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0512] (Z)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0513] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0514] (Z)-3-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0515] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide;

[0516] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide;

[0517] (Z)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylacetamide;

[0518] (Z)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0519] (Z)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylbutyramide;

[0520] (Z)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylhexanoamide;

[0521] (Z)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylheptamide; and

[0522] (Z)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyloctamide.

[0523] In some embodiments, the compounds provided herein are selected from the following: tautomers, stereoisomers, pharmaceutically acceptable salts, or hydrates thereof:

[0524] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0525] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12-tetraoxapentadecan-15-amide;

[0526] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide;

[0527] (Z)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylheptamide; and

[0528] (Z)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyloctamide.

[0529] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0530] (Z)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylacetamide;

[0531] (Z)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0532] (Z)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylbutyramide;

[0533] (Z)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylhexanoamide;

[0534] (Z)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylheptamide; and

[0535] (Z)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyloctamide.

[0536] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0537] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0538] (Z)-2-(2,6-dioxopiperidin-3-yl)-4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)isodihydroindole-1,3-dione;

[0539] (Z)-3-(4-((1-((1-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione; and

[0540] (Z)-3-(4-((1-((4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)methyl)piperidin-4-yl)amino)-1-oxoisodihydroindole-2-yl)piperidin-2,6-dione.

[0541] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0542] (Z)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindol-4-yl)amino)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0543] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0544] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0545] (Z)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)ethoxy)ethoxy)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylpropionamide;

[0546] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadecane-18-amide;

[0547] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide; and

[0548] (Z)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-4-yl)amino)-N-(2-(4-(1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methyl-3,6,9,12,15-pentaoctadecane-18-amide).

[0549] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0550] (Z)-3-(8-((2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethyl)amino)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidin-2,6-dione; and

[0551] (Z)-3-(8-(2-(4-(2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.

[0552] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are selected from:

[0553] 3-(5-(4-((1-(4-(1-((4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0554] (S)-3-(5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0555] (S,E)-3-(5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione;

[0556] (E)-3-(5-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione.

[0557] In a specific embodiment, the compound having ER degradation activity is (S,E)-3-(5-(4-((1-(4-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione.

[0558] In some embodiments, the compound with ER degradation activity provided herein, or its tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are pharmaceutically acceptable salts of compounds of formula (I), (IA) or (II-A).

[0559] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are one or more compounds selected from Table 1A.

[0560] ■ Table 1A. Exemplary Compounds of this Disclosure

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616] In some embodiments, the compound with ER degradation activity (also known as an ER degrader) has a structure according to formula (IC):

[0617]

[0618] Or its tautomers, stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, esters, or hydrates, wherein:

[0619] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0620] L is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0621] R 1 and R 2 Each is independently selected from H, C1-C6 alkyl, halogen, alkyloxy, acyl, hydroxyl, and mercapto groups, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0622] R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0623] R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 replace;

[0624] R 5 Independently selected from C1-C6 alkyl, halogen, cyano, and hydroxyl groups;

[0625] Y is (H,H) or O;

[0626] In some embodiments of the compound of formula (IC), the compound is a trans olefin or a cis olefin or a mixture thereof.

[0627] In some embodiments, the estrogen receptor (ER) degraders provided herein are compounds of formula (IB) or their tautomers, stereoisomers, or mixtures thereof, pharmaceutically acceptable salts, or hydrates:

[0628]

[0629] in:

[0630] R 1Selected from H, C1-C6 acyl or C1-C6 alkyl, each of which is surrounded by 0, 1, 2 or 3 R groups. 6 replace;

[0631] R 2 and R 3 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0632] Each R 4 Independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy or C1-C3 haloalkyl, each of which is marked by 0, 1, 2 or 3 R. 6 Replace, or two Rs 4 The groups combine to form an oxo group;

[0633] R 5 Selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 haloalkyl, -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 6 replace;

[0634] X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0635] X 3 and X 4 Each is independently selected from H or halogen;

[0636] L is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 7 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 6 replace;

[0637] Each R 6 Independently selected from C1-C6 alkyl, halogen, cyano, and hydroxyl groups.

[0638] Each R 7 Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs 7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups.

[0639] In some embodiments of compounds of formula (I) or formula (IB), R 1 Selected from H or C1-C6 alkyl groups, each of which is surrounded by 0, 1, 2 or 3 R groups. 6 Replacement. In some implementations, R 1 It can be selected from H or methyl, each of which is separated by 0, 1, 2 or 3 R. 6 Replacement. In some embodiments, R 1 Each can be H or methyl independently. In some embodiments, R 1 It is H. In some implementations, R 1 It is a methyl group.

[0640] In some embodiments of compounds of formula (I) or formula (IB), R 2 and R 3 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 Replacement. In some implementations, R 2 and R 3 Each is independently selected from H and methyl, each separated by 0, 1, 2 or 3 R groups. 6 Replacement. In some implementations, R 2 and R 3 Each is independently selected from H and methyl. In some embodiments, R 2 It can be H and R 3 It can be H. In some implementations, R 2 It can be H and R 3 It can be methyl. In some embodiments, R 2 It can be methyl and R 3 It can be H. In some implementations, R 2 It can be methyl and R 3 It can be methyl.

[0641] In some embodiments of compounds of formula (I) or formula (IB), each R 4 Independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy or C1-C3 haloalkyl, each of which is marked by 0, 1, 2 or 3 R. 6 Replace, or two Rs 4 The groups combine to form an oxo group. In some embodiments, each R... 4 Independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy or C1-C3 haloalkyl, or two R 4 The groups combine to form an oxo group. In some embodiments, R 4 It is H. In some implementations, two Rs 4The groups combine to form an oxo group.

[0642] In some embodiments of compounds of formula (I) or formula (IB), R 5 Selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 haloalkyl, -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 6 Replacement. In some implementations, R 5 Selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 haloalkyl, -N(R) 7 )2 and -CN. In some implementations, R 5 R5 is selected from hydrogen. In some embodiments, R5 is selected from halogens. In some embodiments, R... 5 It can be F.

[0643] In some embodiments of compounds of formula (I) or formula (IB), X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 Replacement. In some implementations, X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl. In some embodiments, X 1 and X 2 Each is independently selected from H, F, CN, methyl, methoxy, and trifluoromethyl. In some embodiments, X 1 It is H and X 2 It is H. In some implementations, X 1 It is F and X 2 It is F. In some implementations, X 1 It is H and X 2 It is methyl. In some embodiments, X 1 It is methyl and X 2 It is H. In some implementations, X 1 It is H and X 2 It is F. In some implementations, X 1 It is F and X 2 It is H. In some implementations, X 1 It is H and X 2 It is a methoxy group. In some embodiments, X 1 It is methoxy group and X 2 It is H. In some implementations, X 1 It is F and X2 It is methyl. In some embodiments, X 1 It is methyl and X 2 It is F. In some implementations, X 1 It is F and X 2 It is a methoxy group. In some embodiments, X 1 It is methoxy group and X 2 It is F. In some implementations, X 1 It is F and X 2 It is trifluoromethyl. In some embodiments, X 1 It is trifluoromethyl and X 2 It is F.

[0644] In some embodiments of compounds of formula (I) or formula (IB), X 3 and X 4 Each is independently selected from H or halogen. In some embodiments, X 3 and X 4 Each is independently selected from H or F. In some embodiments, X 3 It is H and X 4 It is H. In some embodiments, X 3 It is F and X 4 It is F. In some embodiments, X 3 It is H and X 4 It is F. In some embodiments, X 3 It is F and X 4 It is H.

[0645] In some embodiments of compounds of formula (I) or formula (IB), L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 20 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 18 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R5 Substitution. In some embodiments, L is a linker with a length of 1 to 16 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 14 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 12 carbon atoms, wherein one or more carbon atoms are each optionally and independently substituted with a group selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 10 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0646] In some embodiments of compounds of formula (I) or formula (IB), L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 6 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker with a length of 1 to 4 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0647] In some embodiments of compounds of formula (I) or formula (IB), L is a linker, wherein two carbon atoms are each independently substituted by a heterocycle, each independently substituted by 0, 1, 2, or 3 R atoms. 5 Substitution. In some embodiments, L is a connector in which one carbon atom is replaced by a heterocyclic ring and another carbon atom is replaced by a cycloalkyl ring, each independently replaced by 0, 1, 2, or 3 R atoms. 5 Substitution. In some embodiments, L is a linker in which more than one carbon atom is independently substituted by a group selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 Substitution. In some embodiments, L is a linker in which more than one carbon atom is independently substituted by a group selected from: C(O), O, and NR. 4 Each of them is composed of 0, 1, 2 or 3 R. 5 replace.

[0648] In some embodiments of compounds of formula (I) or formula (IB), L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is

[0649] In some embodiments of the compound of formula (I) or formula (IB), the compound of formula (I) is a stereoisomer. In some embodiments, the compound of formula (I) or formula (IB) is a cis isomer.

[0650] In some embodiments, the compounds with ER-degrading activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts, or hydrates, are compounds of formula (IB)*:

[0651]

[0652] In some embodiments, the ER degrading agent has a structure according to formula III-C:

[0653]

[0654] in:

[0655] R 1 Selected from H, C1-C6 acyl or C1-C6 alkyl, each of which is surrounded by 0, 1, 2 or 3 R groups. 6 replace;

[0656] R 2 and R 3 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0657] Each R 4 It is independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy or C1-C3 haloalkyl, each of which is substituted by 0, 1, 2 or 3 R6 groups, or two R4 groups are combined to form an oxo group;

[0658] R 5 Selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 haloalkyl, -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 6 replace;

[0659] X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0660] X 3 and X 4 Each is independently selected from H or halogen;

[0661] L is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 7 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 6 replace;

[0662] Each R 6 Independently selected from C1-C6 alkyl, halogen II, cyano, and hydroxyl groups.

[0663] Each R 7Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs 7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups.

[0664] In some embodiments, the compound with ER degradation activity provided herein, or its tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are pharmaceutically acceptable salts of compounds of formula (IB) or (IB)*.

[0665] In some embodiments, the compounds with ER degradation activity provided herein, or their tautomers, stereoisomers, pharmaceutically acceptable salts or hydrates, are one or more compounds selected from Table 1B.

[0666] ■ Table 1B. Exemplary Compounds of this Disclosure

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681] In some embodiments, the compound of formula (IC) and / or (III-C) may include both cis and trans isomers. In some embodiments, the compound of formula (IC) and / or (III-C) may be a mixture of cis and trans isomers. In some embodiments, the compound of formula (IC) and / or (III-C) may be a cis isomer.

[0682] In some embodiments, compounds of formula (IC) and / or (III-C) may include both stereoisomers and mixtures of stereoisomers. In some embodiments, compounds of formula (IC) and / or (III-C) are stereoisomers. In some embodiments, compounds of formula (IC) and / or (III-C) may include both racemic isomers and enantiomers.

[0683] In some implementations, the ER degrading agent is fulvestrant or tamoxifen. Fulvestraant has the following structure:

[0684] Tamoxifen has the following structure:

[0685] ■ CDK inhibitors

[0686] The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins, including, for example, retinoblastoma proteins, laminin, histone H1, and components of the mitotic spindle. CDK-mediated catalytic steps involve phosphate transfer reactions from ATP to macromolecular enzyme substrates. Several groups of compounds have been identified (reviewed, for example, in Fischer, PMCurr. Opin. Drug Discovery Dev. 2001, 4, 623-634) as possessing antiproliferative properties due to CDK-specific ATP antagonism.

[0687] In some implementations, the CDK inhibitor can inhibit any CDK, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, and CDK13. In some implementations, the CDK inhibitor is a CDK6 and / or CDK6 inhibitor.

[0688] In some implementations, CDK1 inhibitors have a structure according to formula (II):

[0689]

[0690] Or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates.

[0691] in:

[0692] M is a bond, -NH- or -C(O)-;

[0693] L is hydrogen, alkyl, carbocycloyl, arylalkyl, heteroarylalkyl, or heterocyclic, each of which is optionally substituted by one or more substituents;

[0694] Q is CH2, O, S, or a bond;

[0695] W and Y are independently CH or N, provided that at least one of W or Y is N, and Q is O or S when W is CH; and

[0696] R1 and R2 are independently selected from hydrogen, halogen, alkyl, and heterocyclic groups, wherein each alkyl and heterocyclic group is optionally substituted by one or more substituents; or

[0697] R1 and R2, together with the atoms they are attached to, form a carbocyclic or heterocyclic group, each of which is optionally substituted by one or more substituents; and

[0698] R9 is hydrogen, halogen, or alkyl, wherein the alkyl group is optionally substituted.

[0699] In some implementations, L is C 1-3 Alkyl group. In some embodiments, L is ethyl. In some embodiments, L is H.

[0700] L is a carbocyclic, arylalkyl, heteroarylalkyl, or heterocyclic group, each of which may optionally be substituted by one or more substituents.

[0701] In some embodiments of the CDK1 inhibitor of formula (II), W is N. In some embodiments, Y is N. In some embodiments, both W and Y are N. In some embodiments, R9 is hydrogen.

[0702] In some implementations, the CDK1 inhibitor of formula (II) has a structure according to formula (III):

[0703]

[0704] Or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates.

[0705] in:

[0706] M is a bond, -NH- or -C(O)-;

[0707] L is H, alkyl, carbocyclic, arylalkyl, heteroarylalkyl, or heterocyclic, each of which is optionally substituted by one or more substituents;

[0708] R1 and R2 are independently selected from hydrogen, halogen, alkyl, and heterocyclic groups, wherein the alkyl and heterocyclic groups are optionally substituted by one or more substituents; and

[0709] Alternatively, R1 and R2 together with the atoms they are attached to form a carbocyclic or heterocyclic group, each of which may optionally be substituted by one or more substituents.

[0710] In some implementations, L is C 1-3 Alkyl group. In some embodiments, L is ethyl. In some embodiments, L is H.

[0711] In some embodiments of the CDK1 inhibitor of formula (II), L is substituted with one or more halogens, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups, wherein each of the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups is optionally substituted with one or more substituents. In some embodiments, each of the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups is optionally substituted with one or more substituents selected from: halogens, nitro, hydroxyl, alkyl, aryl, heterocyclic, -C(O), -C(O)NR. g R h , where R g and R h Each is independently hydrogen or alkyl. In some embodiments, L is (i) an aryl group optionally substituted with a halogen and a heteroaryl alkyl group optionally substituted with -C(O), (ii) an aryl alkyl group optionally substituted with a heteroaryl group optionally substituted with one or more halogens, -C(O), or combinations thereof; or (iii) an aryl group optionally substituted with a heteroaryl group optionally substituted with -C(O)NR. g R h Replace, where R g and R h Each is independently hydrogen or alkyl. In some embodiments, L is optionally replaced by halogen and heteroarylalkyl groups. 5-8 The aryl group, wherein the heteroarylalkyl group comprises an 8- to 12-membered heteroaryl ring having one to four atoms independently selected from nitrogen, oxygen, and sulfur, and is optionally substituted with one or more substituents. In some embodiments, L is a C6 aryl group substituted with a halogen and a heteroarylalkyl group, wherein the heteroarylalkyl group comprises a 10-membered heteroaryl ring having two nitrogen atoms and is substituted with -C(O). In some embodiments, L is a C6 aryl group optionally substituted with a 10- to 15-membered heteroaryl group. 5-8 Aryl-C 1-3The alkyl group, wherein the 10-15-membered heteroaryl group has one to four atoms independently selected from nitrogen, oxygen, and sulfur, and is optionally substituted with one or more halogens, -C(O), or combinations thereof. In some embodiments, L is a C6 aryl-C1 alkyl group substituted with a 13-membered heteroaryl group, wherein the 13-membered heteroaryl group has two nitrogen atoms and is substituted with a halogen and -C(O). In some embodiments, L is a C6 aryl-C1 alkyl group optionally substituted with a 6-12-membered heteroaryl group. 5-8 The aryl group, wherein the 6- to 12-membered heteroaryl group has one to four atoms independently selected from nitrogen, oxygen, and sulfur, and is optionally surrounded by -C(O)NR g R h Replace, where R g and R h Each is independently hydrogen or alkyl. In some embodiments, L is a C6 aryl group substituted with a 9-membered heteroaryl group having two nitrogen atoms and being substituted with -C(O)NH2.

[0712] In some embodiments of the CDK1 inhibitor of formula (II) or formula (III), L is selected from:

[0713]

[0714] in:

[0715] Ring A represents a fused aryl or heteroaryl group, which is optionally substituted by one or more substituents selected from the following: halogen, nitro, hydroxyl, ether, thiol, thioether, amino, alkyl, aryl, and heterocyclic; and R8 is hydrogen or halogen.

[0716] In some embodiments of the CDK1 inhibitor of formula (II) or formula (III), L is

[0717]

[0718] in:

[0719] Ring A represents a fused aryl or heteroaryl group, optionally substituted by one or more substituents selected from: halogen, nitro, hydroxyl, amino, alkyl, aryl, and heterocyclic; and

[0720] R8 is hydrogen or halogen.

[0721] In some embodiments of the CDK1 inhibitor of formula (II) or (III), ring A is a C5-8 aryl group. In some embodiments, ring A is benzene. In some embodiments, R8 is selected from H, Cl, and F.

[0722] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R1 is a halogen. In some embodiments, R2 is a 6- to 12-membered heteroaryl group optionally substituted with one or more substituents. In some embodiments, R2 is a 9-membered heteroaryl group substituted with one or more substituents selected from halogens, alkyl groups, and combinations thereof.

[0723] In some implementations of CDK1 inhibitors of formula (II) or (III), R2 is

[0724]

[0725] in

[0726] n is 0, 1, 2, or 3;

[0727] Each R3 is independently a halogen or an alkyl group; and

[0728] R6 is an alkyl or cycloalkyl group, each of which is optionally substituted by one or more substituents.

[0729] In some embodiments of the CDK1 inhibitor of formula (II) or (III), n is 1. In some embodiments, R3 is C 1-3 Alkyl group. In some embodiments, R6 is C6. 1-3 Alkyl group. In other embodiments, R2 is selected from:

[0730]

[0731] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R2 is:

[0732]

[0733] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R1 and R2 together with the atoms to which they are attached form a heteroaryl group optionally substituted with one or more substituents. In some embodiments, R1 and R2 together with the atoms to which they are attached form a 5- to 6-membered heteroaryl group substituted with one or more substituents selected from halogens, alkyl groups, cycloalkyl groups, and combinations thereof.

[0734] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R1 and R2 together with the atoms to which they are attached form rings selected from the following:

[0735]

[0736] in:

[0737] R4 is hydrogen or -C(O)NR a Rb , where R a and R b Each is independently selected from hydrogen and alkyl; and

[0738] R5 is a cycloalkyl group.

[0739] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R1 and R2 together with the atoms to which they are attached form

[0740]

[0741] R5 is cyclopentyl, and R4 is -C(O)N(CH3)2.

[0742] In some embodiments of the CDK1 inhibitor of formula (II) or (III), R5 is cyclopentyl, and R a and R b Each one is a methyl group.

[0743] In some embodiments of the CDK1 inhibitor of formula (II) or (III), the compound is selected from:

[0744]

[0745]

[0746] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[0747] In some implementations, the CDK inhibitors of formulas (II) and (III) are described in U.S. Publication No. 2019 / 0202806, which are hereby incorporated herein by reference in their entirety for all purposes.

[0748] In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abeciclib, or pharmaceutically acceptable salts, polymorphs, or solvates thereof. In some embodiments, the CDK4 / 6 inhibitor is a pharmaceutically acceptable salt of palbociclib, ribociclib, or abeciclib. In some embodiments, the CDK4 / 6 inhibitor is a polymorph of palbociclib, ribociclib, or abeciclib. In some embodiments, the CDK4 / 6 inhibitor is a solvate of palbociclib, ribociclib, or abeciclib.

[0749] In some implementations, a CDK4 / 6 inhibitor is administered. In some implementations, an FDA-approved CDK4 / 6 inhibitor is administered. In some implementations, the FDA-approved CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abeciclib. The structures of palbociclib, ribociclib, and abeciclib are as follows.

[0750]

[0751] Pabocini,

[0752]

[0753] Rebocinia, or

[0754]

[0755] Abessini.

[0756] The indications and dosages for FDA-approved palbociclib, ribociclib, and abeciclib are described in Table 2.

[0757] Table 2. FDA-approved CDK4 / 6 inhibitors

[0758]

[0759]

[0760] ■ preparation

[0761] This disclosure also provides pharmaceutical compositions comprising one or more ER degraders disclosed herein and one or more CDK inhibitors disclosed herein.

[0762] In some embodiments, the pharmaceutical compositions described herein may be combined with one or more therapeutically active agents used in the treatment of cancer. Additional therapeutic agents may be administered subsequently, simultaneously, or sequentially (e.g., before or after) relative to the ER degrader.

[0763] In some embodiments of this disclosure, pharmaceutical compositions comprising one or more of the compounds described herein and pharmaceutically acceptable excipients or adjuvants are provided. Pharmaceutically acceptable excipients and adjuvants are added to the compositions or formulations for various purposes. In other embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier includes pharmaceutically acceptable excipients, binders, and / or diluents. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silica, viscous paraffin, hydroxymethyl cellulose, and polyvinylpyrrolidone.

[0764] In some embodiments, the pharmaceutical compositions of this disclosure may additionally contain other additional components conventionally found in pharmaceutical compositions at the level of use defined in its field. Thus, for example, the pharmaceutical composition may contain additional, compatible pharmaceutically active materials, such as antipruritics, astringents, local anesthetics, or anti-inflammatory agents, or may contain additional materials useful in the various dosage forms in which the compositions of the invention are physically formulated, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickeners, and stabilizers. However, such materials should not excessively interfere with the bioactivity of the components of the compositions of the invention when added. The formulation may be sterilized and, if desired, may be mixed with adjuvants (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic substances, etc., that do not adversely interact with the oligonucleotides of the formulation).

[0765] For the purposes of this disclosure, the compounds of this disclosure can be formulated in formulations containing pharmaceutically acceptable carriers, adjuvants, and solvents for administration by various routes, including oral, parenteral, inhalation spray, local, or rectal administration. As used herein, parenteral administration includes subcutaneous, intravenous, intramuscular, and intra-arterial injection, as well as various infusion techniques. Intra-arterial and intravenous injection, as used herein, include administration via catheter.

[0766] The compounds disclosed herein can be formulated according to conventional procedures suitable for the desired route of administration. Therefore, the compounds disclosed herein can be in the form of suspensions, solutions, or emulsions in oily or aqueous solvents, and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. The compounds disclosed herein can also be formulated as formulations for implantation or injection. Therefore, the compounds can be formulated, for example, using suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives (e.g., as slightly soluble salts). Alternatively, the active ingredient can be in powder form for preparation with a suitable solvent (e.g., sterile, pyrogen-free water) prior to use. Suitable formulations for each of these routes of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0767] In some embodiments, the pharmaceutical compositions of this disclosure are prepared using known techniques, including but not limited to mixing, dissolving, granulating, sugar-coated pelleting, grinding, emulsifying, encapsulating, embedding, or tableting processes.

[0768] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more of the compounds disclosed herein in combination with a pharmaceutically acceptable carrier. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffers or saline solutions (e.g., about 0.8%) from about 0.01 M to about 0.1 M. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for use in this application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).

[0769] Suitable aqueous carriers for use in this application include, but are not limited to, water, ethanol, alcohol / aqueous solutions, glycerol, emulsions, or suspensions, including saline and buffer media. Oral carriers may be elixirs, syrups, capsules, tablets, etc.

[0770] Suitable liquid carriers for use in this application can be used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier (such as water, organic solvents, mixtures of both, or pharmaceutically acceptable oils or fats). The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure modifiers.

[0771] Suitable liquid carriers for use in this application include, but are not limited to, water (partially containing additives such as those described above, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydroxy alcohols and polyhydroxy alcohols, such as ethylene glycol) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also include oleic esters, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid forms containing compounds for parenteral administration. The liquid carriers disclosed herein for pressurized compounds may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0772] Suitable solid carriers for use in this application include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, etc. The solid carrier may further include one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow aids, compression aids, binders, or tablet disintegrants; it may also be an encapsulation material. In powders, the carrier may be a finely ground solid mixed with finely ground active compounds. In tablets, the active compound is mixed with a carrier having the necessary compressibility in a suitable proportion and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low-melting-point waxes, and ion-exchange resins. Tablets may be manufactured by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, said active ingredient optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium hydroxyacetic acid starch, crospovidone, crospovidone sodium carboxymethyl cellulose), surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein, using, for example, different proportions of hydroxypropyl methylcellulose to provide a desired release profile. Tablets with an enteric coating can optionally be provided to provide release in the intestinal portion other than the stomach.

[0773] Suitable parenteral carriers for use in this application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, and non-volatile oils. Intravenous carriers include fluids and nutritional supplements, electrolyte supplements such as those based on Ringer's dextrose. Preservatives and other additives such as, for example, antimicrobial agents, antioxidants, chelating agents, inert gases, etc., may also be present.

[0774] The carrier suitable for use in this application may be mixed with disintegrants, diluents, granulators, lubricants, binders, etc., as needed, using conventional techniques known in the art. As is generally known in the art, the carrier may also be sterilized using methods that do not adversely react with the compounds.

[0775] Diluents can be added to the formulations of the present invention. Diluents increase the volume of solid pharmaceutical compositions and / or combinations and can make pharmaceutical dosage forms containing compositions and / or combinations easier for patients and caregivers to handle. Diluents used for solid compositions and / or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextran binders, dextrin, dextrose, calcium hydrogen phosphate dihydrate, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethyl acrylate (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0776] In various embodiments, the pharmaceutical composition may be selected from solids, powders, liquids, and gels. In some embodiments, the pharmaceutical compositions disclosed herein are solids (e.g., powders, tablets, capsules, granules, and / or aggregates). In some such embodiments, the solid pharmaceutical composition comprises one or more excipients known in the art, including but not limited to starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrants.

[0777] Solid pharmaceutical compositions compressed into dosage forms such as tablets may include excipients that function to help bind the active ingredient and other excipients upon compression. Binders used in solid pharmaceutical compositions and / or combinations include gum arabic, alginate, carbomer (e.g., carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, astragalus gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethyl methacrylate, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

[0778] By adding disintegrants to compositions and / or combinations, the dissolution rate of compacted solid pharmaceutical compositions in a patient's stomach can be increased. Disintegrants include alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silica, croscarmellose sodium carboxymethyl cellulose, croscarmellose (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium pluckleinate, powdered cellulose, pregelatinized starch, sodium alginate, sodium hydroxyacetic acid starch (e.g., EXPLOTAB), potato starch, and starch.

[0779] Gliders can be added to improve the flowability of uncompacted solid compositions and / or combinations and to improve the accuracy of drug administration. Excipients that can function as gliders include colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and calcium phosphate.

[0780] When manufacturing dosage forms such as tablets by pressing a powdered composition, the composition is subjected to pressure from the punch and die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can cause dents and other surface irregularities in the product. Lubricants can be added to the composition and / or combination to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc, and zinc stearate.

[0781] Flavoring agents and flavor enhancers make dosage forms more palatable to patients. Common flavoring agents and flavor enhancers that may be included in the compositions and / or combinations of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0782] Solid and liquid compositions can also be stained with any pharmaceutically acceptable staining agent to improve their appearance and / or facilitate patient identification of product and unit dosage levels.

[0783] In some embodiments, the pharmaceutical compositions of the present invention are liquids (e.g., suspensions, elixirs, and / or solutions). In some such embodiments, liquid pharmaceutical compositions are prepared using ingredients known in the art (including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents).

[0784] Liquid pharmaceutical compositions can be prepared using the compounds disclosed herein and any other solid excipients, wherein the components are dissolved or suspended in a liquid carrier (such as water, vegetable oil, ethanol, polyethylene glycol, propylene glycol, or glycerin).

[0785] For example, formulations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, plant-derived oils, hydrogenated naphthalene, etc., as commonly used excipients. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of the active compound. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain, for example, lactose as an excipient, or may be an aqueous solution containing, for example, polyoxyethylene-9-auryl ether, glycocholate, and deoxycholate, or an oil solution for administration as nasal drops or as a gel for intranasal application. Formulations for parenteral administration may also include glycocholate for oral administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[0786] Liquid pharmaceutical compositions may contain emulsifiers to uniformly disperse active ingredients or other excipients that are insoluble in a liquid carrier throughout the composition and / or combination. Emulsifiers that may be useful in the liquid compositions and / or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, astragalus gum, carrageenan, pectin, methylcellulose, carbomer, a mixture of stearyl alcohol and cetyl alcohol, and cetyl alcohol.

[0787] Liquid pharmaceutical compositions may also contain viscosity enhancers to improve the product's mouthfeel and / or coat the gastrointestinal lining. These agents include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethyl cellulose, a mixture of stearyl alcohol and hexadecyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, astragalus gum, and xanthan gum.

[0788] Sweeteners such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0789] Preservatives and chelating agents at safe intake levels, such as ethanol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and EDTA, can be added to improve storage stability.

[0790] Liquid compositions may also contain buffers such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The selection of excipients and the amount used can be readily determined by the formulator based on experience and consideration of standard procedures and reference work in the field.

[0791] In some embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some such embodiments, the pharmaceutical composition comprises a carrier and is formulated in an aqueous solution (such as water or a physiologically compatible buffer, such as Hanks' solution, Ringer's solution, or saline buffer). In some embodiments, other components are included (e.g., components that contribute to solubility or act as preservatives). In some embodiments, an injectable suspension is prepared using a suitable liquid carrier, suspending agent, etc. Some injectable pharmaceutical compositions are present in a unit dosage form (e.g., in an ampoule or multi-dose container). Some injectable pharmaceutical compositions are suspensions, solutions, or emulsions in oily or aqueous solvents and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Certain solvents suitable for use in injectable pharmaceutical compositions include, but are not limited to, lipophilic solvents and fatty oils (such as sesame oil), synthetic fatty acid esters (such as ethyl oleate or triglycerides), and liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the drug, so as to enable the preparation of highly concentrated solutions.

[0792] Sterile injectable formulations can also be sterile injectable solutions or suspensions (such as solutions in 1,3-butanediol) in non-toxic, parenteral-acceptable diluents or solvents, or prepared as lyophilized powders. Acceptable solvents and media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils can generally be used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (such as oleic acid) can also be used in the preparation of injectable formulations. Formulations for intravenous administration may contain solutions in sterile isotonic aqueous buffers. Where necessary, formulations may also include solubilizers and local anesthetics to reduce pain at the injection site. Generally, the ingredients are supplied individually or in combination in unit dosage forms (e.g., as dry lyophilized powders or anhydrous concentrates in sealed, closed containers (such as ampoules or capsules) indicating the amount of active agent). When the compound is administered by infusion, it can be formulated in an infusion bottle containing sterile pharmaceutical-grade water, saline, or dextrose / water. When the compound is administered by injection, a single ampoule of sterile water for injection or saline can be provided to mix the components prior to administration.

[0793] Suitable formulations further include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic agents, bactericidal antibiotics, and solutes that make the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0794] In some embodiments, the pharmaceutical compositions of the present invention are formulated as depot preparations. Some of these long-acting preparations typically have a longer duration of action than non-long-acting preparations. In some embodiments, such preparations are administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In some embodiments, the long-acting preparations are prepared using suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives (e.g., as slightly soluble salts).

[0795] In some embodiments, the pharmaceutical compositions of the present invention comprise a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of a solid hydrophobic polymer. In some embodiments, the sustained-release system, depending on its chemical properties, can release the agent over periods of hours, days, weeks, or months.

[0796] A suitable pharmaceutical composition of this disclosure can be determined based on any clinically acceptable route of administration to a subject. The manner of administration depends in part on the cause and / or location. Those skilled in the art will recognize the advantages of certain routes of administration. Methods include administering an effective amount of one or more of Formula I (including compounds in Table 1A or Table 1B) or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof (or a composition comprising the foregoing) to achieve a desired biological response, such as an amount effective in all or part of alleviating, improving, or preventing symptoms of the condition to be treated. In various embodiments, the route of administration is systemic, such as oral or by injection.

[0797] In some embodiments, the pharmaceutical composition of this disclosure is prepared for oral administration. In some such embodiments, the pharmaceutical composition is formulated by combining one or more reagents and a pharmaceutically acceptable carrier. Certain such carriers enable the pharmaceutical composition to be formulated as tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject. Suitable excipients include, but are not limited to, fillers such as sugars (including lactose, sucrose, mannitol, or sorbitol), cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). In some embodiments, this mixture is optionally ground and excipients are optionally added. In some embodiments, the pharmaceutical composition is formed to obtain a tablet or sugar-coated pill core. In some embodiments, a disintegrant (e.g., croscarmellose, agar, or alginate or a salt thereof, such as sodium alginate) is added.

[0798] In some embodiments, a coated sugar-coated core is provided. In some such embodiments, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carboplatin gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coating of the tablet or sugar-coated core.

[0799] In some embodiments, the pharmaceutical composition for oral administration is a push-in, co-operated capsule made of gelatin. Some of these push-in, co-operated capsules contain one or more of the pharmaceutical agents of the present invention mixed with one or more fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally, stabilizers. In some embodiments, the pharmaceutical composition for oral administration is a soft, closed capsule made of gelatin and a plasticizer (such as glycerin or sorbitol). In some soft capsules, one or more of the compounds disclosed herein are dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, or liquid polyethylene glycol). Additionally, stabilizers may be added.

[0800] In some embodiments, a pharmaceutical composition for oral administration is prepared. Some of these pharmaceutical compositions are tablets or lozenges formulated in a conventional manner.

[0801] In some embodiments, a pharmaceutical composition for transmucosal administration is prepared. In some such embodiments, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art.

[0802] In some embodiments, pharmaceutical compositions for administration by inhalation are prepared. Certain such inhalation pharmaceutical compositions are prepared as aerosol sprays in pressurized packages or nebulizers. Some of these pharmaceutical compositions contain a propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In some embodiments using pressurized aerosols, the dosage unit can be determined using a valve that delivers the metering amount. In some embodiments, capsules and cartridges for use in inhalers or blowpipes can be formulated. Some of these formulations comprise a mixture of the pharmaceutical agent of the present invention and a suitable powder base (such as lactose or starch).

[0803] In other embodiments, the compounds of this disclosure are administered via an intravenous route. In further embodiments, parenteral administration may be provided by bolus injection or infusion.

[0804] In some embodiments, pharmaceutical compositions for rectal administration, such as suppositories or retention enemas, are prepared. Some of these pharmaceutical compositions contain known ingredients, such as cocoa butter and / or other glycerides.

[0805] In some embodiments, pharmaceutical compositions for topical administration are prepared. Some of these pharmaceutical compositions comprise a mild, moisturizing base, such as an ointment or cream. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum with volatile silicones, and lanolin and water-in-oil emulsions. Exemplary suitable cream bases include, but are not limited to, cold creams and hydrophilic ointments.

[0806] In some embodiments, one or more of the compounds disclosed herein are formulated as prodrugs. In some embodiments, upon administration in vivo, the prodrug is chemically converted to a biologically, pharmaceutically, or therapeutically more active form. In some embodiments, the prodrug is useful because it is easier to administer than the corresponding active form. For example, in some cases, the prodrug may be more bioavailable than the corresponding active form (e.g., by oral administration). In some cases, the prodrug may have improved solubility compared to the corresponding active form. In some embodiments, the prodrug is less water-soluble than the corresponding active form. In some cases, such prodrugs have excellent transmembrane transport, where water solubility is detrimental to flowability. In some embodiments, the prodrug is an ester. In some such embodiments, the ester is metabolized and hydrolyzed into a carboxylic acid after administration. In some cases, the compound containing the carboxylic acid is the corresponding active form. In some embodiments, the prodrug comprises a short peptide (polyamino acid) bound to an acid group. In some such embodiments, the peptide is cleaved after administration to form the corresponding active form.

[0807] In some implementations, prodrugs are produced by modifying a pharmaceutically active compound so that the active compound will be regenerated after administration in vivo. Prodrugs can be designed to alter the metabolic stability or transport characteristics of a drug, mask side effects or toxicity, improve the flavor of a drug, or change other characteristics or properties of a drug. With knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art can design prodrugs of a pharmaceutically active compound once it is known (see, for example, Nogrady (1985), Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pp. 388-392).

[0808] In various respects, the amounts of the compounds disclosed herein may be administered from about 0.001 mg / kg to about 100 mg / kg body weight, including all values ​​in between (e.g., about 0.01 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 5 mg / kg, including all ranges and values ​​in between).

[0809] The concentration of the compounds disclosed herein in a pharmaceutically acceptable mixture will vary depending on several factors, including the amount of the compound to be administered, the pharmacokinetic characteristics of the compound used, and the route of administration. The reagent may be administered in a single dose or repeated doses. Dosage regimens using the compounds of the invention are selected based on a variety of factors, including patient type, species, age, weight, sex, and medical condition, the severity of the condition to be treated, the route of administration, the patient's renal and hepatic function, and the specific compound or its salt used. Treatment may be administered once daily or more frequently, depending on many factors, including the patient's overall health condition and the formulation and route of administration of the selected compound.

[0810] The compounds or pharmaceutical compositions disclosed herein may be manufactured and / or administered in a single unit dosage form or in multiple unit dosage forms.

[0811] Toxicity and therapeutic efficacy can be determined through standard pharmaceutical procedures in cell cultures or laboratory animals, such as those used to determine LD50. 50 (The dose that is lethal to 50% of the population) and ED 50 (The dose that is effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and it can be expressed as LD50. 50 / ED 50 Ratio. Compositions exhibiting a large therapeutic index are preferred.

[0812] Data obtained from cell culture assays or animal studies can be used to develop dosage ranges for use in humans. Therapeutic effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother. Reports 50(4):219-244(1966) and the equivalent surface area dosage factors in the table below).

[0813] Table 2. Equivalent Surface Area Dosage Factor

[0814]

[0815] The preferred dosage of these compounds is within the range of ED compounds that are almost non-toxic or non-toxic. 50 The dosage can vary within the circulating concentration range, depending on the dosage form and route of administration used. Generally, the therapeutically effective dose can vary with the subject's age, condition, sex, and the severity of the subject's medical condition. The dosage can be determined by the physician and adjusted as needed to suit the observed therapeutic effect.

[0816] ■Treatment methods

[0817] In some embodiments, this document provides the use of a pharmaceutical combination comprising an estrogen receptor (ER) degrader and a cyclin-dependent kinase (CDK) inhibitor in a therapeutic treatment. In some embodiments, the ER degrader and CDK inhibitor are administered in an amount synergistically effective for treating the disease or condition disclosed herein (e.g., cancer). In some embodiments, the estrogen receptor (ER) degrader and cyclin-dependent kinase (CDK) inhibitor are administered as a pharmaceutical formulation further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier. In some embodiments, the therapeutic treatment is for treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some embodiments, the therapeutic treatment is for treating breast cancer. In some embodiments, the therapeutic treatment is for treating lung cancer. In some embodiments, the therapeutic treatment is for treating ovarian cancer. In some embodiments, the therapeutic treatment is for treating endometrial cancer. In some embodiments, the therapeutic treatment is for treating prostate cancer. In some embodiments, the therapeutic treatment is for treating esophageal cancer. In some embodiments, the therapeutic treatment is for treating estrogen-related diseases and conditions. In some embodiments, the therapeutic treatment is for treating infertility. In some implementations, the therapeutic treatment is for treating ovulation dysfunction. In some implementations, the therapeutic treatment is for treating postmenopausal osteoporosis. In some implementations, the therapeutic treatment is for treating estrogen-related gynecomastia in men. In some implementations, the therapeutic treatment is for treating sexual dysfunction due to menopause. In some implementations, the therapeutic treatment is for treating retroperitoneal fibrosis. In some implementations, the therapeutic treatment is for treating idiopathic sclerosing mesenteric inflammation.

[0818] In some embodiments, this document provides the use of the pharmaceutical combinations disclosed herein in the preparation of a medicament. In some embodiments, this document provides a method for inhibiting cell growth, comprising contacting cells with a pharmaceutical combination comprising a compound of formula (I), formula (IA), formula (II-A), formula (IB), formula (IB)*, formula (IC), formula (III-C), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, and a cyclin-dependent kinase (CDK) inhibitor. In some embodiments, the cells may express ERα. In some embodiments, the estrogen receptor (ER) degrader and the cyclin-dependent kinase (CDK) inhibitor are administered as a pharmaceutical formulation further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

[0819] In some embodiments, the drug combinations disclosed herein are administered to treat cancer. In some embodiments, the compounds disclosed herein are administered to treat cancer.

[0820] In one implementation, the cancer is a solid tumor. The term "solid tumor" specifically refers to melanoma, breast cancer, ovarian cancer, colorectal cancer, and gastrointestinal cancer in general, cervical cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, or prostate cancer. This combination inhibits the growth of both solid and liquid tumors. Furthermore, depending on the tumor type and the specific combination used, a reduction in tumor volume can be achieved. The combinations of the invention disclosed herein are also suitable for preventing the metastasis and spread of tumors and the growth or development of micrometastases. The combinations of the invention disclosed herein are suitable for treating patients with poor prognoses, particularly those with colon cancer, rectal cancer, colorectal cancer, breast cancer, gastric cancer, or pancreatic cancer.

[0821] In some implementations, the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. In some implementations, the cancer is breast cancer. In some implementations, the cancer is lung cancer. In some implementations, the cancer is ovarian cancer. In some implementations, the cancer is endometrial cancer. In some implementations, the cancer is prostate cancer. In some implementations, the cancer is esophageal cancer.

[0822] In some implementations, the cancer is positive for estrogen receptor α.

[0823] In some embodiments, the method is for treating estrogen-related diseases and conditions. In some embodiments, the estrogen-related disease and condition is infertility. In some embodiments, the estrogen-related disease and condition is ovulation dysfunction. In some embodiments, the estrogen-related disease and condition is postmenopausal osteoporosis. In some embodiments, the estrogen-related disease and condition is estrogen-related gynecomastia. In some embodiments, the estrogen-related disease and condition is dyspareunia due to menopause. In some embodiments, the estrogen-related disease and condition is retroperitoneal fibrosis. In some embodiments, the estrogen-related disease and condition is idiopathic sclerosing mesenteric inflammation.

[0824] In some implementation schemes, cancer is colorectal cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), tyrosine kinase-activated leukemia, endometrial cancer, neuroblastoma, testicular cancer, germ cell tumors, Ewing's sarcoma, malignant lymphoma, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0825] In other embodiments, the breast cancer is hormone receptor (HR) positive breast cancer and / or human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor (HR) positive breast cancer, and the patient has disease progression following endocrine therapy and / or chemotherapy in a previous metastatic setting.

[0826] In some embodiments, the breast cancer is human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, and the patient has experienced disease progression following endocrine therapy and / or chemotherapy in a previous metastatic setting. In other embodiments, the ovarian cancer is recurrent epithelial ovarian cancer. In some embodiments, the ovarian cancer is BRCA-mutated ovarian cancer. In some embodiments, the BRCA-mutated ovarian cancer is BRCA-mutated serous ovarian cancer. In some embodiments, the patient has suspected harmful germline BRCA-mutated advanced ovarian cancer. In some embodiments, the patient has been treated with three or more lines of previous chemotherapy.

[0827] In some implementations, the cancer is triple-negative breast cancer (TNBC), characterized by breast cancer cells that are negative for estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (HER2-). A negative result for all three tests signifies a triple-negative cancer. In some implementations, the cancer is estrogen receptor-positive breast cancer.

[0828] In another implementation, the cancer may be selected from one or more of the following: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, Kaposi's sarcoma, lymphoma, anal cancer, appendiceal cancer, astrocytoma, childhood atypical teratoid / rhabditis tumors, basal cell carcinoma, skin cancer (non-melanoma), childhood bile duct cancer, extrahepatic bladder cancer, bone cancer, Ewing sarcoma family tumors, osteosarcoma and malignant fibrous histiocytoma, brainstem glioma, brain tumor, embryonal tumor, germ cell tumor, craniopharyngioma, ependymoma, bronchial tumor, Burkitt lymphoma (non-Hodgkin lymphoma), carcinoid tumor, gastrointestinal cancer of unknown primary origin, and cardiac cancer. Cardiac tumors, lymphomas, primary cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelodysplastic anomaly, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, ductal carcinoma in situ, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, extrahepatic bile duct cancer, ocular cancer, intraocular melanoma, retinoblastoma, malignant fibrous histiocytoma and osteosarcoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, extragonadal carcinoma, ovarian cancer, testicular cancer. Gestational trophoblastic disease, glioma, brainstem cancer, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Langerhans cell carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, kidney cancer, renal cell carcinoma, Wilms' tumor and other pediatric kidney tumors, Langerhans cell histiocytosis, laryngeal cancer, leukemia, chronic lymphocytic carcinoma, chronic myeloid carcinoma, hairy cell carcinoma, lip and oral cancer, primary liver cancer, lobular carcinoma in situ (LCIS), lung cancer, non-small cell carcinoma, small cell carcinoma, lymphoma, cutaneous T-cell cancer (mycosis fungoides and Cezari syndrome), Hodgkin's cancer, non-Hodgkin's cancer. Waldenström macroglobulinemia, male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, intraocular (eye) cancer, Merkel cell carcinoma, mesothelioma, malignant and metastatic squamous neck cancer with occult primary origin, mid-truncation carcinoma involving the NUT gene, oral cancer (Mouth Cancer), multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell carcinoma, mycosis fungoides, myelodyplasia / myeloproliferative neoplasm, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative neoplasm, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer (OralCancer, oral cancer, lip and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, epithelial cancer, low-grade malignant potential tumors, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papilloma, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumors, plasmacytoma / multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, rectal cancer, renal cell (kidney) carcinoma, retinoblastoma, rhabdomyosarcoma. Salivary gland cancer, sarcoma, Ewing's carcinoma, Kaposi's carcinoma, osteosarcoma (bone cancer), soft tissue cancer, uterine cancer, Cézari syndrome, skin cancer, childhood melanoma, Merkel cell carcinoma, non-melanoma, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, skin cancer (non-melanoma), childhood squamous neck cancer with occult primary origin, metastatic cancer, stomach cancer, T-cell lymphoma, cutaneous cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, unknown primary cancer in children, abnormal cancer in children, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilm's tumor, and cancers in women.

[0829] The ER degrader is administered at any suitable dose, such as approximately 0.01 mg, approximately 0.05 mg, approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 35 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg. g, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1 g, including all values ​​in between. ER degrading agents are administered in doses ranging from about 0.01 mg to about 1 g, including doses from about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 35 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, and about 375 mg. The range is approximately 1 g, including all values ​​between 1 g and 1 g. In some embodiments, the ER degrading agent is administered at doses ranging from approximately 30 mg to approximately 600 mg.

[0830] CDK inhibitors can be administered at any suitable dose, such as approximately 0.5 mg, approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 35 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg. Approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 525 mg, approximately 550 mg, approximately 575 mg, approximately 600 mg, approximately 625 mg, approximately 650 mg, approximately 675 mg, approximately 700 mg, approximately 725 mg, approximately 750 mg, approximately 775 mg, approximately 800 mg, approximately 825 mg, approximately 850 mg, approximately 875 mg, approximately 900 mg, approximately 925 mg, approximately 950 mg, approximately 975 mg, or approximately 1 g, including all values ​​in between. In some implementations, CDK inhibitors can be administered in doses ranging from about 0.5 mg to about 1 g, including doses ranging from about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 35 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg. Approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 525 mg, approximately 550 mg, approximately 575 mg, approximately 600 mg, approximately 625 mg, approximately 650 mg, approximately 675 mg, approximately 700 mg, approximately 725 mg, approximately 750 mg, approximately 775 mg, approximately 800 mg, approximately 825 mg, approximately 850 mg, approximately 875 mg, approximately 900 mg, approximately 925 mg, approximately 950 mg, approximately 975 mg to approximately 1 g, including all ranges in between.

[0831] In some embodiments, the CDK inhibitor is palbociclib, ribociclib, or abeciclib. The CDK inhibitor may be administered at one or more FDA-approved doses (i.e., as provided on the FDA-approved label as of the date of this application) or at a reduced dose. As used herein, "reduced dose" means a dose lower than the approved dose provided on the FDA-approved label. In some embodiments, the reduced dose may be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% lower than the approved dose.

[0832] In some embodiments, the method comprises administering palbociclib from about 25 mg to about 200 mg, from about 50 mg to about 150 mg, or from about 75 mg to about 125 mg, including all ranges and values ​​in between. In some embodiments, the oral dosage form comprises about 125 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg of palbociclib, including all values ​​and ranges in between.

[0833] In some embodiments, the method comprises administering ribociclib succinate in an amount ranging from about 50 mg to about 600 mg (e.g., 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or 600 mg, including all values ​​and ranges between these). In some embodiments, the oral dosage form comprises ribociclib succinate with a free base equivalent of about 150 mg to about 600 mg (inclusive of all ranges and values ​​between these). In some embodiments, the oral dosage form comprises about 200 mg of free base equivalent of ribociclib.

[0834] In some embodiments, the methods disclosed herein comprise administering abexianib at a dose of about 25 mg to about 500 mg (e.g., 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg, including all values ​​and ranges between these), about 50 mg to about 200 mg, or about 50 mg to about 300 mg, including all ranges and values ​​between these. In some embodiments, oral dosage forms comprise about 50 mg, about 100 mg, about 150 mg, or about 200 mg of abexianib.

[0835] In some embodiments, a combination of an estrogen receptor (ER) degrader and a cyclin-dependent kinase (CDK) inhibitor is provided, either in a single dosage form or in a single dosage form. In some embodiments, a combination of an estrogen receptor (ER) degrader and a cyclin-dependent kinase (CDK) inhibitor is provided, in a single dosage form, administered via the same or different routes of administration. In some embodiments, the single dosage forms of the drug combinations provided herein are administered concurrently, sequentially, overlappingly, at intervals, continuously, or in combination thereof. In some embodiments, the dosage form is an oral dosage form. In some embodiments, the oral dosage form is a tablet or capsule.

[0836] The dosage form of this invention can be administered hourly, daily, weekly, or monthly. The dosage form of this invention can be administered once a day, twice a day, three times a day, four times a day, etc. The dosage form of this invention can be administered with or without food.

[0837] In some implementations, palbociclib is administered to subjects in combination with an estrogen receptor (ER) degrader at an initial dose of approximately 125 mg / day.

[0838] In some implementations, ribociclib succinate is administered to subjects in combination with an estrogen receptor (ER) degrader at an initial dose of approximately 600 mg / day of ribociclib free base equivalent.

[0839] In some embodiments, abexinib is administered to a subject in combination with an estrogen receptor (ER) degrader at an initial dose of about 150 mg twice daily to about 200 mg twice daily. In some embodiments, abexinib is administered to a subject at an initial dose of about 150 mg twice daily. In some embodiments, abexinib is administered to a subject at an initial dose of about 200 mg twice daily.

[0840] In some embodiments, the drug combination comprising an ER degrader and a CDK inhibitor is administered together with an additional therapeutic agent. The additional therapeutic agent may provide additive or synergistic value relative to the individual administration of one or more compounds in the combinations disclosed herein. The additional therapeutic agent may be selected from, for example, hormones and hormone analogs, signal transduction pathway inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolite oncogens, antibiotic oncogens, alkylating agents, antimicrotubule agents, platinum coordination complexes, aromatase inhibitors, and antimitotic agents.

[0841] In some embodiments, the additional therapeutic agent may be a hormone or hormone analogue. In some embodiments, the additional therapeutic agent may be a signal transduction pathway inhibitor. In some embodiments, the additional therapeutic agent may be a topoisomerase I inhibitor. In some embodiments, the additional therapeutic agent may be a topoisomerase II inhibitor. In some embodiments, the additional therapeutic agent may be an antimetabolite tumor agent. In some embodiments, the additional therapeutic agent may be an antibiotic tumor agent. In some embodiments, the additional therapeutic agent may be an alkylating agent. In some embodiments, the additional therapeutic agent may be an antimicrotubule agent. In some embodiments, the additional therapeutic agent may be a platinum coordination complex. In some embodiments, the additional therapeutic agent may be an aromatase inhibitor. In some embodiments, the additional therapeutic agent may be an antimitotic agent.

[0842] In some embodiments, the aromatase inhibitor may be selected from anastrozole, letrozole, vortexil, fazodazole, exemestane, and formemestane. 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 vortexil. In some embodiments, the aromatase inhibitor may be fazodazole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formemestane.

[0843] In some embodiments, the antimitotic agent may be selected from paclitaxel, docetaxel, and abraxane. In some embodiments, the antimitotic agent may be paclitaxel. In some embodiments, the antimitotic agent may be docetaxel. In some embodiments, the antimitotic agent may be abraxane.

[0844] In some implementations, the additional treatment agent is tamoxifen. In some implementations, the additional treatment agent is fulvestrant.

[0845] Implementation Plan

[0846] 1. Methods for treating cancer in patients in need, which involve administering estrogen receptor (ER) degraders and cyclin-dependent kinase (CDK) inhibitors.

[0847] 2. The method of embodiment 1, wherein the estrogen receptor (ER) degrader is a compound of formula (I):

[0848]

[0849] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates;

[0850] in:

[0851] Is it a single bond or a double bond?

[0852] --- indicates a single key or that the key does not exist;

[0853] Y is either -CH3 or -O-;

[0854] When Y is -CH3, --- does not exist and It is a double bond; and when Y is -O-, --- and Both are single bonds;

[0855] Z is

[0856] X 3 and X 4Each is independently selected from H or halogen;

[0857] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0858] A is selected from:

[0859]

[0860]

[0861] Each of them is R 55 Or 0, 1, 2 or 3 Rs 5 replace;

[0862] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0863] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0864] R 1 and R 2 Each is independently selected from H, C1-C6 acyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0865] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0866] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 replace;

[0867] Each R 55 Independently selected from halogens, hydroxyl groups, C1-C3 alkyl groups, C1-C3 alkyl groups, C1-C3 haloalkyl groups, and -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R5 replace;

[0868] Each R 7 Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs 7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups;

[0869] Each R 5 Independently selected from C1-C6 alkyl, C1-C6 alkyl group, C1-C6 haloalkyl group, oxo group, halogen group, cyano group, and hydroxyl group;

[0870] R 22 and R 33 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 5 replace;

[0871] in Represents A and X 2 The connection points; and

[0872] p is 1 or 2.

[0873] 3. The method of embodiment 1 or 2, wherein the estrogen receptor (ER) degrader is a compound of formula (IA):

[0874]

[0875] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates;

[0876] in:

[0877] X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace;

[0878] A is selected from:

[0879]

[0880] Each of its 0, 1, 2 or 3 R 5 replace;

[0881] B is selected from 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heterocyclic, and 5- to 6-membered heteroaryl, each of which is surrounded by 0, 1, 2, or 3 Rs. 5 replace;

[0882] L* is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 5 replace;

[0883] R 1 and R 2 Each is independently selected from H, C1-C6 alkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto groups, each marked with 0, 1, 2, or 3 R groups. 5 replace;

[0884] Each R 3 Independently selected from H, C1-C6 alkyl, halogen, and hydroxyl;

[0885] Each R 4 Independently selected from H, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 5 Replace; and

[0886] Each R 5 Independently selected from C1-C6 alkyl, halogen, cyano, oxo, and hydroxyl groups;

[0887] in Represents A and X 2 The connection point.

[0888] 4. Implement the method in Scheme 3, where A is:

[0889]

[0890] 5. Implement method 3 or 4, where B is controlled by 0, 1, 2, or 3 Rs. 5 The replaced 5-membered heterocycle.

[0891] 6. Implement method 3 or 4, where B is selected from:

[0892] in This represents the connection point between B and A.

[0893] 7. Implement method 3 or 4, where B is controlled by 0, 1, 2, or 3 Rs. 5 The replaced 6-membered heterocycle.

[0894] 8. The method of any one of implementation schemes 3-7, wherein R 1 and R 2Each is independently selected from H, C1-C3 alkyl, halogen, alkyloxy, acyloxy, hydroxyl, and mercapto groups, and each can be 0, 1, 2, or 3 R groups. 5 replace.

[0895] 9. The method of implementation scheme 8, wherein R 1 and R 2 Each can be H or OH independently.

[0896] 10. The method of any one of implementation schemes 3-9, wherein X 1 and X 2 Each is independently selected from C(R) 3 2. NR 4 O, S, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl, each independently bound by 0, 1, 2 or 3 R 5 replace.

[0897] 11. The method of implementation scheme 10, wherein R 4 Selected from H, C1-C3 alkyl and acyl groups, each of which is surrounded by 0, 1, 2 or 3 R groups. 5 replace.

[0898] 12. The method of implementation scheme 10, wherein X 1 It is selected from 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl.

[0899] 13. The method of any one of implementation schemes 3-9, wherein X l Selected from acridine, aziridine, pyrrolidine, piperidinyl, piperazinyl, pyrrolyl, pyridinyl, pyrimidinyl, ethylene oxide, oxadiazine, tetrahydrofuranyl, furanyl, pyranyl, tetrahydropyranyl, dioxidine, imidazolyl, pyrazolyl, oxazole, isoxazole, thiazole, isothiazole, triazole, tetraazole, indole, benzimidazole, benzofuran, benzoxazole, benzothiazole, quinoline, isoquinoline, and quinazoline, each independently bound by 0, 1, 2, or 3 R groups. 5 replace.

[0900] 14. The method of any one of implementation schemes 3-9, wherein X 1 Selected from:

[0901]

[0902] 15. The method of any one of implementation schemes 3-9, wherein X 2 Selected from:

[0903]

[0904] 16. The method of any one of embodiments 3-15, wherein L* is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently substituted with a group selected from: C(O), O, NR 4 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 5 replace.

[0905] 17. The method of any one of embodiments 3-15, wherein L* is a linker, wherein one carbon atom is replaced by a heterocyclic ring and one carbon atom is replaced by a cycloalkyl ring, each independently replaced by 0, 1, 2 or 3 R... 5 replace.

[0906] 18. The method of any one of implementation schemes 3-15, wherein L* is selected from:

[0907]

[0908]

[0909] 19. The method of any one of embodiments 1-18, wherein the estrogen receptor (ER) degrader is a compound from Table 1A.

[0910] 20. The method of embodiment 1 or 2, wherein the estrogen receptor (ER) degrader is a compound of formula (IB):

[0911]

[0912] Or its stereoisomers or mixtures thereof, pharmaceutically acceptable salts or hydrates.

[0913] in:

[0914] R 1 Selected from H, C1-C6 acyl or C1-C6 alkyl, each of which is surrounded by 0, 1, 2 or 3 R groups. 6 replace;

[0915] R 2 and R 3 Each is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0916] Each R 4 Independently selected from H, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy or C1-C3 haloalkyl, each of which is marked by 0, 1, 2 or 3 R. 6 Replace, or two Rs 4 The groups combine to form an oxo group;

[0917] R 5 Selected from hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 haloalkyl, -N(R) 7 )2 and -CN, each of which is bounded by 0, 1, 2 or 3 R 6 replace;

[0918] X 1 and X 2 Each is independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, each being separated by 0, 1, 2, or 3 R groups. 6 replace;

[0919] X 3 and X 4 Each is independently selected from H or halogen;

[0920] L is a linker with a length of 1 to 22 carbon atoms, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 7 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each of which is surrounded by 0, 1, 2 or 3 R 6 replace;

[0921] Each R 6 Independently selected from C1-C6 alkyl, halogen, cyano, and hydroxyl groups.

[0922] Each R 7 Independently selected from hydrogen, C1-C6 alkyl and acyl groups, each marked with 0, 1, 2 or 3 R groups. 6 Replace, or two Rs 7 The groups combine to form 3- to 6-membered heterocycles or heteroaryl groups.

[0923] 21. The method of implementation scheme 20, wherein R 1 It is H or methyl.

[0924] 22. Implement the method of scheme 20 or 21, wherein R 2 and R 3 Each is independently selected from H and methyl.

[0925] 23. The method of any one of implementation schemes 20-22, wherein R 4 It is H.

[0926] 24. The method of implementing any one of schemes 20-22, wherein two R 4 The groups combine to form an oxo group.

[0927] 25. The method of any one of implementation schemes 20-24, wherein R5 It is hydrogen or halogen.

[0928] 26. The method of any one of implementation schemes 20-25, wherein X 1 and X 2 Each is independently selected from H, F, CN, methyl, methoxy, and trifluoromethyl.

[0929] 27. The method of any one of implementation schemes 20-26, wherein X 3 and X 4 Each is independently selected from H or halogen.

[0930] 28. The method of any one of implementation schemes 20-27, wherein X 3 and X 4 Each is independently selected from H or F.

[0931] 29. The method of any one of embodiments 20-28, wherein L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are optionally and independently substituted by groups selected from: C(O), O, NR. 7 S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl, each independently bounded by 0, 1, 2 or 3 R 6 replace.

[0932] 30. The method of any one of embodiments 20-29, wherein L is a linker, wherein one carbon atom is replaced by a heterocyclic ring and one carbon atom is replaced by a cycloalkyl ring, each of which is independently replaced by 0, 1, 2 or 3 R... 6 replace.

[0933] 31. The method of any one of implementation schemes 20-28, wherein L is selected from:

[0934]

[0935]

[0936] 32. The method of any one of embodiments 20-31, wherein the compound is a stereoisomer.

[0937] 33. The method of implementation scheme 32, wherein the compound is a cis isomer.

[0938] 34. The method of embodiment 32, wherein the compound has the formula (IB)*:

[0939]

[0940] 35. The method of any one of embodiments 20-34, wherein the estrogen receptor (ER) degrader is a compound from Table 1B.

[0941] 36. The method of any of the preceding embodiments, wherein the CDK inhibitor is a CDK1 inhibitor.

[0942] 37. The method of any of the preceding embodiments, wherein the CDK inhibitor has a structure according to formula (II):

[0943]

[0944] Or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates.

[0945] in:

[0946] M is a bond, -NH- or -C(O)-;

[0947] L is hydrogen, alkyl, carbocycloyl, arylalkyl, heteroarylalkyl, or heterocyclic, each of which is optionally substituted by one or more substituents;

[0948] Q is CH2, O, S, or a bond;

[0949] W and Y are independently CH or N, provided that at least one of W or Y is N, and Q is O or S when W is CH; and

[0950] R1 and R2 are independently selected from hydrogen, halogen, alkyl, and heterocyclic, wherein each of the alkyl and heterocyclic groups is optionally substituted by one or more substituents; or

[0951] R1 and R2, together with the atoms they are attached to, form a carbocyclic or heterocyclic group, each of which is optionally substituted by one or more substituents; and

[0952] R9 is hydrogen, halogen, or alkyl, wherein the alkyl group is optionally substituted.

[0953] 38. The method of any of the preceding embodiments, wherein the CDK inhibitor has a structure according to formula (III):

[0954]

[0955] Or its tautomers, stereoisomers, or mixtures of stereoisomers, or pharmaceutically acceptable salts or hydrates.

[0956] in:

[0957] M is a bond, -NH- or -C(O)-;

[0958] L is H, a carbocyclic group, an arylalkyl group, a heteroarylalkyl group, or a heterocyclic group, each of which is optionally substituted by one or more substituents; and

[0959] R1 and R2 are independently selected from hydrogen, halogen, alkyl and heterocyclic, wherein the alkyl and heterocyclic are optionally substituted by one or more substituents;

[0960] Alternatively, R1 and R2 together with the atoms they are attached to form a carbocyclic or heterocyclic group, each of which may optionally be substituted by one or more substituents.

[0961] 39. The method of embodiment 37 or 38, wherein L is substituted by one or more halogens, aryl, heteroaryl, arylalkyl, heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, heteroarylalkyl are optionally substituted by one or more substituents.

[0962] 40. The method of embodiment 39, wherein each of the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups is optionally substituted by one or more substituents selected from: halogen, nitro, hydroxyl, alkyl, aryl, heterocyclic, -C(O), -C(O)NR g R h , where R g and R h Each is independently hydrogen or alkyl.

[0963] 41. The method of embodiment 39 or 40, wherein L is: (i) an aryl group optionally substituted with a halogen and a heteroaryl alkyl group, said heteroaryl alkyl group optionally substituted with -C(O); (ii) an aryl alkyl group optionally substituted with a heteroaryl group, said heteroaryl group optionally substituted with one or more halogens, -C(O) or combinations thereof; or (iii) an aryl group optionally substituted with a heteroaryl group, said heteroaryl group optionally substituted with -C(O)NR g R h Replace, where R g and R h Each is independently hydrogen or alkyl.

[0964] 42. The method of embodiment 41, wherein L is a C that is optionally substituted with a halogen and a heteroarylalkyl group. 5-8 The aryl group comprises an 8- to 12-membered heteroaryl ring having one to four atoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted by one or more substituents.

[0965] 43. The method of embodiment 42, wherein L is a C6 aryl group substituted with halogen and heteroaryl alkyl group, the heteroaryl alkyl group comprising a 10-membered heteroaryl ring having 2 nitrogen atoms and being substituted with -C(O).

[0966] 44. The method of implementation scheme 39 or 40, wherein L is C optionally substituted with a 10-15 methyl aryl group. 5-8 Aryl-C 1-3Alkyl groups, the 10-15 aryl groups having one to four atoms independently selected from nitrogen, oxygen and sulfur and optionally substituted by one or more halogens, -C(O) or combinations thereof.

[0967] 45. The method of embodiment 44, wherein L is a C6 aryl-C1 alkyl group substituted with a 13-membered heteroaryl group, the 13-membered heteroaryl group having two nitrogen atoms and being substituted with a halogen and -C(O).

[0968] 46. ​​The method of implementation scheme 39 or 40, wherein L is C optionally substituted with a 6-12 heteroaryl group. 5-8 The aryl group, wherein the 6- to 12-membered heteroaryl group has one to four atoms independently selected from nitrogen, oxygen, and sulfur and is optionally surrounded by -C(O)NR g R h Replace, where R g and R h Each is independently hydrogen or alkyl.

[0969] 47. The method of embodiment 46, wherein L is a C6 aryl group substituted with a 9-membered heteroaryl group, the 9-membered heteroaryl group having two nitrogen atoms and being substituted with -C(O)NH2.

[0970] 48. The method of implementation scheme 37, wherein L is selected from:

[0971]

[0972] in:

[0973] Ring A represents a fused aryl or heteroaryl group, which is optionally substituted by one or more substituents selected from the following: halogen, nitro, hydroxyl, ether, thiol, thioether, amino, alkyl, aryl, and heterocyclic; and R8 is hydrogen or halogen.

[0974] 49. The method of implementation scheme 48, wherein L is:

[0975]

[0976] in:

[0977] Ring A represents a fused aryl or heteroaryl group, optionally substituted by one or more substituents selected from: halogen, nitro, hydroxyl, amino, alkyl, aryl, and heterocyclic; and

[0978] R8 is hydrogen or halogen.

[0979] 50. The method of implementation scheme 49, wherein ring A is C 5-8 Aryl.

[0980] 51. The method of implementation scheme 49, wherein ring A is benzene.

[0981] 52. The method of any one of implementation schemes 49-51, wherein R8 is selected from H, Cl and F.

[0982] 53. The method of any one of embodiments 37-52, wherein R1 is a halogen.

[0983] 54. The method of any one of embodiments 37-53, wherein R2 is a 6- to 12-membered heteroaryl group optionally substituted with one or more substituents.

[0984] 55. The method of any one of embodiments 37-53, wherein R2 is a 9-membered heteroaryl group substituted with one or more substituents selected from halogens, alkyl groups and combinations thereof.

[0985] 56. The method of any one of implementation schemes 37-53, wherein R2 is:

[0986]

[0987] in

[0988] n is 0, 1, 2, or 3;

[0989] Each R3 is independently a halogen or an alkyl group; and

[0990] R6 is an alkyl or cycloalkyl group, each of which is optionally substituted by one or more substituents.

[0991] 57. The method of any one of implementation schemes 54-56, wherein R2 is selected from:

[0992]

[0993] 58. The method of any one of embodiments 37-52, wherein R1 and R2 together with the atoms to which they are attached form a heteroaryl group, which is optionally substituted by one or more substituents.

[0994] 59. The method of embodiment 58, wherein R1 and R2 together with the atoms to which they are attached form a 5- to 6-membered heteroaryl group, which is substituted by one or more substituents selected from halogens, alkyl groups, cycloalkyl groups and combinations thereof.

[0995] 60. The method of embodiment 59, wherein R1 and R2, together with the atoms to which they are attached, form a ring selected from:

[0996]

[0997] in:

[0998] R4 is hydrogen or -C(O)NR a R b , where Ra and R b Each is independently selected from hydrogen and alkyl; and

[0999] R5 is a cycloalkyl group.

[1000] 61. The method of any of the preceding embodiments, wherein the CDK inhibitor is selected from:

[1001]

[1002]

[1003]

[1004] Or its tautomers, stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or hydrates.

[1005] 62. The method of any one of embodiments 1-63, wherein the estrogen receptor (ER) degrader and the cyclin-dependent kinase (CDK) inhibitor are in a single dosage form or in separate dosage forms.

[1006] 63. The method of implementation scheme 62, wherein the individual dosage form is administered via the same or different routes of administration.

[1007] 64. The method of implementation scheme 63, wherein the single dosage form is administered by simultaneous administration, sequential administration, staggered administration, intermittent administration, continuous administration, or a combination thereof.

[1008] 65. The method of any one of implementation schemes 1-64, wherein the dosage form is an oral dosage form.

[1009] 66. The method of any one of implementation schemes 1-65, wherein the CDK inhibitor is a CDK4 / 6 inhibitor.

[1010] 67. The method of implementation scheme 66, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abeciclib, or pharmaceutically acceptable salts, polymorphs, or solvates thereof.

[1011] 68. The method of any one of embodiments 65-67, wherein the oral dosage form comprises about 125 mg, about 100 mg or about 75 mg of palbociclib.

[1012] 69. The method of any one of embodiments 65-67, wherein the oral dosage form comprises ribociclib succinate with a free base equivalent of about 200 mg.

[1013] 70. The method of any one of embodiments 65-67, wherein the oral dosage form of abexinib is about 50 mg, about 100 mg, about 150 mg or about 200 mg of abexinib.

[1014] 71. The method of any one of embodiments 65-70, wherein the oral dosage form is a tablet or a capsule.

[1015] 72. The method of any one of embodiments 1-71, wherein the estrogen receptor (ER) degrader and cyclin-dependent kinase (CDK) inhibitor are administered as a pharmaceutical formulation further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

[1016] 73. The method of any one of implementation schemes 1-72, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer and esophageal cancer.

[1017] 74. The method of any one of implementation schemes 1-73, wherein the cancer is positive for ERα.

[1018] 75. The method of implementation plan 67, comprising administering to a subject an initial dose of about 125 mg / day of palbociclib in combination with an estrogen receptor (ER) degrader.

[1019] 76. The method of implementation plan 67, comprising administering to a subject ribociclib succinate at an initial dose of about 600 mg / day of free base equivalent of ribociclib in combination with an estrogen receptor (ER) degrader.

[1020] 77. The method of embodiment 67, comprising administering to a subject an initial dose of abexinib in combination with an estrogen receptor (ER) degrader, ranging from about 150 mg twice daily to about 200 mg twice daily.

[1021] 78. The method of any one of embodiments 1-77, wherein the estrogen receptor (ER) degrader is administered at a dose from 30 mg to 600 mg once or twice daily.

[1022] 79. The method of implementation scheme 1-19, wherein the ER degrading agent is selected from:

[1023] Or its pharmaceutically acceptable salt.

[1024] 80. The method of implementation scheme 79, wherein the ER degrading agent is:

[1025] Or its pharmaceutically acceptable salt.

[1026] 81. The method of implementation scheme 79, wherein the ER degrading agent is:

[1027] Or its pharmaceutically acceptable salt.

[1028] 82. The method of implementation scheme 79, wherein the ER degrading agent is:

[1029] Or its pharmaceutically acceptable salt.

[1030] 83. The method of any one of embodiments 20-35, wherein the ER degrading agent is selected from:

[1031]

[1032] Or its pharmaceutically acceptable salt.

[1033] 84. The method of implementation scheme 83, wherein the ER degrading agent is:

[1034] Or its pharmaceutically acceptable salt.

[1035] 85. The method of implementation scheme 83, wherein the ER degrading agent is:

[1036] Or its pharmaceutically acceptable salt.

[1037] 86. The method of implementation scheme 83, wherein the ER degrading agent is:

[1038] Or its pharmaceutically acceptable salt.

[1039] 87. The method of implementation scheme 83, wherein the ER degrading agent is:

[1040] Or its pharmaceutically acceptable salt.

[1041] 88. The method of implementation scheme 83, wherein the ER degrading agent is:

[1042] Or its pharmaceutically acceptable salt.

[1043] The invention has now been generally described, and will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the invention.

[1044] Example

[1045] The examples and formulations provided below further illustrate and demonstrate the compounds disclosed herein and methods for preparing such compounds. It should be understood that the scope of this disclosure is not in any way limited by the scope of the examples and formulations provided below.

[1046] Synthesis method

[1047] The compounds and intermediates of the present invention can be prepared in many ways known to those skilled in the art of organic synthesis. Some of the ER degraders described herein can be synthesized by methods described in U.S. Patent Nos. US 10,696,659 and US 10,800,770, the contents of each of which are hereby incorporated by reference in their entirety. Starting materials and intermediates may be purchased from commercial sources or manufactured from known procedures. Those skilled in the art will also recognize that the conditions and reagents described herein are interchangeable with alternative, art-recognized equivalents.

[1048] General methods

[1049] T47D cells, an ER-positive human breast cancer cell line, were seeded at 3000 cells / well in 80 μL of RPMI growth medium containing 10% FBS and 1% penicillin-streptomycin in 96-well tissue culture microplates. Cells were incubated overnight at 37°C. The next day, two test compounds were administered to the cells using 10x compound stock solutions prepared in growth medium at various concentrations. After compound administration, cells were then incubated at 37°C for 6 days. The plates were equilibrated at room temperature for approximately 10 minutes prior to CellTiter-Glo assays. 100 μL of the test compound was then added to the plate. Reagent (Promega, G7573) was added to each well. The plate was then incubated at room temperature for 10 minutes, and the luminescence was recorded using an EnSpire plate reader (PerkinElmer).

[1050] MCF-7 cells (breast cancer cell line) in 0.1 mL of PBS mixed with 0.1 mL of matrigel (10 x 10) 6 (Total 0.2 mL) The drug was subcutaneously injected into the right flank of each mouse, which had previously received a 0.18 mg 17β-estradiol tablet subcutaneously in its left flank three days prior. The injection was administered when the average tumor volume reached approximately 175 mm². 3 At that time, the animals are randomly arranged and treatment begins.

[1051] Example 1. ER Degrading Agent + Palbociclib

[1052] ER-positive T47D cells were treated with the following: escalating concentrations of the ER-degrading agent 160a disclosed herein. Figure 1 0 nM palbociclib), and separately escalating concentrations of palbociclib (CDK4 / 6 inhibitors) (such as in Figure 1 The Y-axis shows the cell growth inhibition curves when the concentration of ER degrader 160a is 0 nM, and the concentrations of palbociclib are 10 nM, 30 nM, and 100 nM, or a combination of 160a and increasing concentrations of palbociclib. Figure 1 It is displayed in the middle.

[1053] These results indicate that ER degrader 160a synergistically inhibits cell growth in vitro with the CDK4 / 6 inhibitor palbociclib, exhibiting greater potency than either the ER degrader or the CDK4 / 6 inhibitor alone.

[1054] Example 2. ER Degrading Agent + Abexinib

[1055] ER-positive T47D cells were treated with the following: escalating concentrations of the ER-degrading agent 160a disclosed herein. Figure 2 0 nM abexianib) or alone at escalating concentrations of abexianib (CDK4 / 6 inhibitor) (as in Figure 2 The Y-axis shows the cell growth inhibition curves when the concentration of ER degrader 160a is 0 nM, and the concentrations of abexianib are 10 nM, 30 nM, and 100 nM, or a combination of 160a and increasing concentrations of abexianib. Figure 2 It is displayed in the middle.

[1056] These results indicate that ER degrader 160a, in vitro, synergistically inhibits cell growth with the CDK4 / 6 inhibitor abecil, exhibiting greater potency than the ER degrader alone.

[1057] Example 3. ER Degrading Agent + Palbociclib

[1058] ER-positive T47D cells were treated with the following: escalating concentrations of the ER-degrading agent 86 disclosed herein. Figure 3 0 nM palbociclib), and separately escalating concentrations of palbociclib (CDK4 / 6 inhibitors) (such as in Figure 3 The Y-axis shows the cell growth inhibition curves when the concentration of ER degrader 86 is 0 nM, and the concentrations of palbociclib are 10 nM, 30 nM, and 100 nM, or a combination of ER degrader 86 and increasing concentrations of palbociclib. Figure 3 It is displayed in the middle.

[1059] These results indicate that the ER degrader 86 from Table 1B synergistically inhibits cell growth in vitro with the CDK4 / 6 inhibitor palbociclib, exhibiting greater potency than either the ER degrader or the CDK4 / 6 inhibitor alone.

[1060] Example 4. ER Degrading Agent + Abexinib

[1061] ER-positive T47D cells were treated with the following: escalating concentrations of the ER-degrading agent 86 disclosed herein. Figure 4 0 nM abexianib), and separately escalating concentrations of the CDK4 / 6 inhibitor abexianib (such as in Figure 4The Y-axis shows the cell growth inhibition curves when the concentration of ER degrader 86 is 0 nM and the concentrations of abexianib are 10 nM, 30 nM, and 100 nM, or when the concentrations of ER degrader 86 and increasing concentrations of abexianib are used. Figure 4 It is displayed in the middle.

[1062] These results indicate that ER degrader 86 synergistically inhibits cell growth in vitro with the CDK4 / 6 inhibitor abecil, exhibiting greater potency than either the ER degrader alone or the CDK4 / 6 inhibitor alone.

[1063] Example 5. Antitumor efficacy of ER degrading agent + palbociclib in MCF7 human xenograft tumors

[1064] MCF-7 tumor cells (10 x 10⁻⁶) were mixed with 0.1 mL of base gel in 0.1 mL of PBS. 6 (Total 0.2 mL) was subcutaneously injected into the right flank of each BALB / c nude mouse, which had previously received a 0.18 mg 17β-estradiol tablet subcutaneously in the left flank three days prior. The injection was administered when the average tumor volume reached approximately 175 mm². 3 Animals were randomly assigned and treated for 21 days with either the ER-degrading agent 160a alone, or the CDK4 / 6 inhibitor palbociclib alone, or a combination of ER-degrading agent 160a and palbociclib. Tumor growth curves were observed at... Figure 5 It is displayed in the middle.

[1065] These results indicate that the ER degrader 160a synergistically inhibits tumor growth in vivo with the CDK4 / 6 inhibitor palbociclib, exhibiting greater potency than either the ER degrader or the CDK4 / 6 inhibitor alone.

[1066] Example 6. Antitumor efficacy of ER degrading agent + palbociclib in MCF7 human xenograft tumors

[1067] MCF-7 tumor cells (10 x 10⁻⁶) were mixed with 0.1 mL of base gel in 0.1 mL of PBS. 6 (Total 0.2 mL) was subcutaneously injected into the right flank of each BALB / c nude mouse, which had previously received a 0.18 mg 17β-estradiol tablet subcutaneously in the left flank three days prior. The injection was administered when the average tumor volume reached approximately 175 mm². 3 Animals were randomly assigned and treated for 21 days with either the ER-degrading agent 86 alone, or the CDK4 / 6 inhibitor palbociclib alone, or a combination of 86 and palbociclib. Tumor growth curves were observed at... Figure 6 It is displayed in the middle.

[1068] These results indicate that ER degrader 86 synergistically inhibits tumor growth in vivo with the CDK4 / 6 inhibitor palbociclib, exhibiting greater potency than either the ER degrader or the CDK4 / 6 inhibitor alone.

[1069] Example 7. Antitumor efficacy of ER degrading agent + palbociclib in netamoxifen-treated MCF7 xenograft tumors

[1070] Netamoxifen-treated MCF-7 cells were subcutaneously implanted to establish cell line-derived xenograft tumors. Tamoxifen was administered at 30 mg / kg until the tumor showed sustained growth. This tumor was then defined as generation 0. Tumor fragments were continuously implanted into new animals treated with 30 mg / kg tamoxifen (per generation). For efficacy studies, generation 9 netamoxifen tumor fragments (~30 mm) were implanted. 3 Subcutaneous inoculation was performed on the right flank of each BALB / c nude mouse, which had previously received a 0.36 mg 17β-estradiol tablet subcutaneously in the left flank three days prior. The tumor volume reached approximately 175 mm². 3 Animals were randomly assigned and treated for 28 days. Netamoxifen-treated MCF7 human xenograft tumors were treated with the following: ER-degrading agent 160b alone, or the CDK4 / 6 inhibitor palbociclib alone, or a combination of ER-degrading agent 160b and palbociclib. Tumor growth curves were observed in... Figure 7 It is displayed in the middle.

[1071] These results indicate that the ER degrader 160b synergistically inhibits tumor growth in vivo with the CDK4 / 6 inhibitor palbociclib, exhibiting greater potency than either the ER degrader or the CDK4 / 6 inhibitor alone.

Claims

1. Use of an estrogen receptor (ER) degrader and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor in the preparation of a medicament for treating estrogen receptor-positive (ER+) cancer in patients of need, wherein the ER degrader is , Or its pharmaceutically acceptable salt. The ER+ cancer mentioned above is breast cancer.

2. The use according to claim 1, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abeciclib, or pharmaceutically acceptable salts or polymorphs thereof.

3. The use according to claim 1 or 2, wherein the cancer is positive for ERα.

4. The use according to claim 1 or 2, wherein the ER degrading agent and the CDK4 / 6 inhibitor are in separate dosage forms.

5. The use according to claim 4, wherein the individual dosage form is administered via the same route of administration.

6. The use according to claim 4, wherein the individual dosage form is administered via a different route of administration.

7. The use according to claim 4, wherein the individual dosage form is administered simultaneously, sequentially, alternately, at intervals, continuously, or in combination thereof.

8. The use according to claim 4, wherein the individual dosage forms are oral dosage forms.

9. The use according to claim 1, wherein the ER degrading agent is 。 10. The use according to any one of claims 1, 2 and 9, wherein the ER degrading agent is administered to the patient once daily.

11. The use according to any one of claims 1, 2 and 9, wherein the patient is given 5 mg to 975 mg of the ER degrading agent.

12. The use according to any one of claims 1, 2 and 9, wherein the CDK4 / 6 inhibitor is administered to the patient once or twice daily.

13. The use according to any one of claims 1, 2 and 9, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib and abeciclib or pharmaceutically acceptable salts thereof.

14. The use according to claim 13, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

15. The use according to claim 14, wherein 25 mg to 200 mg of palbociclib is administered to the patient.

16. The use according to claim 14, wherein the patient is given about 125 mg, about 100 mg, or about 75 mg of palbociclib.

17. The use according to claim 14, wherein the CDK4 / 6 inhibitor is administered to the patient once daily.

18. The use according to claim 13, wherein the CDK4 / 6 inhibitor is abexinib or a pharmaceutically acceptable salt thereof.

19. The use according to claim 18, wherein the patient is given 25 mg to 500 mg of abexinib.

20. The use according to claim 18, wherein 50 mg, 100 mg, 150 mg or 200 mg of abexinib is administered to the patient.

21. The use according to claim 18, wherein the CDK4 / 6 inhibitor is administered to the patient twice daily.

22. The use according to claim 13, wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

23. The use according to claim 22, wherein the patient is given 50 mg to 600 mg equivalent of the free base of ribociclib.

24. The use according to claim 22, wherein the patient is given 200 mg, 400 mg or 600 mg equivalent of the free base of ribociclib.

25. The use according to claim 22, wherein the CDK4 / 6 inhibitor is administered to the patient once daily.

26. The use according to claim 8, wherein the oral dosage form is a tablet or capsule.

27. The use according to any one of claims 1, 2 and 9, wherein the ER degrader and the CDK4 / 6 inhibitor are administered as separate pharmaceutical formulations, each of the separate pharmaceutical formulations further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

28. The use according to any one of claims 1, 2 and 9, wherein the estrogen receptor (ER) degrader is administered at a dose of 30 mg to 600 mg once or twice daily.

29. Use of estrogen receptor (ER) degraders and cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors in the preparation of medicaments for the treatment of estrogen receptor-positive (ER+) cancers in patients of need, wherein: The ER degrading agent is , Or its pharmaceutically acceptable salt. The ER+ cancer mentioned is breast cancer that is positive for ERα. The ER degrader and the CDK4 / 6 inhibitor are administered in separate dosage forms. The individual dosage forms are tablets or capsules. The ER-degrading agent was administered to the patient once daily. The patient was given 5 mg to 975 mg of the ER-degrading agent. The CDK4 / 6 inhibitor was administered to the patient once or twice daily, and The CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abeciclib, or pharmaceutically acceptable salts thereof.

30. The use according to claim 29, wherein the ER degrading agent is 。 31. The use according to claim 29 or 30, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

32. The use according to claim 31, wherein 25 mg to 200 mg of palbociclib is administered to the patient.

33. The use according to claim 31, wherein 75 mg, 100 mg or 125 mg of palbociclib is administered to the patient.

34. The use according to claim 31, wherein the CDK4 / 6 inhibitor is administered to the patient once daily.

35. The use according to claim 29 or 30, wherein the CDK4 / 6 inhibitor is abecil or a pharmaceutically acceptable salt thereof.

36. The use according to claim 35, wherein the patient is given 25 mg to 500 mg of abexinib.

37. The use according to claim 35, wherein 50 mg, 100 mg, 150 mg or 200 mg of abexinib is administered to the patient.

38. The use according to claim 35, wherein the CDK4 / 6 inhibitor is administered to the patient twice daily.

39. The use according to claim 29 or 30, wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

40. The use according to claim 39, wherein the patient is given 50 mg to 600 mg equivalent of the free base of ribociclib.

41. The use according to claim 39, wherein the patient is given 200 mg, 400 mg or 600 mg equivalent of the free base of ribociclib.

42. The use according to claim 39, wherein the CDK4 / 6 inhibitor is administered to the patient once daily.

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