WO2025090847A1 - Estrogen receptor degraders and their use in the treatment of cancer - Google Patents

Abstract

Provided herein are small molecule degraders of estrogen receptor and their use in the treatment of cancer. Formula (I)

Description

ESTROGEN RECEPTOR DEGRADERS AND THEIR USE IN THE TREATMENT OF CANCER

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. provisional application No. 63/545,746, filed October 25, 2023, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved with the up and down regulation of gene expression. The natural hormone for the estrogen receptor is 17-beta-estradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes a dimerization of the receptor and the dimer in turn binds to estrogen response elements (ERE's) on DNA. The ER-DNA complex recruits other transcription factors responsible for the transcription of DNA downstream from the ERE into mRNA, which is eventually translated into protein. Alternatively, the interaction of ER with DNA may be indirect through the intermediacy of other transcription factors, most notably fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptor and since the estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through binding of either natural hormones or synthetic ER ligands can have profound effects on the physiology and pathophysiology of the organism.

[0003] There are two different forms of the estrogen receptor, usually referred to as a and p, each encoded by a separate gene (ESRI and ESR2, respectively). Both ERs are widely expressed in different tissue types, but there are some notable differences in their expression patterns. The ERa is found in endometrium, breast cancer cells, ovarian stroma cells, and the hypothalamus. In males, ERa protein is found in the epithelium of the efferent ducts. The expression of the ERP protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells. Development therefore of selective ligands may therefore preserve the beneficial aspects of estrogen.

[0004] A variety of diseases have their etiology and/or pathology mediated by the ER. Collectively these diseases are called estrogen-dependent diseases. Estrogens are critical for sexual development in females. In addition, estrogens play an important role in maintaining bone density, regulation of blood lipid levels, and appear to have neuroprotective effects. Consequently, decreased estrogen production in post-menopausal women is associated with a number of diseases such as osteoporosis, atherosclerosis, depression and cognitive disorders. Conversely, certain types of proliferative diseases such as breast and uterine cancer and endometriosis are stimulated by estrogens and therefore antiestrogens (i.e. estrogen antagonists) have utility in the prevention and treatment of these types of disorders.

[0005] Estrogen receptor plays an important role in gene transcription and the proliferation of breast cancers and other conditions such as osteoporosis. Approximately 75% of all breast cancers which are diagnosed are characterized as estrogen receptor positive (ER+). Despite medical advances, about 30-50% of ER+ tumors become resistant to selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). This has sparked significant interest in developing alternative means to combat ER+ breast and related cancers.

[0006] As such, there is a need for other approaches to antagonise the ER receptor. One approach would be to develop selective ER down regulators or degraders that reduce ER expression at either the transcript or protein level.

SUMMARY

[0007] Provided herein are compounds and compositions which function to recruit ER to E2 enzyme (e.g., UBE2K) for ubiquitination and subsequent degradation. These compounds are designed to be bifunctional in that they comprise an E2 enzyme binding moiety and a target protein binding moiety (i.e., an estrogen receptor/ER binding moiety) bridged by a chemical linker. Such compound include those having the Formula (I):

and pharmaceutically acceptable salts thereof, wherein the variables are as described herein. [0008] Also provided are pharmaceutical compositions comprising the described compounds as well as pharmaceutically acceptable salts thereof.

[0009] Also provided are use of the described compounds, pharmaceutically acceptable salts of the compounds, and the compositions for treating conditions responsive to the degradation of ER (e.g., ERa) such as a cancer.

BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 7, Example 13, and the E2 binding moiety, Compound El.

[0011] FIG. 2 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 7.

[0012] FIG. 3 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 13.

[0013] FIG. 4 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 20.

[0014] FIG. 5 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 21.

[0015] FIG. 6 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 12.

[0016] FIG. 7 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 23.

DETAILED DESCRIPTION

[0017] Provided herein are compounds comprising an E2 binding moiety, a target protein binding moiety, and a linker which covalently attaches the E2 binding moiety to the target protein binding moiety.

[0018] Defintions:

[0019] As used herein, an “E2 binding moiety”, “E2 binder”, or “E2 ligand” refers to a chemical moiety that binds an E2 enzyme. E2 binding moieties, include, but are not limited to those which bind an E2 enzyme selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2D4, UBE2E1, UBE2E2, UBE2E3, UBE2G1, UBE2G2, UBE2H, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2N, UBE2NL, UBE2O, UBE2Q1, UBE2Q2, UBE2QL, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, and BIRC6. In one aspect, the E2 enzyme to which the E2 ligand binds is UBE2K.

[0020] The term “linker” refers to a chemical moiety which covalently attaches the E2 binding moiety to the estrogen receptor binding moiety. In one aspect, the linker is uncleavable in vivo. In one aspect, the linker comprises optimal spatial and chemical properties to effectuate optimal therapeutic activity. In one aspect, the linker does not interfere with the ability of the E2 binding moiety and/or the target protein binding moiety to bind their respective targets. In one aspect, the linker comprises an optionally substituted straight or branched alkyl group which is optionally interrupted by one or more heteroatoms selected from O, N, and S. In one aspect, the linker is a straight or branched alkyl group substituted with one or more oxo groups (=0) and is interrupted by one more heteroatoms selected from O and N. In another aspect, the linker comprises a straight or branched alkyl group interrupted by one or more rings (e.g., an optionally substituted heterocyclyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, or an optionally substituted heteroaryl).

[0021] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which is defined. For example, -NH(Ci-C6)alkyl means that the point of attachment for this group is on the nitrogen atom.

[0022] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0023] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e., (Ci-C4)alkyl.

[0024] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0025] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0026] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHCF2 or -OCF3.

[0027] ‘ ‘Oxo” refers to the divalent function group =0, i.e., an oxygen atom connected to another atom (typically carbon or sulfur) by a double bond.

[0028] The term “heteroaryl” refers to an aromatic ring of the specified size e.g., 5-, 6-, 7-, 8-, or 9-membered ring) containing 1 to 4 heteroatoms independently selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryl include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, etc. When specified, optional substituents on a heteroaryl group may be present on any substitutable position.

[0029] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from oxygen, nitrogen, and sulfur (“3-12 membered heterocyclyl”). In some embodiments, a heterocyclyl comprises 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, a heterocyclyl can be saturated, or partially unsaturated. In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”); polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.

[0030] Spiro heterocyclyl refers to 5 to 12 (e.g., 7 to 9) membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings is an aromatic ring. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:

[0031] As used herein, the term “nitrogen-containing” refers to a structure which contains at least one nitrogen. A nitrogen-containing structure may further include one or more nitrogen atoms, one or more carbon atoms, and/or one or more heteroatoms other than nitrogen (e.g., oxygen, sulfur).

[0032] As used herein, the term “oxygen-containing” refers to a structure which contains at least one oxygen. An oxygen-containing structure may further include one or more oxygen atoms, one or more carbon atoms, and/or one or more heteroatoms other than oxygen (e.g., nitrogen, sulfur).

[0033] The term “cycloalkyl” refers to a monocyclic hydrocarbon of the specified size (e.g., 3-, 4-, 5-, 6-, or 7-membered ring). Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. When specified, optional substituents on a cycloalkyl group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.

[0034] The compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism). Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure. [0035] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifcal and are not mirror images of each other.

[0036] When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “5”) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0037] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0038] When two stereoisomers are depicted by their chemical names or structures, and the chemical names or structures are connected by an “and”, a mixture of the two stereoisomers is intended.

[0039] When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both.

[0040] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0041] Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

[0042] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0043] The term “pharmaceutically acceptable” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0044] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0045] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg/kg body weight/day.

[0046] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0047] Compound Embodiments:

[0048] In a first embodiment, provided is a compound having formula (I):

Tar (I), or a pharmaceutically acceptable salt thereof, wherein

Z¹ and Z² are each independently N or CH;

R¹ is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, or -NR^cR^d, wherein two available hydrogen atoms on said halo(Ci-C6)alkyl and halo(Ci-C6)alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, and halo(Ci-C6)alkoxy;

R² is CN, halo, OH, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, or halo(Ci-C6)alkoxy; or

R¹ and R², when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen-containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, and halo(Ci-C₆)alkyl;

R³ is hydrogen, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl;

Y is CH₂, -CHR^a, -CR^aR^b, S, or SO; p is 0 or 1 ;

R^a and R^b are each independently halo, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl; or R^a and R^b together with the carbon atom they are bound form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which is optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, (Ci-C₆)alkylOH, (Ci-C₆)alkylO(Ci-C₆)alkyl, and OH;

R^c and R^d are each independently hydrogen (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C₆)alkylO(Ci-C₆)alkyl, halo(Ci-C₆)alkylO(Ci-C₆)alkyl, (Ci-C₆)alkyl-O-halo(Ci-C₆)alkyl, halo(Ci-C6)alkyl-O-halo(Ci-C6)alkyl, or (Ci-CejalkylOH; or R^c and R^d together with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo; ring A is aromatic;

X, X¹, and X² are each, as valency permits, independently selected from -CR⁷, N, O, and S;

R⁷ is hydrogen or (Ci-Ce)alkyl; the dotted line in ring B represents a single or double bond; when the dotted line in ring B is a single bond,

R⁵ is selected from hydrogen, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, -S(Ci-C6)alkyl, -SH, OH, (C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, and -NR^eR^f, wherein said (C3-C6)cycloalkyl and 4- to 7-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo;

R^e and R^f are each independently hydrogen, (Ci-C4)alkyl, (Ci-C₄)alkylNH(Ci-C₄)alkyl, (Ci-C₄)alkylN[(Ci-C₄)alkyl]₂, (Ci-C₄)alkylO(Ci-C₄)alkyl;

R⁶ is hydrogen or (Ci-C6)alkyl; when the dotted line in ring B is a double bond,

R⁵ is absent and R⁶ is absent; d, d¹, d² and d³ are each independently selected from CR⁸ and N;

R⁸ is halogen, hydrogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, CN, or OH;

W is absent, NH, -N(Ci-C6)alkyl, O, or S;

L is a linker; and

Tar is a target protein binding moiety which binds estrogen receptor.

[0049] In a second embodiment, provided is a compound represented by structural formula (II):

Tar (II); or a pharmaceutically acceptable salt thereof and the remaining definitions are as defined in the first embodiment. [0050] In a third embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen and the remaining variables are as defined in the first embodiment.

[0051] In a fourth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Z¹ and Z² are each CH and the remaining variables are as defined in the first or third embodiment.

[0052] In a fifth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Y is CH2 and the remaining variables are as defined in the first, third, or fourth embodiment.

[0053] In a sixth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein p is 0 and the remaining variables are as defined in the first, third, fourth, or fifth embodiment.

[0054] In a seventh embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy, or -NR^cR^d; and R^c and R^d together with the nitrogen atom they are bound form a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 halo and the remaining variables are as defined in the first, third, fourth, fifth, or sixth embodiment.

[0055] In an eighth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-C3)alkyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, (Ci-C3)alkoxy, or -NR^cR^d; and R^c and R^d together with the nitrogen atom they are bound form a 5- to 6-membered nitrogen containing heterocyclyl optionally substituted with 1 to 3 halo and the remaining variables are as defined in the first, third, fourth, fifth, sixth, or seventh embodiment.

[0056] In a ninth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R¹ is OCF3, OCHF2, OCH3, CH3, pyrrolidinyl, or piperidinyl, wherein said pyrrolidinyl or piperidinyl is optionally substituted with 1 to 3 halo and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0057] In a tenth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is N and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0058] In an eleventh embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X¹ is CH or N and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0059] In a twelfth embodiment, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X² is CH, N, O, or S and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0060] In a thirteenth embodimentn, provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein

X is N, X¹ is N, and X² is CH;

X is N, X¹ is N, and X² is N;

X is N, X¹ is CH, and X² is S; or

X is N, X¹ is CH, and X² is O and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. [0061] In a fourteenth embodiment, provided is a compound of structural formula (III), (IV), (V), or (VI):

or a pharmaceutically acceptable salt thereof, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0062] In a fifteenth embodiment, provided is a compound of structural formula (VII), (VIII), (IX), (X), or (XI):

Tar (XI), or a pharmaceutically acceptable salt thereof, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0063] In a sixteenth embodiment, provided is a compound of structural formula (I)-(XI), or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen or halo, preferably, hydrogen and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment. In one embodiment, R⁸ is hydrogen.

[0064] In a seventeenth embodiment, provided is a compound of structural formula (I)- (XI), or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen, and R⁶ is selected from hydrogen and (Ci-C4)alkyl (e.g., methyl) and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or sixteenth embodiment. In one embodiment, R⁶ is methyl.

[0065] In an eighteenth embodiment, provided is a compound of structural formula (XII):

or a pharmaceutically acceptable salt thereof, and the remaining variables are as defined in the first embodiment. Alternatively, as part of an eighteenth embodiment, provided is a compound of structural formula (III’) or (X’:)

Tar (ill’) Tar (X’); or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-C3)alkyl or halo(Ci-C3)alkyl, preferably OCF3 or OCHF2; and each is R⁸ is independently hydrogen or halo, preferably, hydrogen and the remaining variables are as defined in the first embodiment.

[0066] In a nineteenth embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein W is S and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment. Alternatively, as part of a nineteenth embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein W is absent, S, NH, or -N(Ci-C3)alkyl and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment.

[0067] In a twentieth embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein W is NH or -NCH3, preferably NH, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment. In one embodiment, W is NH.

[0068] In a twenty-first embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein linker L comprises an optionally substituted straight or branched alkyl group which is optionally interrupted by one to three heteroatoms selected from O, N, and S, and the remaining variables are as defined in the nineteenth or twentieth embodiment.

[0069] In a twenty-second embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein linker L is a straight or branched alkyl group substituted with one to two oxo groups (=0), and the remaining variables are as defined in the nineteenth, twentieth, or twenty-first embodiment.

[0070] In a twenty-third embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein linker L is a straight or branched alkyl group which is interrupted by one or two ring moiety selected from phenyl and 4- to 10- membered nitrogen containing heterocyclyl and the remaining variables are as defined in the nineteenth, twentieth, twenty-first, or twenty- second embodiment.

[0071] In a twenty-fourth embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein linker L is of the following structure:

wherein the asterisk (*) denotes the point of attachment to variable W; e is 0, 1, 2, or 3;

Ai is absent, -C(O)-4- to 6-membered nitrogen containing monocyclic heterocyclyl, phenyl, and 4- to 6-membered nitrogen containing monocyclic heterocyclyl; j is 0, 1, or 2;

A2 is absent, -C(O)-4- to 10-membered nitrogen containing heterocyclyl, or 4- to 6- membered nitrogen containing monocyclic heterocyclyl; provided when Ai, A2 and j are absent, e is not 0, and the remaining variables are as defined in the nineteenth or twentieth embodiment.

[0072] In a twenty-fifth embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein e is 1 or 2; Ai is absent; j is 0; A2 is -C(O)-4- to 6-membered nitrogen containing monocyclic heterocyclyl or -C(O)-7- to 9- membered nitrogen containing spiro heterocyclyl and the remaining variables are as defined in the twenty-fourth embodiment.

[0073] In a twenty-sixth embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein A2 is

-C(O)-6-membered nitrogen containing monocyclic heterocyclyl and the remaining variables are as defined in the twenty-fifth embodiment.

[0074] In a twenty-seventh embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein e is 1 or 2; Ai is 4- to 6- membered nitrogen containing monocyclic heterocyclyl; j is 1; A2 is

-C(O)-6-membered nitrogen containing monocyclic heterocyclyl or 6-membered nitrogen containing monocyclic heterocyclyl and the remaining variables are as defined in the twentyfourth embodiment.

[0075] In a twenty-eighth embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein W is absent; and Linker L is of the following structure:

wherein ring N 1 is 4- to 6-membered nitrogen containing monocyclic heterocyclyl, and is connected with the tricylic ring moiety through a nitrogen ring atom; ring N2 is absent or 4- to 10-membered nitrogen containing heterocyclyl; and

Li is absent, -CH2-, or O and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment.

[0076] In a twenty-ninth embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein ring N2 is absent and the remaining variables are as defined in the twenty-eighth embodiment.

[0077] In a thirtieth embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein ring N2 is

5- to 6-membered nitrogen containing monocyclic heterocyclyl or 7- to 9-membered nitrogen containing spiro heterocyclyl, and Li is -CH2- and the remaining variables are as defined in the twenty-eighth embodiment. Alternatively, as part of a a thirtieth embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein L is X1-A1-X2-A2-X3, wherein XI is absent, (CEh , or (CH2)_VC(O); Al is phenyl, 4- to 10-membered nitrogen containing heterocyclyl, or 5- to 6-membered heteroaryl; X2 is absent, (CtDg, C(O), or (CH2)_gC(O); A2 is absent or is a 4- to 10-membered nitrogen containing heterocyclyl or 5- to 6-membered heteroaryl; X2 is absent, (CHTJI. C(O), or (CH2)fC(O); and v, g, and f are each independently 1 or 2.

[0078] In a thirty-first embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein ring N1 is piperidinyl or piperazinyl and the remaining variables are as defined in the twenty-eighth, twenty-ninth, or thirtieth embodiment. Alternatively, as part of a thirty-first embodiment, provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein L is selected from

, wherein the asterisk (*) denotes the point of attachment to variable W, and the remaining variables are as defined in any one of the first to twentieth embodiments.

[0079] In a thirty-second embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein Tar is a target protein binding moiety which binds estrogen receptor alpha (ERa) and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eight, twenty-ninth, thirtieth, or thirty-first embodiment.

[0080] In a thirty-third embodiment, provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein Tar is of the structure:

wherein the wavy bond denotes the point of attachment to linker L and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eight, twenty-ninth, thirtieth, thirty-first or thirty-second embodiments. In one embodiment, Tar is of the structure

[0081] In one embodiment, Tar is of the structure

.

[0082] Additional compounds are disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. In one embodiment, the compound of formula (I) is not selected from any one of Examples 10, 11, 18, 35, 37, 39, 40, 58, 62, 63, and 68.

[0083] Uses, Formulation and Administration

[0084] One or more compounds described herein may be present as part of a pharmaceutical composition. Therefore, in one aspect, provided are pharmaceutical compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0085] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. [0086] The compounds and compositions described herein are generally useful for modulating the activity of the target protein (e.g., ER or ERa). In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade the target protein (e.g., ER or ERa).

[0087] Thus, provided herein are methods of treating a disease responsive to the degradation of a target protein (e.g., ER or ERa) in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0088] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof for treating a disease responsive to the degradation of a target protein (e.g., ER or ERa).

[0089] Also provided herein are methods of degrading a target protein (e.g., ER or ERa) in a cell, comprising introducing into the cell a compound comprising an E2 binding moiety, a target protein (ER or ERa) binding moiety (z.e., binding moiety that binds to the target protein to be degraded), and a linker which covalently attaches the E2 binding moiety to the target protein binding moiety, thereby degrading the target protein in the cell.

[0090] Also provided herein are methods of degrading a target protein (e.g., ER or ERa) in a subject, comprising administering to the subject an effective amount of a compound comprising an E2 binding moiety, a target protein binding moiety (z.e., binding moiety that binds to the target protein to be degraded), and a linker which covalently attaches the E2 binding moiety to the target protein binding moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof, thereby degrading the target protein in the subject.

[0091] In addition, provided herein are methods of treating a disease responsive to the degradation of a target protein (e.g., ER or ERa) in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of an effective amount of a compound comprising an E2 binding moiety, a target protein binding moiety (z.e., binding moiety that binds to the target protein which, when degraded, treats the disease), and a linker which covalently attaches the E2 binding moiety to the target protein binding moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof, thereby treating the disease. [0092] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease responsive to the degradation of a target protein (e.g., ER or ERa).

[0093] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition.

[0094] In some aspects, the disease to be treated by the present methods is a cancer. Examples of cancers treated using the compounds and methods described herein include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, actue promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt’ s lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T- lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter’s transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary’s disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom’s macroglobulinemia, Warthin’s tumor, and Wilms’ tumor. In certain additional embodiments, the disease is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof. In another embodiment, the disease is breast cancer. EXEMPLIFICATION

[0095] The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention. General starting materials used were obtained from commercial sources or prepared in other examples, unless otherwise noted.

Abbreviations

[0096] All proton NMR experiments were recorded on a Bruker NEO Spectrometer equipped with a BBFO probe at 400 MHz. Deuterated solvents contained less than 0.05% v/v tetramethylsilane which was used as the reference signal (set at 0.00 ppm). When deuterated solvents did not contain tetramethylsilane, the residual nondeuterated solvent peaks were used as a reference signal, as per published guidelines (J. Org. Chem. 1997, 62(21), 7512- 7515). Chemical shifts are expressed in parts per million (ppm, 5 units). Coupling constants are in hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet) or bs (broad singlet).

[0097] LC/MS analyses were performed on an Agilent Technologies UHPLC 1290 Infinity II with a G6125 MS detector.

[0098] Microwave reactions were conducted with a Monowave 300 by Anton Paar GmbH using standard protocols.

[0099] Starting materials and intermediates:

[00100] Protein of Interest (POI):

[00101] Synthesis of POI_4 & POI_5:

[00102] Step 1: Synthesis of 6-(tert-butoxy)-3,4-dihydronaphthalen-l(2H)-one (15):

[00103] To a stirred solution of 6-hydroxy-3,4-dihydronaphthalen-l(2H)-one, 13 (5 g, 30.8 mmol) and tert-butyl 2,2,2-trichloroacetimidate, 14 (13.47 g, 61.7 mmol) in DCM (50 mL) at 25 °C, Pyridinium p-toluenesulfonate (0.775 g, 3.08 mmol) was added and stirred for 16 h.

After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCOa (60 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure to afford crude product. It was purified by Silica gel (230- 400 mesh) column chromatography using 30% EtOAc in petroleum ether to afford 6-(tert- butoxy)-3,4-dihydronaphthalen-l(2H)-one, 15 (1.75 g, 16.03 mmol, 26% yield) as pale brown liquid. ’ H NMR (400 MHz, DMSO-d6) 5 = 7.78-7.81 (m, 1H), 6.90-6.94 (m, 2H), 2.88-2.92 (m, 2H), 2.50-2.56 (m, 2H), 1.97-2.05 (m, 2H), 1.39 (s, 9H); LCMS: 219.2 [M+H], [00104] Step 2: Synthesis of 6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl trifluoromethanesulfonate (17):

[00105] To the stirred solution of 6-(tert-butoxy)-3,4-dihydronaphthalen-l(2H)-one, 15 (5 g, 22.90 mmol) in THF (50 mL) at -78 °C, NaHMDS (IM in THF, 14.89 mL, 29.8 mmol) was added and stirred at the same temperature for 2 h. Then a solution of 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, 16 (9.82 g, 27.5 mmol) in THF (20 mL) was added and stirred at 25 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4CI solution (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure to give the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 30% EtOAc in Petroleum ether to afford 6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl trifluoromethanesulfonate, 17 (4.5 g, 56.1% yield) as brown liquid. ’ H NMR (400 MHz, DMSO-d6) 5 = 7.14 (d, J = 8.40 Hz, 1H), 6.92-6.95 (m, 2H), 6.09 (t, J = 4.80 Hz, 1H), 2.78- 2.82 (m, 2H), 2.47-2.49 (m, 2H), 1.34 (s, 9H); LCMS: 349.0 [M-H],

[00106] Step 3: Synthesis of 4-(6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl)phenol (19):

[00107] To a stirred solution of 6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl trifluoromethanesulfonate, 17 (0.600 g, 1.713 mmol) in 1,4-Dioxane (7 mL) and water (2 mL) at 25 °C, K2CO3 (0.473 g, 3.43 mmol) and (4-hydroxyphenyl)boronic acid, 18 (0.236 g, 1.713 mmol) were added and purged with N2 for 10 minutes. Then PdCh(dppf) (0.125 g, 0.171 mmol) was added, and the reaction mixture was subjected to microwave irradiation at 100 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated under reduced pressure to yield the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 30% EtOAc in Petroleum ether to afford 4-(6-(tert-butoxy)- 3,4-dihydronaphthalen-l-yl)phenol, 19 (0.320 g, 63.5% yield) as brown Liquid. ’ H NMR (400 MHz, DMSO-d6) 5 = 9.44 (s, 1H), 7.08-7.12 (m, 2H), 6.71-6.84 (m, 5H), 5.89 (t, J =

6.00 Hz, 1H), 2.71-2.76 (m, 2H), 2.30-2.33 (m, 2H), 1.30 (s, 9H); LCMS: 295.2 [M+H],

[00108] Step 4: Synthesis of 4-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-l- yl)phenol (20):

[00109] To a stirred solution of 4-(6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl)phenol, 19 (750 mg, 2.55 mmol) in Acetonitrile (10 mL) at 0 °C, NBS (453 mg, 2.55 mmol) was added in portions and stirred at 25 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure to afford the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 30% EtOAc in Petroleum ether to afford 4-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl)phenol, 20 (500 mg, 52.6% yield) as brown gum. ¹ H NMR (400 MHz, DMSO-d6) 5 = 9.52 (s, 1H), 6.95- 6.99 (m, 2H), 6.81-6.84 (m, 3H), 6.65-6.69 (m, 1H), 6.46 (d, J= 11.20 Hz, 1H), 2.86-2.96 (m, 4H), 1.29 (s, 9H); LCMS: 371.0 [M-H],

[00110] Step 5: Synthesis of 4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-l- yl)phenol (22):

[00111] To a stirred solution of 4-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-l- yl)phenol, 20 (0.500 g, 1.339 mmol) in 1,4-Dioxane (6 mL) and water (1.2 mL) at 25 °C, K2CO3 (0.370 g, 2.68 mmol) and phenylboronic acid, 21 (0.163 g, 1.339 mmol) were added and purged with N2 for 10 minutes. Then PdCh(dppf) (0.098 g, 0.134 mmol) was added, and the reaction mixture was subjected to microwave irradiation at 100 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated under reduced pressure to yield the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 20% EtOAc in Petroleum ether to afford 4-(6-(tert-butoxy)-2-phenyl-3,4- dihydronaphthalen-l-yl)phenol, 22 (0.430 g, 87 % yield), as brown Liquid. ^JH NMR (400 MHz, DMSO-d6) 5 = 9.31 (s, 1H), 7.01-7.16 (m, 5H), 6.77-6.85 (m, 3H), 6.61-6.70 (m, 4H), 2.86-2.91 (m, 2H), 2.66-2.74 (m, 2H), 1.31 (s, 9H); LCMS: 371.0 [M+H], [00112] Step 6: Synthesis of rac-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenol (23):

ERa [Racemic]

[00113] To a stirred solution of 4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-l- yl)phenol, 22 (0.500 g, 1.309 mmol) in THF (10 mL), Pd-C (10%, 0.139 g, 1.309 mmol) was added and stirred at 60 °C under H2 [lOkg/cm²] pressure for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a pad of Celite® (z.e., diatomaceous earth), washed with EtOAc (2 x 5 mL) and the filtrate was concentrated under reduced pressure to give the crude product. It was purified by Silica gel (230-400 mesh) using 30% EtOAc in Petroleum ether to afford rac-4-((lR,2S)-6-(tert-butoxy)-2- phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenol, 23 (0.270 g, 54.6% yield) as an off-white solid. ’ H NMR (400 MHz, DMSO-d6) 5 = 9.00 (s, 1H), 7.10-7.18 (m, 3H), 6.76-6.85 (m, 4H), 6.67-6.70 (m, 1H), 6.37 (d, J= 8.80 Hz, 2H), 6.16 (d, J= 8.40 Hz, 2H), 4.19-4.20 (m, 1H), 3.30-3.31 (m, 1H), 2.91-3.08 (m, 2H), 2.06-2.18 (m, 1H), 1.70-1.74 (m, 1H), 1.30 (s, 9H); LCMS: 371.1 [M-H], [00114] Step 7: Synthesis of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenol (POI_4) and rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl- l,2,3,4-tetrahydronaphthalen-l-yl)phenol (POI_5):

, First Eluting peak (POI 5) Second Eluting peak (POI_4)

ERa [Racemic]

[00115] rac-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenol, 23 (800 mg, 2.148 mmol) was purified by SFC Chiral purification using CO2 as primary solvent and 20% MeOH as co-solvent to afford reduced vacuum to obtain rel-4-((lR,2S)-6- (tert-butoxy)-2-phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenol (Second eluting peak, POI_4) (320 mg) as an off-white solid and rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenol (First eluting peak, POI_5) (320 mg) as an off-white solid. Total yield = 80%.

[00116] Spectral data [POI_4] : SFC Chiral purity = 100%, ^JH NMR (400 MHz, DMSO-d6) 5 = 9.01 (s, 1H), 7.12-7.18 (m, 3H), 6.67-6.85 (m, 5H), 6.37 (d, J = 8.80 Hz, 2H), 6.16 (d, J = 8.40 Hz, 2H), 4.19-4.20 (m, 1H), 3.30-3.31 (m, 2H), 2.92-3.08 (m, 1H), 2.06-2.17 (m, 1H), 1.70-1.74 (m, 1H), 1.30 (s, 9H); LCMS: 371.1 [M-H], SOR = -333.60 [C= 0.50 g/100 mL in ethyl acetate, 25 °C] .

[00117] Spectral data [POI_5] : SFC Chiral purity = 100%, ¹ H NMR (400 MHz, DMSO-d6) 5 = 9.01 (s, 1H), 7.12-7.18 (m, 3H), 6.67-6.85 (m, 5H), 6.37 (d, J = 8.40 Hz, 2H), 6.16 (d, J = 8.40 Hz, 2H), 4.19-4.20 (m, 1H), 2.96-3.08 (m, 2H), 2.07-2.16 (m, 1H), 1.70-1.74 (m, 1H), 1.30 (s, 9H); LCMS: 371.1 [M-H], SOR = +333.76 [C= 0.50 g/100 mL in ethyl acetate, 25 °C],

[00118] Linkers (L): The following linkers are either commercially available or synthesized as per the literature and used for synthesizing the disclosed examples.

[00119] Linker Lil was prepared as reported in PCT Publication No. WO 2020/201080.

[00120] E2 Ligase Ligands (E):

[00121] Synthesis of El:

[00122] Step 1: Synthesis of N-((lH-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide

(33):

[00123] To a stirred solution of 2-(trifluoromethoxy)benzoic acid, 31 (2 g, 9.70 mmol) and (lH-pyrazol-3-yl)methanamine, 32 (0.942 g, 9.70 mmol) in DMF (25 mL) at 0 °C, HATU (3.69 g, 9.70 mmol) and DIPEA (4.24 ml, 24.26 mmol) were added and stirred at 25 °C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into crushed water (200 g) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvents were concentrated under reduced pressure to yield the crude product. It was purified by Silica gel (60-120 nm mesh) column chromatography using 100% ethyl acetate to afford N-((1H- pyrazol-3-yl) methyl)-2-(trifluoromethoxy)benzamide,33 (2.1 g, 75 % yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) 5 = 12.59 (bs, 1H), 8.83 (bs, 1H), 7.56-7.65 (m, 3H), 7.41-7.48 (m, 2H), 6.18 (d, J= 1.60 Hz, 1H), 4.44 (t, J= 5.60 Hz, 2H); LCMS: 286.2 [M+H], [00124] Step 2: Synthesis of N-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl) methyl)-2- (trifluoromethoxy)benzamide (34):

[00125] To a stirred solution of N-((lH-pyrazol-3-yl) methyl)-2- (trifluoromethoxy)benzamide, 33 (2.1 g, 7.36 mmol) in DCM (20 mL) at 25 °C, pTsOH (0.280 g, 1.473 mmol) and 3,4-dihydro-2H-pyran (2.015 ml, 22.09 mmol) were added and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (50 mL), washed with saturated NaHCOa solution (10 mL x 2) and bine (20 mL). The organic layer was dried over Na2SO4 filtered and concentrated under reduced pressure to give the crude product. It was purified by using Silica gel (60-120 mesh) column chromatography using Petroleum ether: EtOAc (55: 45) to afford N-(( 1- (tetrahydro - 2H-pyran-2-yl)-lH-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide, 34 (1.8 g, 61.6 % yield) as an off-white solid. ’ H NMR (400 MHz, DMSO-d6) 5 = 8.87 (t, J = 6.00 Hz, 1H), 7.81 (s, 1H), 7.57-7.80 (m, 2H), 7.42-7.48 (m, 2H), 6.22 (d, J = 2.40 Hz, 1H), 5.32-5.35 (m, 1H), 4.40 (d, J = 6.00 Hz, 2H), 3.90-3.93 (m, 1H), 3.58-3.64 (m, 1H), 2.07-2.11 (m, 1H), 1.86-1.96 (m, 2H), 1.50-1.70 (m, 3H); LCMS: 370.0 [M+H],

[00126] Step 3: Synthesis of N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-(trifluoromethoxy)benzamide (35) :

[00127] To a stirred solution of N-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-(trifluoromethoxy)benzamide, 34 (2.97 g, 8.04 mmol) in dry THF (30 mL) at - 78 °C, n-Butyllithium (1.6M in hexanes, 10.05 mL, 16.08 mmol) was added slowly and stirred for an hour. Then a solution of iodine (2.245 g, 8.85 mmol) in dry THF (25 ml) was added and slowly warmed to -20 ° C and stirred for 45 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHSOs solution (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the solvents were concentrated under reduced pressure to afford the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 25% EtOAc in petroleum ether to afford N-((5-iodo-l- (tetrahydro-2H-pyran-2-yl)- lH-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide, 35 (2.4 g, 58.4% yield) as an off-white solid. ^!H NMR (400 MHz, DMSO-d6) 5 = 8.92 (t, J= 7.60 Hz, 1H), 7.56-7.62 (m, 2H), 7.42-7.49 (m, 2H), 6.45 (s, 1H), 5.33-5.37 (m, 1H), 4.38 (d, J = 8.00 Hz, 2H), 3.90-3.94 (m, 1H), 3.56-3.64 (m, 1H), 2.23-2.36 (m, 1H), 1.97-2.00 (m, 1H), 1.49-1.87 (m, 4H); LCMS: 496.1 [M+H],

[00128] Step 4: Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (37):

[00129] A mixture of N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)methyl)-2- (trifluoromethoxy)benzamide, 35 (2.4 g, 4.85 mmol), (2-aminophenyl)boronic acid, 36 (0.796 g, 5.82 mmol) and Na2COa (1.284 g, 12.12 mmol) in 1,4-dioxane (24 mL) and water (6 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.56 g, 0.485 mmol) was then added and the resulting mixture was stirred at 100 °C for 12 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a pad of Celite® (z.e., diatomaceous earth), washed with EtOAc (2 x 5 mL). The combined filtrates were concentrated under reduced pressure to give crude material which was purified by Silica gel (230-400 mesh) column chromatography, eluting with 50% EtOAc in petroleum ether, affording N-((5-(2- aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)methyl)-2- (trifluoromethoxy)benzamide, 37 as pale brown solid (2.1 g, 78% yield). ’ H NMR (400 MHz, DMSO-d6) 5 = 8.90 (t, J = 7.60 Hz, 1H), 7.55-7.63 (m, 2H), 7.42-7.49 (m, 2H), 7.12-7.17 (m, 1H), 7.01-7.04 (m, 1H), 6.77-6.80 (m, 1H), 6.62-6.67 (m, 1H), 6.26 (s, 1H), 4.95-4.99 (m, 1H), 4.90 (bs, 2H), 4.44-4.48 (m, 2H), 3.89-3.93 (m, 1H), 3.39-3.40 (m, 1H), 2.28-2.40 (m, 1H), 1.49-1.92 (m, 5H); LCMS: 461.1 [M+H],

[00130] Step 5: Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (38):

[00131] To a stirred solution of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide, 37 (2.1 g, 3.79 mmol) in DCM (20 mL) at 0 °C. HC1 (g) in dioxane (4M, 18.93 mL, 76 mmol) was added Reaction mixture warmed to RT and stirred for 12 h. After completion of the reaction (monitored by LCMS), the reaction mixture was evaporated under reduced pressure to afford the residue. The residue was triturated with EtOAc (50 mL), the solid thus obtained was filtered to get the crude product. It was basified with saturated NaHCO3 solution and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure to afford N-((5-(2-aminophenyl)-lH-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide, 38 (1.3 g, 84 % yield) as pale-yellow gum. ¹ H NMR (400 MHz, DMSO-d6) 5 = 12.77 (s, 1H), 9.00 (t, J = 5.60 Hz, 1H), 7.57-7.68 (m, 2H), 7.40-7.51 (m, 3H), 6.96-6.98 (m, 1H), 6.70-6.72 (m, 1H), 6.53-6.57 (m, 2H), 6.30 (bs, 2H), 4.52 (d, J = 6.00 Hz, 2H); LCMS: 377.1 [M+H],

[00132] Step 6: Synthesis of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (El):

[00133] To a stirred solution of N-((5-(2-aminophenyl)-lH-pyrazol-3-yl)methyl)-2- (trifluoromethoxy)benzamide, 38 (1.36 g, 3.32 mmol) in Pyridine (31 mL) and Water (8.5 mL) at 25 °C, carbon disulfide (31 mL, 513 mmol) was added and stirred at 100 °C for 12 h. After completion of the reaction (monitored by LCMS), the reaction mixture was poured into crushed ice (300 g), the solid thus precipitated was filtered, washed with water (10 mL x 2), and dried to yield N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-

(trifluoromethoxy)benzamide, El (1.15 g, 71.9% yield) as an off-white solid. ^!H NMR (400 MHz, DMSO-d6) 5 = 13.53 (s, 1H), 9.18 (t, J = 6.00 Hz, 1H), 8.09 (d, J = 7.60 Hz, 1H), 7.70-7.73 (m, 1H), 7.60-7.64 (m, 3H), 7.42-7.52 (m, 3H), 7.25 (s, 1H), 4.65 (d, J= 6.00 Hz,

2H); LCMS: 419.0 [M+H],

[00134] Synthesis of E2:

[00135] Step 1: Synthesis of N-((lH-pyrazol-3-yl) methyl)-2-methoxybenzamide (40):

[00136] The title compound was prepared by following a similar procedure described for intermediate-33, starting from 2-methoxybenzoic acid, 39 (500 mg, 3.29 mmol), (1H- pyrazol-3-yl) methanamine, 32 (319 mg, 3.29 mmol) and was obtained as colourless liquid (500 mg, 75% yield). ’ H NMR (400 MHz, DMSO-d6) 5 = 12.61 (bs, 1H), 8.59 (t, J = 5.60 Hz, 1H), 7.79-7.82 (m, 1H), 7.60 (s, 1H), 7.46-7.51 (m, 1H), 7.14-7.16 (m, 1H), 7.03-7.07 (m, 1H), 6.18 (d, J= 2.00 Hz, 1H), 4.49 (d, J= 5.60 Hz, 2H), 3.89 (s, 3H); LCMS: 232.2 [M+H],

[00137] Step 2: Synthesis of 2-methoxy-N-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)benzamide (41):

[00138] The title compound was prepared by following a similar procedure described for intermediate-34, starting from N-((lH-pyrazol-3-yl)methyl)-2-methoxybenzamide, 40 (940 mg, 3.33 mmol), 3,4-dihydro-2H-pyran (0.914 mL, 10.00 mmol), and was obtained as an off- white gum (0.870 g, 82.7% yield). ^JH NMR (400 MHz, DMSO-d6) 5 = 8.64 (t, J = 7.20 Hz, 1H), 7.79-1.50 (m, 2H), 7.46-7.52 (m, 1H), 7.14-7.17 (m, 1H), 7.02-7.08 (m, 1H), 6.23 (s, 1H), 5.33-5.37 (m, 1H), 4.45 (d, J = 7.20 Hz, 2H), 3.88-4.05 (m, 4H), 3.57-3.66 (m, 1H), 2.07-2.12 (m, 1H), 1.86-1.96 (m, 2H), 1.50-1.69 (m, 3H); LCMS: 316.3 [M+H],

[00139] Step 3: Synthesis of N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-methoxybenzamide (42):

[00140] The title compound was prepared by following a similar procedure described for intermediate-35, starting from 2-methoxy-N-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)benzamide, 41 (591 mg, 1.874 mmol), n-BuLi (1.6 M in hexanes, 2.342 mL) and Iodine (0.523 g, 2.061 mmol), and was obtained as an off-white solid (0.300 g, 33.7% yield) ’ H NMR (400 MHz, DMSO-d6) 5 = 8.66 (t, J = 5.60 Hz, 1H), 7.78-7.80 (m, 1H), 7.47-7.51 (m, 1H), 7.15-7.17 (m, 1H), 7.03-7.07 (m, 1H), 6.47 (s, 1H), 5.33-5.36 (m, 1H), 4.43 (d, J = 5.60 Hz, 2H), 3.90-3.94 (m, 4H), 3.57-3.64 (m, 1H), 2.29-2.33 (m, 1H), 1.98-2.02 (m, 1H), 1.85-1.89 (m, 1H), 1.50-1.72 (m, 3H); LCMS: 442.0 [M+H],

[00141] Step 4: Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-methoxybenzamide (43):

[00142] The title compound was prepared by following a similar procedure described for intermediate-37, starting from N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-methoxybenzamide, 42 (397 mg, 0.900 mmol), (2-aminophenyl)boronic acid, 36 (148 mg, 1.080 mmol) and was obtained as pale brown gum (0.300 g with 77% LCMS purity). It was taken as such to the next step. LCMS: 407.3 [M+H].

[00143] Step 5: Synthesis of N-((5-(2-aminophenyl)-lH-pyrazol-3-yl)methyl)-2- methoxybenzamide (44):

[00144] The title compound was prepared by following a similar procedure described for intermediate-38, starting from N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-methoxybenzamide, 43 (300 mg, 0.568 mmol), HC1 (g) in dioxane (4M, 1.5 mL), and was obtained as pale brown solid (0.200 g, crude). It was taken as such to the next step. LCMS: 323.1 [M+H].

[00145] Step 6: Synthesis of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- methoxybenzamide (E2):

[00146] The title compound was prepared by following a similar procedure described for El, starting from N-((5-(2-aminophenyl)-lH-pyrazol-3-yl)methyl)-2-methoxybenzamide, 44 (180 mg, 0.441 mmol), carbon disulfide (5 ml, 83 mmol), and was obtained as an off-white solid (124 mg, 76% yield). ’ H NMR (400 MHz, DMSO-d6) 5 = 13.51 (bs, 1H), 8.99 (t, J = 5.20 Hz, 1H), 8.13-8.15 (m, 1H), 7.87-7.89 (m, 3H), 7.50-7.60 (m, 1H), 7.27-7.43 (m, 1H), 7.27 (s, 1H), 7.18-7.20 (m, 1H), 7.06-7.09 (m, 1H), 4.72 (d, J = 5.60 Hz, 2H), 3.98 (s, 3H);

LCMS: 365.1 [M+H],

[00147] ER Degraders:

[00148] Example 6:

[00149] Scheme III:

[00150] Step 1: Synthesis of rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidine-l -carboxylate (53):

[00151] To a stirred solution of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenol, POI_4, (100 mg, 0.268 mmol) in ACN (2 mL) at 25 °C, CS2CO3 (262 mg, 0.805 mmol) was added and stirred at 80 °C for an hour. Then tert-butyl 4- (tosyloxy)piperidine-l -carboxylate (143 mg, 0.403 mmol) was added to 25 °C and stirred at 80 °C for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was filtered, washed with ACN (5 mL) and the filtrate was concentrated under reduced vacuum to obtain the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 10% EtOAc in Petroleum ether to afford rel-tert-butyl 4-(4- (( lR,2S)-6-(tert-butoxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenoxy)piperidine- 1- carboxylate, 53 (110 mg, 70.8% yield) as an off-white solid. LCMS: 456.4 [M⁺-(Boc)].

[00152] General procedure (GP2):

[00153] To a stirred solution of intermediates (53) (1 equiv.) in dry DCM at 0 °C, HC1 (g) in dioxane (4M, 5 Vol) was added and stirred at 25 °C. After completion of the reaction (monitored by LCMS), the reaction mixture was evaporated under reduced pressure to yield the crude product which was taken as such to the next step.

[00154] Step 2: rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4-yloxy)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol, 54 was synthesized using general procedure (GP2) and the crude product was purified by preparative HPLC to afford the title product.

[00155] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.12 (s, 1H), 7.12-7.17 (m, 3H), 6.82-6.83 (m, 2H), 6.48-6.67 (m, 5H), 6.25 (d, J = 8.80 Hz, 2H), 4.16-4.20 (m, 2H), 3.28-3.29 (m, 1H), 2.87-2.98 (m, 4H), 2.46-2.50 (m, 1H), 2.08-2.11 (m, 1H), 1.70-1.82 (m, 3H), 1.24-1.37 (m, 2H); LCMS: 400.2 [M+H],

[00156] General procedure (GP3):

[00157] To a stirred solution of Acid [52] (1.0 equiv.) and Amines [54] (1.0 equiv.) in DMF at 25 °C, EhN (3.0 equiv.) and HATU (1.5 equiv.) were added and stirred for 4 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to yield the crude product. It was purified by preparative HPLC to afford the title product.

[00158] Step 3: Synthesis of Example 6: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl- l,2,3,4-tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)-2-oxoethyl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00159] Final step of Acid amine coupling was carried employing general procedure (GP3) and the crude product was purified by preparative HPLC to obtain Example 6.

[00160] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.13-9.19 (m, 2H), 8.20-8.22 (m, 1H), 7.45- 7.82 (m, 7H), 7.26 (s, 1H), 7.12-7.16 (m, 3H), 6.84 (d, J = 6.40 Hz, 2H), 6.62-6.69 (m, 4H), 6.49-6.52 (m, 1H), 6.30 (d, J = 8.80 Hz, 2H), 4.70 (d, J = 6.00 Hz, 2H), 4.47-4.55 (m, 3H), 4.19-4.20 (m, 1H), 3.84-3.88 (m, 2H), 3.51-3536.00 (m, 1H), 3.20-3.32 (m, 2H), 2.93-2.99 (m, 2H), 1.48-2.13 (m, 6H); LCMS: 858.2 [M+H],

[00161] Examples 7 to 10 :

[00162] Scheme IV:

[00163] Step 1: Synthesis of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (55):

[00164] To a stirred solution of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenol, POI_4 (200 mg, 0.537 mmol) and 1, 1,2, 2, 3, 3, 4,4,4- nonafluorobutane- 1 -sulfonyl fluoride (487 mg, 1.611 mmol) in THF (2 mL) and ACN (2 mL) at 25 °C, K2CO3 (297 mg, 2.148 mmol) was added and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite, washed with THF (2 mL) and the filtrate was concentrated under reduced pressure to afford rel-4- (( lR,2S)-6-(tert-butoxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (350 mg, 91% yield) as colorless gum. LCMS: 653.1 [M-H],

[00165] Step 2: Synthesis of intermediates (13):

[00166] General procedure (GP4):

[00167] To a stirred solution of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate, 55 (1.0 equiv.) in Toluene (10 Vol) at 25 °C, Ligands, L12, L20, L21, & L24 (2.0 equiv.) was added and purged with N2 for 5 minutes. Then NaO/Bu (3.0 equiv.) and Pd(OAc)2 (0.2 equiv.) and XPhos (0.3 equiv.) were added, purged with N2 for 5 minutes and the reaction mixture was subjected to microwave irradiation for 2 h at 100 °C. After completion of the reaction (monitored by UPLC), the reaction mixture was filtered through celite, washed with MeOH (2 mL x 2) and the filtrate was concentrated under reduced vacuum to obtain the crude product. It was purified by Silica gel column chromatography to afford the title product.

[00168] Step 3: Synthesis of intermediates (14):

[00169] Method A: Deprotection using HC1 (g) in dioxane: General procedure (GP2) was followed.

[00170] Method B: Deprotection using ZnBr : General procedure (GP5): For spirocycles.

[00171] To a stirred solution of Spirocyclic intermediates 13 (1.0 equiv.) in DCM (10 Vol) at 25 °C, Zinc bromide (4.0 equiv.) was added and stirred for 16 h. After completion of the reaction (monitored by UPLC), the reaction mixture was filtered through celite, washed with DCM (2 mL x 2) and the filtrate was concentrated under reduced vacuum to obtain the crude product. It was taken as such to the next step.

[00172] Step 4: Syntheses of Examples 7 to 10:

[00173] Final step of Acid amine coupling was carried employing general procedure (GP3) and the crude products were purified by preparative HPLC to obtain examples 7 to 10. [00174] The following examples were synthesized using the above general procedure. [00175] Example 7: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazin-l-yl)-2-oxoethyl)thio)pyrazolo[l,5-c]quinazolin-

2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00176] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.19 (t, J = 5.60 Hz, 1H), 9.13 (s, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.45-7.76 (m, 7H), 7.25 (s, 1H), 7.13-7.18 (m, 3H), 6.86 (d, J = 7.60 Hz, 2H), 6.49-6.67 (m, 5H), 6.26 (d, J = 8.40 Hz, 2H), 4.69 (d, J = 6.00 Hz, 2H), 4.49 (s, 2H), 4.17-4.18 (m, 1H), 3.60-3.81 (m, 4H), 3.18-3.37 (m, 3H), 2.93-3.02 (m, 4H), 2.08-2.14 (m, 1H), 1.71-1.73 (m, 1H); LCMS: 843.3 [M+H],

[00177] Example 8: rel-N-((5-((2-(2-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00178] ’H NMR (400 MHz, DMSO-d6) 5 = 9.19 (t, J = 5.60 Hz, 1H), 9.13 (s, 1H), 8.20 (d, J = 7.60 Hz, 1H), 7.45-7.75 (m, 7H), 7.26 (s, 1H), 7.13-7.21 (m, 3H), 6.83-6.86 (m, 2H), 6.60-6.66 (m, 3H), 6.06-6.23 (m, 4H), 4.70 (d, J = 6.00 Hz, 2H), 4.33 (d, J = 9.20 Hz, 2H), 4.13-4.18 (m, 1H), 3.61-3.96 (m, 7H), 2.93-3.02 (m, 4H), 2.08-2.25 (m, 3H), 1.71-1.73 (m, 1H); LCMS: 869.2 [M+H],

[00179] Example 9: rel-N-((5-((2-(6-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00180] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.19 (t, J = 5.60 Hz, 1H), 9.09 (s, 1H), 8.21- 8.23 (m, 1H), 7.45-7.78 (m, 7H), 7.26 (s, 1H), 7.12-7.16 (m, 3H), 6.83 (d, J = 6.40 Hz, 2H), 6.48-6.65 (m, 3H), 6.10-6.22 (m, 4H), 4.60-4.70 (m, 4H), 3.93-4.14 (m, 5H), 3.85-3.93 (m, 4H), 2.92-2.98 (m, 2H), 2.00-2.12 (m, 2H), 1.70-1.76 (m, 1H); LCMS: 856.0 [M+H], [00181] Example 10: rel-N-((5-((2-(2-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00182] ¹ H NMR (400 MHz, DMSO-d6) 5 = 9.19 (t, J = 5.60 Hz, 1H), 9.09 (s, 1H), 8.20- 8.22 (m, 1H), 7.46-7.79 (m, 7H), 7.26 (s, 1H), 7.12-7.16 (m, 3H), 6.84 (d, J = 6.80 Hz, 2H), 6.47-6.65 (m, 3H), 6.06-6.20 (m, 4H), 4.48-4.70 (m, 4H), 4.12-4.13 (m, 1H), 3.50-3.64 (m, 8H), 3.20-3.30 (m, 1H), 2.92-2.98 (m, 2H), 2.00-2.12 (m, 2H), 1.69-1.88 (m, 4H); LCMS: 883.3 [M+H],

[00183] Example 11:

[00184] Scheme V:

[00185] Step 1: rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4-tetrahydronaphthalen-l- yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate, 56 was synthesized from rel-4- (( lR,2S)-6-(tert-butoxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenol [POI_5] using the procedure described for intermediate 55.

[00186] Step 2: rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazine-l -carboxylate, 57 was synthesized using general procedure [GP4].

Step 3: rel-(5R,6S)-6-phenyl-5-(4-(piperazin- l-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 58 was synthesized using general procedure, GP2

[00187] Step 4: Synthesis of Example 11: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperazin- 1 -yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00188] Final step of Acid amine coupling was carried employing general procedure (GP3) and the crude product was purified by preparative HPLC to obtain Example 11.

[00189] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.18 (t, J = 6.00 Hz, 1H), 9.12 (s, 1H), 8.19- 8.21 (m, 1H), 7.45-7.77 (m, 7H), 7.25 (s, 1H), 7.13-7.18 (m, 3H), 6.86 (d, J = 6.80 Hz, 2H), 6.26-6.68 (m, 7H), 4.69 (d, J = 5.60 Hz, 2H), 4.49 (s, 2H), 4.17-4.18 (m, 1H), 3.61-3.81 (m, 4H), 2.93-3.18 (m, 6H), 2.07-2.18 (m, 1H), 1.72-1.78 (m, 1H); LCMS: 843.3 [M+H],

[00190] Example 12:

[00191] Scheme VI:

[00192] Step 1: rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)-3,6-dihydropyridine- l(2H)-carboxylate (59):

[00193] To a stirred solution of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate, 55 (160 mg, 0.244 mmol) in 1,4-Dioxane (2 mL) and water (0.6 mL) at 25 °C, K2CO3 (67.6 mg, 0.489 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- l(2H)-carboxylate, L23 (76 mg, 0.244 mmol) were added and purged with N2 for 10 minutes. Then PdCh(dppf) (17.89 g, 0.024 mmol) was added, and the reaction mixture was subjected to microwave irradiation at 100 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated under reduced pressure to yield the crude product. It was purified by Silica gel (230-400 mesh) column chromatography using 30% EtOAc in Petroleum ether to afford rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl- 1, 2, 3, 4-tetrahydronaphthalen- 1- yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate, 60 (55 mg, 41.8% yield) as pale brown solid. LCMS: 482.2 | M⁺-( /-butyl )| .

[00194] Step 2: rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)-3,6-dihydropyridine- l(2H)-carboxylate (60):

[00195] To the solution of rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate, 59 (55mg, 0.102 mmol) in THF (2 mL) at 25 °C, Pd-C (10%, 10.88 mg, 0.102 mmol) was added and stirred under H2 (bladder pressure) for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc (5 mL) and the filtrate was concentrated under reduced pressure to afford rel-tert-butyl 4-(4-((lR,2S)-6-(tert- butoxy)-2-phenyl- 1 ,2, 3, 4-tetrahydronaphthalen- 1 -yl)phenyl)-3,6-dihydropyridine- 1(2H)- carboxylate, 60 (45 mg, 82% yield) as a pale-brown gum. It was taken as such to the next step. LCMS: 484.3 [M⁺-(t-butyl)].

[00196] Step 3: rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4-yl)phenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol, 61 was synthesized using general procedure, GP2.

[00197] Step 4: Synthesis of Example 12: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperidin- 1 - yl ) - 2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

Final step of Acid amine coupling was carried employing general procedure (GP3) and the crude product was purified by preparative HPLC to obtain Example 12

[00198] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.20 (t, J = 6.00 Hz, 1H), 9.16 (s, 1H), 8.20- 8.22 (m, 1H), 7.46-7.75 (m, 7H), 7.26 (s, 1H), 7.12-7.14 (m, 3H), 6.63-6.89 (m, 7H), 6.34 (d, J = 8.00 Hz, 2H), 4.70 (d, J = 6.00 Hz, 2H), 4.21-4.50 (m, 5H), 2.73-3.26 (m, 4H), 2.08-2.17 (m, 2H), 1.24-1.85 (m, 6H); LCMS: 842.2 [M+H],

[00199] Example 13:

[00200] Scheme VII:

[00201] Step 1: Synthesis of tert-butyl 4-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)piperidine-

1 -carboxylate (62):

[00202] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (100 mg, 0.239 mmol) and tert-butyl 4-

(bromomethyl)piperidine-l -carboxylate, L16 (66.5 mg, 0.239 mmol), and was isolated as a yellow gum (123 mg, 83.6% yield). LCMS: 638.2 [M+Na]. [00203] Step 2: Synthesis of N-((5-((piperidin-4-ylmethyl)thio)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-(trifluoromethoxy)benzamide (63) :

[00204] The title compound was prepared by following general procedure GP2, starting from tert-butyl 4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)methyl)piperidine-l -carboxylate, 62 (127 mg, 0.206 mmol) and HC1 (g) in dioxane (4M, 0.6 mL) , and was isolated as an off-white solid (100 mg, 98%). It was taken as such to the next step without further purification. LCMS: 516.2 [M+H].

[00205] Step 3: Synthesis of tert-butyl 2-(4-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)piperidin- l-yl)acetate (64):

[00206] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-((piperidin-4-ylmethyl)thio)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-(trifluoromethoxy)benzamide, 63 (129 mg, 0.250 mmol) and tert-butyl 2- bromoacetate, LI (48.8 mg, 0.250 mmol), and was isolated as a yellow gum (154 mg, Crude). It was taken as such to the next step without further purification. LCMS: 630.2 [M+H].

Step 4: Synthesis of 2-(4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)methyl)piperidin-l-yl)acetic acid (65):

[00207] To a stirred solution of tert-butyl 2-(4-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)piperidin- l-yl)acetate, 64 (154 mg, 0.245 mmol) in DCM (5 mL) at 0 °C, Trifluoroacetic acid (0.8 mL) was added and stirred at 25 °C for 16 h . After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to afford 2-(4-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)piperidin- l-yl)acetic acid (140 mg, 100%) as pale brown gum. LCMS: 574.2 [M+H].

[00208] Step 5: Synthesis of rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00209] (Example 13):

[00210] The title compound was prepared employing general procedure (GP3), starting from 2-(4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)methyl)piperidin-l-yl)acetic acid, 65 (70 mg, 0.122 mmol) and rel-(5R,6S)-6-phenyl- 5-(4-(piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (48.8 mg, 0.122 mmol), and was isolated as an off-white solid. (35 mg, 29.7% yield). ^JH NMR (400 MHz, DMSO-d6) 5 = 9.12-9.17 (m, 2 H), 8.19-8.21 (m, 1H), 7.45-7.83 (m, 7H), 7.25 (s, 1H), 7.12- 7.16 (m, 3H), 6.83 (d, J = 6.40 Hz, 2H), 6.48-6.68 (m, 5H), 6.27 (d, J = 8.80 Hz, 2H), 4.68 (d, J = 5.60 Hz, 2H), 4.43-4.45 (m, 1H), 4.19 (d, J = 4.80 Hz, 1H), 3.79-3.82 (m, 2H), 2.80-3.35 (m, 11H), 1.33-2.12 (m, 13H); LCMS: 955.3 [M+H],

[00211] Examples 14 to 18:

[00212] The following examples were synthesized using the procedure described for Example 13.

[00213] Example 14: rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00214] The title compound was prepared employing general procedure (GP3), starting from 2-(4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)methyl)piperidin-l-yl)acetic acid, 65 (70 mg, 0.122 mmol) and rel-(5R,6S)-6-phenyl- 5-(4-(piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (synthesized using the procedure described for intermediate- 54 using POI_5) (48.8 mg, 0.122 mmol), and was isolated as an off-white solid (15 mg, 12.7% yield). ’ H NMR (400 MHz, DMSO-d6) 5 = 9.17 (t, J = 5.60 Hz, 1H), 9.12 (s, 1H), 8.19-8.21 (m, 1H), 7.45-7.83 (m, 7H), 7.25 (s, 1H), 7.12- 7.16 (m, 3H), 6.83 (d, J = 6.40 Hz, 2H), 6.48-6.68 (m, 5H), 6.27 (d, J = 8.80 Hz, 2H), 4.68 (d, J = 6.00 Hz, 2H), 4.43-4.45 (m, 1H), 4.19 (d, J = 4.80 Hz, 1H), 3.78-3.82 (m, 2H), 2.80-3.35 (m, 11H), 1.33-2.12 (m, 13H); LCMS: 955.4 [M+H],

[00215] Example 16: rel-N-((5-((2-(4-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperazin- 1 -yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00216] The title compound was prepared employing general procedure (GP3), starting from 2-(4-(2-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5- yl)thio)acetyl)piperazin-l-yl)acetic acid (25 mg, 0.026 mmol) and rel-(5R,6S)-6-phenyl-5-(4- (piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (10.3 mg, 0.026 mmol), and was isolated as an off-white solid (2.8 mg, 11% yield). ^!H NMR (400 MHz, DMSO-d6) 5 = 9.14-9.19 (m, 2H), 8.20-8.22 (m, 1H), 7.46-7.82 (m, 7H), 7.26 (s, 1H), 7.12-7.17 (m, 3H), 6.83 (d, J = 6.00 Hz, 2H), 6.49-6.68 (m, 5H), 6.28 (d, J = 8.40 Hz, 2H), 4.67 (d, J = 5.60 Hz, 2H), 4.16-4.47 (m, 4H), 2.97-3.77 (m, 9H), 2.79-3.29 (m, 6H), 1.40-2.14 (m, 8H); LCMS: 985.3 [M+H],

[00217] Example 17: rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide: [00218] Scheme VIII

[00219] Step 1: Synthesis of tert-butyl 3-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidine- 1 -carboxylate (66):

[00220] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (100 mg, 0.239 mmol) and tert-butyl 3- (bromomethyl)azetidine-l -carboxylate, L22 (59.8 mg, 0.239 mmol), and was isolated as a yellow gum (140 mg, 100% yield). LCMS: 610.2 [M+Na]. [00221] Step 2: Synthesis of N-((5-((azetidin-3-ylmethyl)thio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (67):

[00222] To a stirred solution of tert-butyl 3-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidine- 1 -carboxylate, 66 (143 mg, 0.243 mmol) in DCM (5 mL) at 0 °C, Zinc Bromide (219 mg, 0.973 mmol) was added stirred at 25 °C for 16 h. After completion of the reaction (monitored by LCMS), the reaction was filtered through celite, washed with DCM (2 mL x 2) and the filtrate was evaporated under reduced pressure to afford N-((5-((azetidin-3- ylmethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide (100 mg, Crude) as an off-white solid. It was taken as such to the next step without further purification. LCMS: 488.0 [M+H],

[00223] Step 3: Synthesis of tert-butyl 2-(3-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidin-l- yl)acetate (68):

[00224] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-((azetidin-3-ylmethyl)thio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 67 (100 mg, 0.129 mmol) and tert-butyl 2- bromoacetate, LI (25.2 mg, 0.129 mmol), and was isolated as a yellow solid (9 mg, 7.3%). LCMS: 602.2 [M+H],

[00225] Step 4: Synthesis of 2-(3-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidin-l- yl) acetic acid (69):

[00226] To a stirred solution of tert-butyl 2-(3-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidin-l- yl)acetate, 68 (9 mg, 0.015 mmol) in DCM (1 mL) at 0 °C, Trifluoroacetic acid (0.05 mL) was added and stirred at 25 °C for 16 h . After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to afford 2-(3-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidin-l- yl)acetic acid (8 mg, crude) as pale brown gum. LCMS: 546.2 [M+H].

[00227] Step 5: Synthesis of Example 17: rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1,2,3, 4-tetr ahydronaphthalen- l-yl)phenoxy)piperidin- l-yl)-2-oxoethyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00228] The title compound was prepared employing general procedure (GP3), starting from 2-(3-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5- yl)thio)methyl)azetidin-l-yl)acetic acid, 69 (8 mg, 0.015 mmol) and rel-(5R,6S)-6-phenyl-5- (4-(piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (5.86 mg, 0.015 mmol), and was isolated as an off-white solid (3 mg, 21.4% yield). ^!H NMR (400 MHz, DMSO-d6) 5 = 9.13 (s, 1H), 9.06 (t, J = 5.60 Hz, 1H), 7.86-7.88 (m, 1H), 7.10-7.67 (m, 10H), 6.94 (s, 1H), 6.82 (d, J = 6.80 Hz, 2H), 6.26-6.68 (m, 7H), 4.41-4.54 (m, 3H), 4.12-4.19 (m, 2H), 3.65-3.77 (m, 4H), 3.51 (bs, 2H), 2.92-3.32 (m, 9H), 1.40-2.11 (m, 6H); LCMS: 927.3 [M+H], [00229] Example 18: rel-N-((5-((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00230] Scheme IX:

[00231] Step 1: Synthesis of tert-butyl 4-((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidine- 1 - carboxylate (70):

[00232] To a stirred solution of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (100 mg, 0.239 mmol) in DMF (1 mL) at 25 °C. tert-butyl 4-(tosyloxy)piperidine-l -carboxylate, L10 (85 mg, 0.239 mmol) and K2CO3 (49.5 mg, 0.359 mmol) were added and stirred at 80 °C for 16 h .After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite, washed with EtOAc (5 mL) and the filtrate was concentrated under reduced pressure to give the crude product, It was purified by Silica gel (60-120 mesh) column chromatography using 20% EtOAc in Petroleum ether to afford tert-butyl 4-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-

5-yl)thio)piperidine-l -carboxylate, 70 (48 mg, 33.3% yield). LCMS: 624.2 [M+Na].

[00233] Step 2: Synthesis of N-((5-(piperidin-4-ylthio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (71):

[00234] The title compound was prepared by following general procedure GP2, starting from tert-butyl 4-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)piperidine- 1 -carboxylate, 70 (48 mg, 0.080 mmol) and HC1 (g) in dioxane (4M, 0.3 mL), and was isolated as an off-white solid (40 mg, 98%). It was taken as such to the next step without further purification. LCMS: 502.2 [M+H].

[00235] Step 3: Synthesis of tert-butyl 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetate (72):

[00236] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-(piperidin-4-ylthio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 71 (41 mg, 0.082 mmol) and tert-butyl 2- bromoacetate, LI (15.95 mg, 0.082 mmol), and was isolated as a yellow solid (40 mg, Crude). LCMS: 616.2 [M+H],

[00237] Step 4: Synthesis of 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetic acid (73):

[00238] To a stirred solution of tert-butyl 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetate, 72 (41 mg, 0.067 mmol) in DCM (1 mL) at 0 °C, Trifluoroacetic acid (0.25 mL) was added and stirred at 25 °C for 16 h . After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to afford 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetic acid (30 mg, crude) as pale brown gum. LCMS: 560.0 [M+H].

[00239] Step 5: Synthesis of Example 18: rel-N-((5-((l-(2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00240] The title compound was prepared employing general procedure (GP3), starting from 2-(4-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)piperidin-l-yl)acetic acid, 73 (28 mg, 0.050 mmol) and rel-(5R,6S)-6-phenyl-5-(4- (piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (19.99 mg, 0.050 mmol), and was isolated as an off-white solid (3.5 mg, 7.4% yield). ^JH NMR (400 MHz, DMSO-d6) 5 = 9.13-9.18 (m, 2H), 8.19-8.21 (m, 1H), 7.45-7.82 (m, 7H), 7.25 (s, 1H), 7.14-7.16 (m, 3H), 6.83 (d, J = 6.40 Hz, 2H), 6.49-6.68 (m, 5H), 6.27 (d, J = 8.80 Hz, 2H), 4.67 (d, J = 5.60 Hz, 2H), 4.43-4.47 (m, 1H), 3.80-4.19 (m, 4H), 2.79-3.29 (m, 9H), 1.40-2.46 (m, 12H); LCMS: 941.3 [M+H], [00241] Example 19: rel-N-((5-(((l-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00242] Scheme X:

[00243] Step 1: Synthesis of rel-l-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)-4-(dimethoxymethyl)piperidine (74):

The title compound was synthesized using the general procedure, GP4 starting from rel-4- (( lR,2S)-6-(tert-butoxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate, 55 (55 mg, 0.076 mmol) and 4- (dimethoxymethyl)piperidine, Lil (18.24 mg, 0.115 mmol), and was obtained as pale brown solid (18 mg, 45.3% yield). LCMS: 514.2 [M+H],

[00244] Step 2: Synthesis of rel-l-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)piperidine-4-carbaldehyde (75):

[00245] To a stirred solution of rel-l-(4-((lR, 2S)-6-(tert-butoxy)-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)-4-(dimethoxymethyl)piperidine, 74 (30 mg, 0.058 mmol) in THF (1 mL) at 0 °C, aqueous H2SO4 (2M) (1.2 mL) was added and stirred at 70 °C for 1 h. After completion of the reaction (monitored by UPLC), the reaction mixture was cooled to 0 °C, neutralized with saturated NaHCOa to pH =7 and extracted with EtOAc (2 mL x 2). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and the solvents were concentrated under reduced pressure to obtain rel-l-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3,4-tctrahydronaphthalcn- l -yl)phcnyl)pipcridinc-4-carbaldchydc, 75 (20 mg, 83.3% yield) as yellow gum. LCMS: 412.1 [M+H].

[00246] Step 3: Synthesis of Example 19: General procedure for Reductive Amination (GP6):

[00247] To a stirred solution of corresponding amines (1.5 equiv.) in DCM, at 25 °C, Sodium acetate (4 equiv.) was added and stirred for 15 minutes. Then a solution of corresponding aldehyde, (1 equiv.) in THF (10 Vol) was added and stirred for 15 minutes. Then sodium triacetoxyborohydride (2.0 equiv.) was added and the reaction mixture was stirred for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered, washed with DCM (5 mL x 2) and the filtrate was concentrated under reduced vacuum to obtain the crude product. It was purified by preparative HPLC to yield the title product.

[00248] ^JH NMR (400 MHz, DMSO-d6) 5 = 9.09-9.16 (m, 2H), 8.19-8.21 (m, 1H), 7.45- 7.84 (m, 7H), 7.24 (s, 1H), 7.11-7.15 (m, 3H), 6.84 (d, J = 6.40 Hz, 2H), 6.47-6.65 (m, 5H), 6.20 (d, J = 8.40 Hz, 2H), 4.68 (d, J = 6.00 Hz, 2H), 4.12-4.13 (m, 1H), 3.36-3.50 (m, 4H), 2.61-3.00 (m, 5H), 1.07-2.11 (m, 18H); LCMS: 911.2 [M+H],

[00249] Examples 20 to 22:

[00250] Example 20: rel-N-((5-(((l-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00251] The title compound was prepared using the general procedure, GP6 starting from

N-((5-((azetidin-3-ylmethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-

(trifluoromethoxy)benzamide, 67 (10 mg, 0.021 mmol), rel-l-(4-((lR,2S)-6-hydroxy-2- phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenyl)piperidine-4-carbaldehyde, 75 (12.66 mg, 0.021 mmol), and was obtained as an off-white solid (1.8 mg, 9.9% yield). ^JH NMR (400 MHz, DMSO-d6) 5 = 9.09-9.16 (m, 2H), 8.19-8.21 (m, 1H), 7.45-7.84 (m, 7H), 7.24 (s, 1H), 7.11-7.15 (m, 3H), 6.83 (d, J = 6.40 Hz, 2H), 6.47-6.66 (m, 5H), 6.19 (d, J = 8.40 Hz, 2H), 4.68 (d, J = 6.00 Hz, 2H), 4.12-4.13 (m, 1H), 3.32-3.61 (m, 7H), 2.80-2.95 (m, 5H), 1.15-2.46 (m, 11H); LCMS: 883.4 [M+H],

[00252] Example 21: rel-N-((5-((l-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00253] The title compound was prepared using the general procedure, GP6 starting from N-((5-(piperidin-4-ylthio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-

(trifluoromethoxy)benzamide, 71 (18.28 mg, 0.036 mmol), rel-l-(4-((lR,2S)-6-hydroxy-2- phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenyl)piperidine-4-carbaldehyde, 75 (10 mg, 0.024 mmol), and was obtained as an off-white solid (6.5 mg, 29.5% yield). ¹ H NMR (400 MHz, DMSO-d6) 5 = 9.09-9.16 (m, 2H), 8.19-8.21 (m, 1H), 7.45-7.82 (m, 7H), 7.24 (s, 1H), 7.12-7.16 (m, 3H), 6.84 (d, J = 6.40 Hz, 2H), 6.47-6.66 (m, 5H), 6.21 (d, J = 8.40 Hz, 2H), 4.67 (d, J = 5.60 Hz, 2H), 4.13-4.14 (m, 2H), 2.72-3.53 (m, 7H), 1.24-2.34 (m, 17H); LCMS: 897.3 [M+H],

[00254] Example 22: rel-N-((5-((2-(l-((l-(4-((lR, 2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)ethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00255] The title compound was prepared using the general procedure, GP6 starting from

N-((5-((2-(piperidin-4-yl)ethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-

(trifluoromethoxy)benzamide (9.65 mg, 0.018 mmol), rel-l-(4-((lR,2S)-6-hydroxy-2-phenyl- l,2,3,4-tetrahydronaphthalen-l-yl)phenyl)piperidine-4-carbaldehyde, 75 (5 mg, 0.012 mmol), and was obtained as an off-white solid (2.7 mg, 23% yield). ^JH NMR (400 MHz, DMSO-d6) 5 = 9.10-9.14 (m, 2H), 8.19-8.21 (m, 1H), 7.45-7.82 (m, 7H), 7.24 (s, 1H), 7.11-7.24 (m, 3H), 6.84 (d, J = 6.80 Hz, 2H), 6.47-6.66 (m, 5H), 6.20 (d, J = 8.80 Hz, 2H), 4.68 (d, J = 5.60 Hz, 2H), 4.12-4.13 (m, 1H), 3.27-3.51 (m, 10H), 2.81-2.96 (m, 4H), 1.13-2.11 (m, 15H); LCMS: 925.2 [M+H],

[00256] Example 23: rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide

[00257] Scheme XI:

Example 23

[00258] Step 1: Synthesis of N-((5-(methylthio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (76):

[00259] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (250 mg, 0.598 mmol) and lodomethane (85 mg, 0.598 mmol), and was isolated as an off-white solid (220 mg, 85.3% yield). LCMS: 433.0 [M+H]. Step 2: Synthesis of N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (77):

[00260] To a stirred solution of N-((5-(methylthio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)- 2-(trifluoromethoxy)benzamide (200 mg, 0.463 mmol) in DCM (5 mL) at 0 °C, meta- Chloroperoxybenzoic acid (mCPBA) (77%, 349 mg, 0.925 mmol) was added and stirred for 10 min and at 25 °C for additional 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aqueous sodium sulfite solution (5 mL) at 0 °C and resulting mixture was stirred at 25 °C for 1 h. The layers were separated, and the organic layer was washed with brine (2 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to afford N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (200 mg, Crude) as an off-white solid. It was taken as such to the next step. LCMS: 465.1 [M+H].

[00261] Step 3: Synthesis of rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (Example 23):

[00262] A mixture of N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, 77 (50 mg, 0.054 mmol) and of rel-(5R,6S)-6-phenyl-5-(4- (piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (21.51 mg, 0.054 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 100 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was evaporated under reduced pressure to yield the crude product. It was purified by preparative HPLC using lOmM NH4HCO3 in water: ACN to afford rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)pyrazolo [ 1 ,5-c] quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (17 mg, 39.9% yield) as an off-white solid. ^JH NMR (400 MHz, DMSO-d6) 5 = 9.12-9.13 (m, 2H), 8.05-8.07 (m, 1H), 7.39-7.69 (m, 7H), 7.13-7.17 (m, 4H), 6.83-6.85 (m, 2H), 6.49-6.70 (m, 5H), 6.29 (d, J = 8.80 Hz, 2H), 4.67 (d, J = 5.60 Hz, 2H), 3.63-4.54 (m, 6H), 2.98-3.30 (m, 3H), 1.71-2.10 (m, 6H); LCMS: 784.2 [M+H],

[00263] Example 27: rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide

[00264] Scheme XII:

[00265] Step 1 : tert-butyl 4-(2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5- c]quinazolin-5-yl)piperazine-l-carboxylate (78) was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (18 mg, 0.039 mmol) and tertbutyl piperazine- 1 -carboxylate, L12 (7.22 mg, 0.039 mmol), was obtained as an off-white sold (5.8 mg, 26.2% yield). LCMS: 571.0 [M+H],

[00266] Step 2: N-((5-(piperazin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (79) was synthesized using the general procedure, GP2. [00267] Step 3: Synthesis of rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (Example 27):

[00268] The title compound was prepared using the general procedure, GP6 starting from N-((5-(piperazin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-

(trifluoromethoxy)benzamide, 79 (4.63 mg, 9.84 pmol), rel-l-(4-((lR,2S)-6-hydroxy-2- phenyl-l,2,3,4-tetrahydronaphthalen-l-yl)phenyl)piperidine-4-carbaldehyde, 75 (2.7 mg, 6.56 pmol), and was obtained as an off-white solid (0.75 mg, 12.9% yield). LCMS: 866.3 [M+H],

[00269] Example 33: rel-N-((5-((3-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-3-oxopropyl)thio)pyrazolo[ 1 ,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00270] The title compound was synthesized using the procedure described for Steps 1 to 3 of Example 1, starting from 3-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1,5- c]quinazolin-5-yl)thio)propanoic acid (22.10 mg, 0.045 mmol) and rel-(5R,6S)-6-phenyl-5- (4-(piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (18 mg, 0.045 mmol), was obtained as an off-white sold (13 mg, 32.9% yield). LCMS: 872.1 [M+H]. [00271] Example 35: rel-N-((5-((4-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)-2-oxoethyl)benzyl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00272] Step 1 : Synthesis of 2-(4-(((2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5- yl)thio)methyl)phenyl)acetic acid

[00273] To a stirred solution of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (25 mg, 0.060 mmol) in DMF (0.2 mL) at 25 °C, 2-(4- (bromomethyl)phenyl)acetic acid (13.69 mg, 0.060 mmol) and K2CO3 (12.39 mg, 0.090 mmol) were added and stirred for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was poured into crushed ice (5 g) and extracted with ethyl acetate (5mL x 2). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under redued pressure to get the title compound (25 mg, crude). LCMS: 568.0 [M+H],

[00274] Step 2: Synthesis of Example 35:

[00275] The title compound was synthesized using the procedure described for Steps 1 & 3 of Example 1, starting from 2-(4-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5- yl)thio)methyl)phenyl)acetic acid (26.6 mg, 0.047 mmol) and rel-(5R,6S)-6-phenyl-5-(4- (piperidin-4-yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (21 mg, 0.047 mmol), was obtained as an off-white sold (11 mg, 24.7% yield). LCMS: 948.2 [M+H].

[00276] Example 36: rel-N-((5-((S)-3-((2-(4-((lR*,2S*)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)pyrrolidin-l- yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00277] Step 1: N-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (100 mg, 0.140 mmol) and (S)-pyrrolidin-3- ylmethanol (14.16 mg, 0.140 mmol), was obtained as an off-white sold (34 mg, 50% yield). LCMS: 486.0 [M+H]

[00278] Step 2: Synthesis of (S)-N-((5-(3-formylpyrrolidin-l-yl)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-(trifluoromethoxy)benzamide:

[00279] Dess-martinperiodinane (89 mg, 0.210 mmol)was added to astirred mixture of (S)- N-((5-(3-(hydroxymethyl)pyrrolidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (34 mg, 0.070 mmin DCM (2 mL) at 0 °C and stirred at 25 °C for 7 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated sodium sulfite solution extracted with DCM (5 mL x 2), the combined organic layers were dried over sodium sulphate, filtered and concentrated to get the title proudct (26 mg, crude). It was taken as such to the next step without further purification. LCMS: 484.1 [M+H],

[00280] Step 3: Synthesis of Example 36:

[00281] The title compound was prepared using the general procedure, GP6 starting from (S)-N-((5-(3-formylpyrro lidin- l-yl)pyrazolo[ l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (13 mg, 0.027 mmol), rel-(5R,6S)-5-(4-(2,6- diazaspiro[3.4]octan-2-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (16.56 mg, 0.040 mmol), and was obtained as an off-white solid (1.2 mg, 4.87% yield). LCMS: 878.3 [M+H],

[00282] Example 37: rel-N-((5-((S)-3-((4-(4-((lR*,2S*)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-l-yl)methyl)pyrrolidin-l-yl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00283] The title compound was prepared using the general procedure, GP6 starting from (S)-N-((5-(3-formylpyrro lidin- l-yl)pyrazolo[ l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (13 mg, 0.027 mmol), rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 61 (4.33 mg, 0.011 mmol), and was obtained as an off-white solid (1.4 mg, 21.8% yield). LCMS: 851.3 [M+H],

[00284] Example 38: rel-N-((5-(4-((4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)methyl)piperidin-l-yl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00285] Step 1: N-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (27 mg, 0.058 mmol) and 4- (dimethoxymethyl)piperidine, Lil (9.26 mg, 0.058 mmol), was obtained as an off-white sold (22 mg, 70% yield). LCMS: 544.2 [M+H],

[00286] Step 2: N-((5-(4-formylpiperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide was synthesized using the procedure described for intermediate 75. LCMS: 498.2 [M+H],

[00287] Step 3: Synthesis of Example 38:

[00288] The title compound was prepared using the general procedure, GP6 starting from N-((5-(4-formylpiperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (25 mg, 0.050 mmol), rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4- yloxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 54 (30.1 mg, 0.075 mmol), and was obtained as an off-white solid (11 mg, 24.6% yield). LCMS: 881.3 [M+H].

[00289] Example 39: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazin-l-yl)-2-oxoethyl)thio)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-methoxybenzamide

[00290] Step 1: Synthesis of 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)acetic acid:

[00291] To a stirred solution of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- methoxybenzamide, E2 (100 mg, 0.274 mmol) in DMF (1 mL) at 25°C, tert-butyl 2- bromoacetate, LI (53.5 mg, 0.274 mmol) and K2CO3 (56.9 mg, 0.412 mmol) were added and stirred for 16 h. After completion of the reaction (moniotred by LCMS), the reaction mixture was poured into crushed ice (10 g) and extracted with EtOAc (5 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford the crude product. It was purifed by Silica gel (60-120 mesh) column chromatography using 70% EtOAc in petroleum ether to afford the title compound (108 mg, 78% yield) as pale yellow solid. LCMS: 479.3 [M+H].

[00292] Step 2: Synthesis of 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)acetic acid:

[00293] To a stirred solution of tert-butyl 2-((2-((2- methoxybenzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)acetate (108 mg, 0.226 mmol) in DCM (2 mL) at 0°C, Trifluoroacetic acid (0.5 mL) was added and stirred at 25 °C. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to afford the title compound (140 mg, Crude). It was taken as such to the next step. LCMS: 423.2 [M+H].

[00294] Step 3: Synthesis of Example 39: [00295] The title compound was synthesized using the procedure described for Step 3 of Example 1, starting from 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5-c]quinazolin-5- yl)thio)acetic acid (26.4 mg, 0.062 mmol) and rel-(5R,6S)-6-phenyl-5-(4-(piperazin-l- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (20 mg, 0.052 mmol), was obtained as an off- white sold (5 mg, 12.2% yield). LCMS: 789.3 [M+H],

[00296] Example 40: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazin-l-yl)-2-oxoethyl)(methyl)amino)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide

[00297] Step 1: Synthesis of N-methyl-N-(2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)glycine:

[00298] A mixture of N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (50 mg, 0.108 mmol) and tert-butyl methylglycinate (15.63 mg, 0.108 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 100 °C for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was evaporated under reduced pressure to get the crude product. It was purified by preparative HPLC to afford the title compound (6 mg, 10.52 % yield). LCMS: 530.2 [M+H].

[00299] Step 2: Synthesis of N-methyl-N-(2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)glycine:

[00300] A mixture of tert-butyl N-methyl-N-(2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)glycinate (6 mg, 0.011 mmol) and TFA (0.5 mL, 6.49 mmol) was subjected to microwave irradiation at 100 °C for 5 minutes. After completion of the reaction [monitored by LCMS], the reaction mixture was concentrated under reduced pressure to afford the title compound (6 mg, crude). LCMS: 474.1 [M+H],

[00301] Step 3:Synthesis of Example 40: [00302] The title compound was synthesized using the procedure described for Step 3 of Example 1, starting from N-methyl-N-(2-((2-

(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)glycine (6 mg, 0.013 mmol) and rel-(5R,6S)-6-phenyl-5-(4-(piperazin- l-yl)phenyl)-5,6,7,8-tetrahydronaphthalen- 2-ol (5.85 mg, 0.015 mmol), was obtained as an off-white sold (1.2 mg, 10.9% yield). LCMS:

840.3 [M+H],

[00303] The following additional examples were made according to the procedures described above using the appropriate starting materials.

Biological Assays

Cell based assays for E2-ER based degraders

1. ERa degradation with a UBE2K recruiter by Western blot

[00304] MCF-7 cells (0.8 million cells/well in 2 mL of Phenol red-free DMEM containing 5% charcoal stripped FBS) were seeded in 6 well plates and placed back in the cell culture incubator overnight. The next day, 3-fold serial dilutions of compounds were prepared in DMSO and added to the cells (final DMSO in each well is 0.5%). The cells were incubated with compound dilutions for 24 h and were harvested. Cell lysates were prepared in lx cell lysis buffer and 20 pg each of the lysates were used to estimate the levels of ERa by Western blot. Antibody used: ERa primary antibody, Thermofisher Scientific #MA5- 14501, 1:1000 dilution. 5% Nonfat dry milk powder in TBST was used for blocking. Representative data when treated with Examples 7 and 13 is shown in Tables 1 and 2, respectively. The data shows that significant degradation of ERa observed upon treatment with Examples 7 and 13. In addition, a dose dependent effect was observed. See FIG. 1.

Table 1. ERa Degradation when treated with Example 7

Table 2. ERa Degradation when treated with Example 13

Table 3. ERa Degradation when treated with additional examples

N/A = no degradation observed

2. DRCs of ERa degraders in T47D cells (Immunofluorescence)

[00305] T47D cells (20k cells/well in 25 |aL of Phenol red- free RPMI containing 5% charcoal stripped FBS) were seeded in 384 well plates and placed back in the cell culture incubator overnight. Next day, 3-fold serial dilutions of test compounds were prepared in DMSO in a 384 well polypropylene plate. 10 pL of each dilution was transferred to ECHO source plate (Labcyte #LP-0200). 125 nL of each compound dilution was stamped on the cells in 384 well plates using ECHO acoustic liquid dispenser. The plate was transferred to the cell culture incubator and incubated for 24 h. After compound treatment, the cells were fixed using 25 pL of 8% paraformaldehyde in PBS (Electron Microscopy Science #15710) for 30 mins at RT. Paraformaldehyde was removed, and the cells were permeabilized with 0.1% Triton in PBS for 30 mins at RT. Permeabilization solution was removed and the 50 pL of blocking buffer (Licor #927-60001) was added to the plate and placed on a rocker for 1 h at RT. Blocking buffer was removed and 25 pL diluted primary antibodies (1:500 dilution each of Thermofisher Scientific #MA5- 14501 and CST #13258 in blocking buffer) was added to the wells and the plate was incubated overnight at 4° C. The following day, primary antibody was removed, and wells were washed with 80 pL PBST three times. 25 pL of diluted secondary antibody solution (1:1000 of Abeam #abl50077 & 1:10000 dilution of Hoechst 33342 Thermofisher Scientific #H3570 in blocking buffer) was added and incubated at RT for 2 h. The secondary antibody was removed, and the wells were washed with 80 pL PBST three times. Finally, 50 pL of PBS was added to all the wells in the plate and imaging (lOx magnification) was done using Cytation5 imager (Biotechnie). For image analysis, cell nuclei were marked as primary mask and ERa levels were measured with in the determined primary mask area.

[00306] Examples 7, 12, 13, 20, 21, and 23 were tested as representative compounds.

[00307] As shown in FIG. 5-10, a significant dose dependent degradation of ERa in T47D cells was confirmed upon treatment with the compounds disclosed herein. Additional data is shown below in Table 4.

Table 4.

N/A = no observable activity

3. Rescue of Example 7 mediated ERa degradation by MG-132

[00308] T47D cells (0.5million cells/well in 2 mL of Phenol red-free RPMI containing 5% charcoal stripped FBS) were seeded in 6 well plates and placed back in the cell culture incubator overnight. The following day, cells were treated with 2 pM of MG 132 (final DMSO 0.1%) for 1 h. The cells were then treated with serial dilutions of test compounds prepared in DMSO (final DMSO in each well is 0.5%). Cells were harvested 6 h and 12 h post compound treatment. Cell lysates were prepared in lx cell lysis buffer and 0.5 pg/mL (pL) each of the lysates were used to estimate the levels of ERa using Protein Simple.

Antibody used: ERa primary antibody, Thermofisher Scientific #MA5- 14501, 1:30 dilution. Results are shown in Table 5 below.

Table 5. Comparitive ERa Degradation when treated with Example 7 in the presence and absence of MG 132

3. DRCs of ERalpha degraders in ESRI HiBiT MCF7 cells

[00309] ESRI HiBiT MCF7 cells (3k cells/well in 25p L of Phenolred-free DMEM containing 10% charcoal stripped FBS) were seeded in 384well plates and placed back in the cell culture incubator overnight. Next day, 3-fold serial dilutions of test compounds were prepared in DMSO in a 384well polypropylene plate. lOpL of each dilution was transferred to ECHO source plate (Labcyte #LP-0200). 125nL of each compound dilution was stamped on the cells in 384well plates using ECHO acoustic liquid dispenser. The plate was transferred to the cell culture incubator and incubated for 24hrs. After compound treatment, the plates were transferred to RT for 30 mins to equilibrate temperature. Fresh HiBiT reagent was prepared (1:50 of substrate & 1:100 LgBiT Protein in lysis buffer) and 25uL was added to all wells of the plates. The plates were then incubated at RT for 10 mins on a plate shaker and subsequently transferred to work bench and left alone for 10 mins. Luminescence in the wells was captured using Envision plate reader. Results are shown in Table 6 below.

Table 6.

[00310] While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[00311] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Claims

1. A compound having formula (I):

Tar (I); or a pharmaceutically acceptable salt thereof, wherein

Z¹ and Z² are each independently N or CH;

R¹ is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, or -NR^cR^d, wherein two available hydrogen atoms on said halo(Ci-C6)alkyl and halo(Ci-C6)alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, and halo(Ci-C6)alkoxy;

R² is CN, halo, OH, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, or halo(Ci-C6)alkoxy; or

R¹ and R², when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen-containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, and halo(Ci-C₆)alkyl;

R³ is hydrogen, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl;

Y is CH₂, -CHR^a, -CR^aR^b, S, or SO; p is 0 or 1 ;

R^a and R^b are each independently halo, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl; or R^a and R^b together with the carbon atom they are bound form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which is optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, (Ci-C₆)alkylOH, (Ci-C₆)alkylO(Ci-C₆)alkyl, and OH;

R^c and R^d are each independently hydrogen (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C₆)alkylO(Ci-C₆)alkyl, halo(Ci-C₆)alkylO(Ci-C₆)alkyl, (Ci-C₆)alkyl-O-halo(Ci-C₆)alkyl, halo(Ci-C6)alkyl-O-halo(Ci-C6)alkyl, or (Ci-CejalkylOH; or R^c and R^d together with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo; ring A is aromatic;

X, X¹, and X² are each, as valency permits, independently selected from -CR⁷, N, O, and S;

R⁷ is hydrogen or (Ci-Ce)alkyl; the dotted line in ring B represents a single or double bond; when the dotted line in ring B is a single bond,

R⁵ is selected from hydrogen, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, -S(Ci-C6)alkyl, -SH, OH, (C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, and -NR^eR^f, wherein said (C3-C6)cycloalkyl and 4- to 7-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci- Ce)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo;

R^e and R^f are each independently hydrogen, (Ci-C4)alkyl, (Ci-C₄)alkylNH(Ci-C₄)alkyl, (Ci-C₄)alkylN[(Ci-C₄)alkyl]₂, (Ci-C₄)alkylO(Ci-C₄)alkyl;

R⁶ is hydrogen or (Ci-C6)alkyl; when the dotted line in ring B is a double bond,

R⁵ is absent and R⁶ is absent; d, d¹, d² and d³ are each independently selected from CR⁸ and N;

R⁸ is halogen, hydrogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, CN, or OH;

W is absent, NH, -N(Ci-C6)alkyl, O, or S;

L is a linker; and

Tar is a target protein binding moiety which binds estrogen receptor.

2. The compound of Claim 1, wherein the compound is of Formula (II):

Tar (II); or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Z¹ and Z² are each CH.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein p is 0.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy, or -NR^cR^d; and R^c and R^d together with the nitrogen atom they are bound form a 5- to 6- membered heterocyclyl optionally substituted with 1 to 3 halo.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-C3)alkyl, halo(Ci-C3)alkyl, halo(Ci-C3)alkoxy, (Ci-C3)alkoxy, or -NR^cR^d; and R^c and R^d together with the nitrogen atom they are bound form a 5- to 6- membered nitrogen containing heterocyclyl optionally substituted with 1 to 3 halo.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R¹ is OCF3, OCHF2, OCH3, CH3, pyrrolidinyl, or piperidinyl, wherein said pyrrolidinyl or piperidinyl is optionally substituted with 1 to 3 halo.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is N.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X¹ is CH or N.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein X² is CH, N, O, or S.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein

X is N, X¹ is N, and X² is CH;

X is N, X¹ is N, and X² is N;

X is N, X¹ is CH, and X² is S; or

X is N, X¹ is CH, and X² is O.

14. The compound of any one of Claims 1 to 13, wherein the compound is of Formula (III), (IV), (V), or (VI):

or a pharmaceutically acceptable salt thereof.

15. The compound of any one of Claims 1 to 14, wherein the compound is of Formula

(VII), (VIII), (IX), (X), or (XI):

or a pharmaceutically acceptable salt thereof.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen or halo, preferably, hydrogen.

17. The compound of any one of Claims 1 to 13 and 16, or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen, and R⁶ is selected from hydrogen and (Ci-C4)alkyl (e.g., methyl).

18. The compound of Claim 1, wherein the compound is of the Formula (XII):

or a pharmaceutically acceptable salt thereof.

19. The compound of Claim 1, wherein the compound is of the Formula (III’) or (X’ :)

or a pharmaceutically acceptable salt thereof, wherein

R¹ is (Ci-C3)alkyl or halo(Ci-C3)alkyl, preferably OCF3 or OCHF2; and each is R⁸ is independently hydrogen or halo, preferably, hydrogen.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is absent, S, NH, or -N(Ci-C3)alkyl.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein W is S.

22. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein W is NH or -NCH3, preferably NH.

23. The compound of Claim 21 or 22, or a pharmaceutically acceptable salt thereof, wherein linker L comprises an optionally substituted straight or branched alkyl group which is optionally interrupted by one to three heteroatoms selected from O, N, and S.

24. The compound of any one of Claims 21 to 23, or a pharmaceutically acceptable salt thereof, wherein linker L is a straight or branched alkyl group substituted with one to two oxo groups (=0).

25. The compound of any one of Claims 21 to 24, or a pharmaceutically acceptable salt thereof, wherein linker L is a straight or branched alkyl group which is interrupted by one or two ring moiety selected from phenyl and 4- to 10-membered nitrogen containing heterocyclyl.

26. The compound of Claim 21 or 22, or a pharmaceutically acceptable salt thereof, wherein linker L is of the following structure:

wherein the asterisk (*) denotes the point of attachment to variable W; e is 0, 1, 2, or 3;

Ai is absent, -C(O)-4- to 6-membered nitrogen containing monocyclic heterocyclyl, phenyl, and 4- to 6-membered nitrogen containing monocyclic heterocyclyl; j is 0, 1, or 2;

A2 is absent, -C(O)-4- to 10-membered nitrogen containing heterocyclyl, or 4- to 6- membered nitrogen containing monocyclic heterocyclyl; provided when Ai, A2 and j are absent, e is not 0.

27. The compound of Claim 26, or a pharmaceutically acceptable salt thereof, wherein e is 1 or 2;

Ai is absent; j is 0;

A2 is -C(O)-4- to 6-membered nitrogen containing monocyclic heterocyclyl or -C(O)- 7- to 9-membered nitrogen containing spiro heterocyclyl.

28. The compound of Claim 27, or a pharmaceutically acceptable salt thereof, wherein A2 is -C(O)-6-membered nitrogen containing monocyclic heterocyclyl.

29. The compound of Claim 26, or a pharmaceutically acceptable salt thereof, wherein e is 1 or 2;

Ai is 4- to 6-membered nitrogen containing monocyclic heterocyclyl; j is 1;

A2 is -C(O)-6-membered nitrogen containing monocyclic heterocyclyl or 6-membered nitrogen containing monocyclic heterocyclyl;

30. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is absent; and Linker L is of the following structure:

wherein ring N 1 is 4- to 6-membered nitrogen containing monocyclic heterocyclyl, and is connected with the tricylic ring moiety through a nitrogen ring atom; ring N2 is absent or 4- to 10-membered nitrogen containing heterocyclyl; and

Li is absent, -CH2-, or O.

31. The compound of Claim 30, or a pharmaceutically acceptable salt thereof, wherein ring N2 is absent.

32. The compound of Claim 30, or a pharmaceutically acceptable salt thereof, wherein ring N2 is 5- to 6-membered nitrogen containing monocyclic heterocyclyl or 7- to 9- membered nitrogen containing spiro heterocyclyl, and Li is -CH₂-.

33. The compound of any one of Claims 30 to 32, or a pharmaceutically acceptable salt thereof, wherein ring N1 is piperidinyl or piperazinyl.

34. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein L is X1-A1-X2-A2-X3, wherein

XI is absent, (CH₂)_V, or (CH2)_vC(0);

Al is phenyl, 4- to 10-membered nitrogen containing heterocyclyl, or 5- to 6- membered heteroaryl;

X2 is absent, (CH₂)_g, C(O), or (CH₂)_gC(O);

A2 is absent or is a 4- to 10-membered nitrogen containing heterocyclyl or 5- to 6- membered heteroaryl;

X2 is absent, (CH₂)f, C(O), or (CH₂)fC(O); and v, g, and f are each independently 1 or 2.

35. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein L is selected from

asterisk (*) denotes the point of attachment to variable W.

36. The compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Tar is a target protein binding moiety which binds estrogen receptor alpha (ERa).

37. The compound of any one of Claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Tar is of the structure:

wherein the wavy bond denotes the point of attachment to linker L.

38. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Tar is of the structure

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein Tar is of the structure

40. The compound of Claim 1, wherein the compound is selected from any one of Compounds 1 to 134, or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising the compound of any one of Claim 1 to 40, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

42. A method of treating a disease responsive to degradation of estrogen receptor comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 40.

43. The method of Claim 42, wherein the target protein is estrogen receptor is estrogen receptor alpha (ERa).

44. The method of Claim 42 or 43, wherein the disease is selected from a cancer.