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WO2020051260A1 - Ligands de composés de dégradation sélectifs de récepteurs des androgènes (sard) et procédés d'utilisation associés - Google Patents

Ligands de composés de dégradation sélectifs de récepteurs des androgènes (sard) et procédés d'utilisation associés Download PDF

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WO2020051260A1
WO2020051260A1 PCT/US2019/049618 US2019049618W WO2020051260A1 WO 2020051260 A1 WO2020051260 A1 WO 2020051260A1 US 2019049618 W US2019049618 W US 2019049618W WO 2020051260 A1 WO2020051260 A1 WO 2020051260A1
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optionally substituted
compound
another embodiment
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aryl
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Ramesh Narayanan
Duane D. Miller
Thamarai PONNUSAMY
Dong-Jin Hwang
Yali He
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University of Tennessee Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to novel indole, indazole, benzimidazole, benzotriazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds including A-ring heterocyles, pharmaceutical compositions and uses thereof in treating hyperproliferations of the prostate including pre-malignancies and benign prostatic hypertrophy, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, other AR-expressing cancers, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy’s disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels (through degradation) and/or activity (through inhibition) of any androgen receptor including androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) poly
  • PCa Prostate cancer
  • ADT Androgen-deprivation therapy
  • LHRH luteinizing hormone releasing hormone
  • LHRH antagonists LHRH antagonists
  • CRPC castration-resistant prostate cancer
  • mCRPC metastatic CRPC
  • CRPC patients with CRPC have a median survival of 12-18 months. Though castration-resistant, CRPC is still dependent on the androgen receptor (AR) signaling axis for continued growth.
  • AR androgen receptor
  • AR-SV AR splice variants
  • LBD ligand binding domain
  • a critical barrier to progress in treating CRPC is that AR signaling inhibitors such as enzalutamide, flutamide, bicalutamide, and abiraterone, acting through the LBD, fail to inhibit growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV.
  • NTD N-terminal domain
  • Recent high-impact clinical trials with enzalutamide and abiraterone in CRPC patients demonstrated that 0% of AR-V7 (the predominant AR-SV) expressing patients responded to either of the treatments, indicating the requirement for next generation AR antagonists that target AR-SVs.
  • a significant number of CRPC patients are becoming refractory to abiraterone or enzalutamide, emphasizing the need for next generation AR antagonists.
  • the NTD is biophysically characterized to interact with the SARDs of this invention via fluorescence polarization (FP), surface plasmon resonance (SPR), and NMR (Example 12).
  • Biochemical evidence also supports the SARDs of this invention binding to a domain other than the LBD.
  • SARDs of this invention degrade AR-SV in D567es cells lacking the expression of any AR containing the LBD (Example 7).
  • the R- and S-isomers of the SARDs of this invention possess equipotent SARD activity despite demonstrated differences in the binding and inhibition of androgen-dependent transactivation via the LBD (Example 7, Figure 42D).
  • the report of SARD activity mediated through the NTD of AR is an unprecedented observation that may help explanation the prodigious AR antagonism profiles seen with the SARDs of this invention.
  • Molecules that degrade the AR prevent any inadvertent AR activation through growth factors or signaling pathways, or promiscuous ligand-dependent AR activation.
  • molecules that inhibit the constitutive activation of AR-SVs are extremely important to provide extended benefit to CRPC patients.
  • This invention describes novel AR antagonists with unique pharmacology that strongly (high potency and efficacy) and selectively bind AR (better than known antagonists), antagonize AR, and degrade AR full length (AR-FL) and AR-SV.
  • Selective androgen receptor degrader (SARD) compounds possess dual degradation and AR-SV inhibitory functions and hence are distinct from any available CRPC therapeutics. These novel selective androgen receptor degrader (SARD) compounds inhibit the growth of PCa cells and tumors that are dependent on AR-FL and AR-SV for proliferation.
  • SARDs have the potential to evolve as new therapeutics to treat CRPCs that are untreatable with any other antagonists.
  • This unique property of degrading AR-SV has extremely important health consequences for prostate cancer. Till date only one synthetic molecule (EPI-001) and some marine natural products such as sinkotamides and glycerol ether Napthetenone B, are reported to bind to AR- NTD and inhibit AR function and PCa cell growth, albeit at lower affinity and it has an inability to degrad
  • antiandrogens such as enzalutamide, bicalutamide and flutamide and androgen deprivation therapies (ADT) were approved for use in prostate cancer
  • ADT androgen deprivation therapies
  • antiandrogens could also be used in a variety of other hormonal dependent and hormone independent cancers.
  • antiandrogens have been tested in breast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7), non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity syndrome (PAIS) associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J.
  • Use of a more potent antiandrogen such as a SARD in these cancers may treat the progression of these and other cancers.
  • SARD treatment such as breast cancer, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.
  • PAIS partial androgen insensitivity syndromes
  • NSCLC non-small cell lung cancer
  • gastric cancer colon cancer
  • perianal adenoma or central nervous system cancer.
  • shortened may augment AR transactivation (i.e., hyperandrogenism). It has been found that shortened polyQ polymorphisms are more common in people with alopecia, hirsutism, and acne. Classic antiandrogens are undesirable for these purposes because they are ineffective through dermal dosing and their long-term systemic use raises the risks of untoward sexual effects such as gynecomastia and impotence.
  • T and DHT endogeneous androgens testosterone
  • DHT dihydrotestosterone
  • An emerging concept is the topical application of a SARD to destroy the AR local to the affected areas of the skin or other tissue(s) without exerting any systemic antiandrogenism.
  • a SARD that does not penetrate the skin or is rapidly metabolized would be preferrable.
  • Androgenic alopecia occurs in ⁇ 50% of Caucasian males by midlife and up to 90% by 80 years old.
  • Minoxidil a topical vasodilator
  • finasteride a systemic 5-alpha reductase type II inhibitor
  • Minoxidil a topical vasodilator
  • finasteride a systemic 5-alpha reductase type II inhibitor
  • ALS Amyotrophic lateral sclerosis
  • ALS patients Transgenic animals of ALS were shown to survive longer upon castration and reduction in AR levels compared to castration + nandrolone (agonist) supplementation. Castration reduces the AR level, which may be the reason for extended survival.
  • Uterine fibroids are common reproductive-age benign tumors that contribute to severe morbidity and infertility. Cumulative incidence is 4 times higher in Africian-Americans compared to Caucasians and constitutes a major health disparity challenge. Fibroids are the leading indication for hysterectomy and their management averages $21 billion annually in the US. No long term minimally invasive therapies exist. Thus, promising drug therapies, with novel chemistry and pharmacological approaches are needed to improve clinical efficacy. Androgens promote uterine proliferation. Higher testosterone levels increase the risk of uterine fibroids. Treatment of uterine fibroids with SARDs would help prevent or treat uterine fibroids.
  • An abdominal aortic aneurysm is an enlarged area in the lower part of the aorta, the major blood vessel that supplies blood to the body.
  • the aorta about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body's main supplier of blood, a ruptured abdominal aortic aneurysm can cause life-threatening bleeding.
  • treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery can be planned if it's necessary.
  • X-linked spinal-bulbar muscular atrophy (SBMA– also known as Kennedy's disease) is a muscular atrophy that arises from a defect in the androgen receptor gene on the X chromosome. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases. The mutation results in a protracted polyglutamine tract added to the N- termin
  • polyQ AR by endogeneous androgens results in unfolding and nuclear translocation of the mutant androgen receptor. These steps are required for pathogenesis and result in partial loss of the transactivation function (i.e., an androgen insensitivity) and a poorly understood neuromuscular degeneration.
  • endogeneous androgens testosterone and DHT
  • Selective androgen receptor degraders such as those reported herein bind to and degrade a variety of androgen receptors (full length, splice variant, antiandrogen resistance mutants, and are likely to degrade polyQ AR polymorphisms as well), indicating that they are promising leads for treatment of SBMA.
  • indole indazole, benzimidazole, benzotriazole, indoline, quinolone, isoquinoline, and carbazole SARDs that bind to LBD and an alternate binding and degradation domain (BDD; located outside the LBD in the NTD), antagonize AR, and degrade AR thereby blocking ligand-dependent and ligand-independent AR activities.
  • BDD alternate binding and degradation domain
  • One embodiment of the invention encompasses a selective androgen receptor degrader (SARD) compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, wherein said SARD compound is represented by the structure of formula XVII:
  • X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted; wherein at least one of X 1 , X 2 , X 3 , X 4 , or X 5 is nitrogen;
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloa
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, keto, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the compound of formula XVII is represented by the structure formula XVII(1):
  • X 1 , X 2 , X 3 , X 4 , X 5 , W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , T, Q, Y, Z, R 1 , R 2 , R 3 , R 4 , n and m are as defined for structure XVII.
  • the compound of formula XVII is represented by the structure formula XVII(2):
  • X1, X2, X3, X4, X5, W1, W2, W3, W4, W5, W6, T, Q, Y, Z, R1, R2, R3, R4, n and m are as defined for structure XVII.
  • W1, W2, W3, W4, W5, and W6 are CH.
  • W2 is N and W1, W3, W4, W5, and W6 are CH.
  • W3 is N and W1, W2, W4, W5, and W 6 are CH.
  • W 1 is N and W 2 , W 3 , W 4 , W 5 , W 6 are CH.
  • only one of X1, X2, X3, X4, and X5 is N.
  • X1 or X5 is N.
  • X2 or X4 is N.
  • X3 is N.
  • X4 is N and X 1 , X 2 , X 3 , and X 5 are CH.
  • Q is H, NO 2 , COR, alkyl, alkoxy, aryl, CN, CF 3 , F, Cl, Br or I.
  • Z is CN.
  • Y is Cl or CF 3 .
  • the compound is represented by the structure of formula XIX:
  • X 1 , X 2 , X 3 , X 4 , X 5 , T, Q, Y, Z, R 1 , R 2 , R 3 , R 4 , n and m are as defined for structure XVII.
  • the compound of formula XVII(1) is represented by the structure of the following compounds: .
  • One embodiment of the invention encompasses the SARD compound having at least one of the following properties: binds to the AR through an alternate binding and degradation domain (BDD), e.g.
  • BDD alternate binding and degradation domain
  • AR-SV AR ligand binding domain
  • AR-FL AR-full length
  • AR-FL inhibitory activity i.e., is an AR-SV antagonist
  • AR-FL inhibitory activity i.e., is an AR-FL antagonist
  • compositions comprising a SARD compound according to this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated for topical use.
  • the topical pharmaceutical composition may be a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soaps or bars, emulsion, mousse, aerosol, or shampoo.
  • the invention encompasses a method of treating prostate cancer (PCa) or increasing survival in a male subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound of this invention.
  • the prostate cancer includes, but is not limited to, advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
  • Another embodiment of the invention encompasses the method further comprising administering androgen deprivation therapy.
  • the method may treat a prostate or other cancer that is resistant to treatment with known androgen receptor antagonist(s) or ADT.
  • the method may treat enzalutamide resistant prostate cancer.
  • the method may treat apalutamide resistant prostate cancer. In another embodiment, the method may treat abiraterone resistant prostate cancer. Yet another embodiment of the invention encompasses a method of treating prostate or other AR antagonist resistant cancer with a SARD compound of the invention wherein the a
  • abiraterone ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.
  • the prostate cancer is AR antagonist resistant prostate cancer which overexpresses the glucocorticoid receptor (GR).
  • GR glucocorticoid receptor
  • activation of the GR provides support for growth of the prostate cancer and/or confers antiandrogen resistance to the prostate cancer.
  • SARDs of this invention can be used to treat GR-dependent or GR- overexpressing prostate cancers, whether antiandrogen resistant or not.
  • Yet another embodiment of the invention encompasses a method of treating prostate or other cancers using a SARD compound of the invention wherein the other cancers are selected from breast cancer such as triple negative breast cancer (TNBC), testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.
  • TNBC triple negative breast cancer
  • TNBC triple negative breast cancer
  • the invention encompasses a method of reducing the levels of AR-splice variants in a subject comprising administering to the subject a therapeutically effective amount of a compound of this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the method may comprise further reducing the levels of AR- full length in the subject.
  • Another embodiment of the invention encompasses a method of treating Kennedy’s disease in a subject comprising administering to the subject a compound of this invention.
  • Yet another embodiment of the invention encompasses a method of: (a) treating acne in a subject, e.g., acne vulgaris; (b) decreasing sebum production in a subject, e.g., treats sehorrhea, seborrheic dermatitis, or acne; (c) treating hirsutism in a subject, e.g., female facial hair; (d) treating alopecia in a subject, e.g., androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring, or alopecia induced by stress; (e) treating a hormonal condition in female, e.g., precocious puberty, early puberty, dysmenorrhea, amen
  • One embodiment of the invention encompasses methods of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering a compound according to this invention.
  • the method may inhibit, degrade, or both the function of the polyglutamine (polyQ) AR polymorphs (polyQ-AR).
  • the polyQ-AR may be a short polyQ polymorph or a long polyQ polymorph.
  • the method further treats dermal disease.
  • the polyQ-AR is a long polyQ polymorph
  • the method further treats Kennedy’s disease.
  • Another embodiment of the invention encompasses methods of treating amyotrophic lateral sclerosis (ALS) in a subject by administering a therapeutically effective amount of the compound of the invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
  • ALS amyotrophic lateral sclerosis
  • Another embodiment of the invention encompasses methods of treating abdominal aortic aneurysm (AAA) in a subject by administering a therapeutically effective amount of the compound of the invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
  • AAA abdominal aortic aneurysm
  • Yet another embodiment of the invention encompasses methods of treating uterine fibroids in a subject by administering a therapeutically effective amount of the compound of this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.
  • the invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of a hormonal condition in a male in need thereof, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound of the invention.
  • a selective androgen receptor degrader (SARD) compound of the invention comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound of the invention.
  • precocious puberty in a male alterations in cognition and mood, depression, hair loss, hyperandrogenic dermatological disorders, precancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers.
  • Figures 1A-1C present inhibition of AR transactivation for the SARD compounds: ( Figure 1A) 14, 18, and 20; ( Figure 1B) 11 and 12; and ( Figure 1C) 11, 23 and 27; of this invention. (Example 5)
  • Figure 2A demonstrates degradation in LNCaP cells using SARD compounds of this invention (11 and 20): LNCaP cells were plated in 6 well plates at 1 million cells/well. The cells were maintained in serum free conditions for 3 days. The cells were treated as indicated in the figure, harvested, protein extracted, and Western blotted for AR.
  • Figure 2B presents the effect of AR antagonists and SARD 11 on LNCaP cell growth: LNCaP cells were plated in 96 well plates at 10,000 cells/well in RPMI + 1% csFBS without phenol red. Cells were treated as indicated in the figure in combination with 0.1 nM R1881 for 6 days with medium change on day 3. At the end of 6 days, the cells were fixed and stained with sulphorhodamine blue stain. (Example 7)
  • Figure 3 presents AR-V7 degradation (PC3-AR-V7 cells) using SARD compounds of this invention (11, 12 and 20).
  • PC-3 prostate cancer cells were serum stably transfected with a lentivirus construct for AR-V7. Once the stable cells were selected, the cells were plated in 6 well plates at 1 million cells/well. The cells were treated as indicated in the figure ( ⁇ M) and Western blot performed for AR and actin.
  • Figure 5 presents SARD degradation of AR in LNCaP cells using 11. (Example 7)
  • Figures 6A-6C present SARD degradation of AR-FL and AR-V7 in 22RV-1 cells using ( Figure 6A) ASC-J9, ( Figure 6B) ARN-509 and ( Figure 6C) 11. (Example 7)
  • Figures 7A-7D present that 11 inhibits transactivation of AR-NTD-DBD-hinge (A/BCD) AR construct which lacks the LBD.
  • AR A/BCD increases GRE-LUC reporter activity.
  • AR A/BCD construct that lacks the ligand binding domain or empty vector was transfected into HEK- 293 cells along with GRE-LUC and CMV-renilla LUC. Forty eight hours after transfection cells were harvested and luciferase assay performed.
  • Figure 7B AR A/BCD activity was inhibited by 11.
  • the A/BCD AR construct that lacks the ligand binding domain (LBD) was transfected along with GRE- LUC and CMV-LUC.
  • Figures 8A-8B present data comparing compounds 11, 12, and 14 with galeterone, EPI- 001, and enzalutamide in AR transactivation studies.
  • Figure 8A 11, 12, and 14, galeterone, EPI- 001, and enzalutamide
  • Figure 8B 11, galeterone, and enzaluatamide.
  • SARDs of this invention more potently inhibited (AR-FL) transactivation.
  • Figures 9A-9D demonstrate that 11 inhibited tumor growth of an aggressive prostate cancer (22RV-1) that expresses an AR splice variant (growth driven by AR-V7).
  • Figure 9A 11 significantly reduced tumor volume and
  • Figure 9B tumor weight in a 22RV-1 xenograft tumor study, whereas AR antagonist enzalutamide did not have any effect compared to vehicle.
  • FIG. 9C shows tumor expressed levels of AR-FL and AR-V7 were decreased by 11 but not enzalutamide, demonstrating that in vivo activity correlated with AR degradation in the tumors; and
  • Figure 9D demonstrates an in vivo antiandrogenic tone in gene expression as the serum PSA in these animals was decreased by 11 but not enzalutamide in this 22RV-1 xenograft study.
  • Figure 11 presents degradation in LNCaP cells using 27, 20, 12, 23 and 32.
  • LNCaP cells were plated in 6 well plates at 1 million cells/well. The cells were maintained in serum free conditions for 3 days. The cells were treated as indicated in the figure, harvested, protein extracted, and Western blotted for AR. SARDs demonstrated selective degradation of AR (i.e., SARD activity) in the nM range, i.e., at concentrations comparable to their antagonist IC50 values.
  • LNCaP cells are known to express the AR mutant T877A, demonstrating the ability to degrade resistance conferring mutant androgen receptors. (Example 7)
  • FIG. 12 presents 22RV-1 Western blots: 22RV-1 cells were plated in 6 well plates at 1- 1.5 million cells/well in growth medium (RPMI + 10% FBS). Next day, medium was changed and treated with vehicle or a dose response of compounds 20, 24 and 30. After overnight treatment (12- 16 hrs), cells were washed in ice cold PBS and harvested by scrapping in 1 mL PBS. Cells were pelleted, protein extracted, quantified using BCA assay, and equal quantity of protein was fractionated on an SDS-PAGE. The proteins were transferred to nylon membrane and Western blotted with AR antibody (N20 from SCBT) and actin antibody.
  • AR antibody N20 from SCBT
  • Figure 14 presents degradation in LNCaP cells using a dose-response of 12 or ARN-509. Using the methods described in the legend for Figure 11 (LNCaP), SARD activity for 12 was compared to known SARD ARN-509. 12 demonstrated activity in the nM range (100-1000 nM) whereas ARN-509 only had activity at 10,000 nM. (Example 7) [0059]
  • Figure 16 presents degradation in LNCaP cells using 70 and 73. Using the methods described in the legend for Figure 11 (LNCaP), SARD activity for 70 and 73 was demonstrated at concentrations as low as 100 nM. This demonstrates that benzimidazoles of this invention also demonstrate potent SARD activity. (Example 7)
  • Figures 17A-17C present biophysical data that suggests that SARDs bind to the N- terminal domain of the AR (in addition to the LBD in the C-terminus).
  • Figure 17A A dose-dependent shift in the fluorescence intensity, i.e., fluorescent quenching, was observed with 11 when incubated with AR AF-1.
  • Figure 17B The fluorescence shoulder observed at 307 nm, which corresponds to tyrosine residues in the AF-1, is shifted by 11. The overall fluorescence is also markedly altered by 11.
  • Figure 17C Data shown was plotted as difference in fluorescence between control and 11 treated samples (fluorescence in the absence of compound– fluorescence in the presence of compound), a dose dependent increase was observed in the presence of 11. Cumulatively, these data suggest a direct interaction between 11 and AR AF-1.
  • Example 12 Example 12
  • Figure 18 demonstrates degradation in LNCaP cells using a SARD compound of this invention (100).
  • LNCaP cells were plated in 6 well plates at 1 million cells/well. The cells were maintained in serum free conditions for 3 days. The cells were treated as indicated in the figure, harvested, protein extracted, and Western blotted for AR. (Example 8)
  • Figure 19 demonstrates via Western blot as described above for Figure 12, that 100, 102, and 130 degraded AR-FL and AR-SV in 22RV-1 cells.100, 102, and 130 were capable of degrading full length androgen receptor (AR-FL) and truncated AR (AR-SV) in 22RV-1 cells, suggesting that SARDs of this invention may be able to overcome AR-V7 dependent prostate cancers.
  • Figure 20 presents degradation in 22RV-1 cells as described above for Figure 12, using 130 vs. galeterone. 130 was compared to galeterone (a clinical lead SARD). 130 demonstrated SARD activity in 22RV-1 (growth dependent on AR-SV, an AR variant lacking a LBD) cells which was comparable to galeterone. (Example 8)
  • Figure 21 presents degradation in LNCaP cells using 135 and 102. Using the methods described in the legend for Figure 11, SARD activities for 135 and 102 were demonstrated. These compo
  • Example 8 such as these may be useful in advanced prostate cancer and/or CRPC.
  • Figure 22 presents degradation in LNCaP cells and 22RV-1 cells using 103 and 104.
  • 103 and 104 demonstrated SARD activity in both LNCaP (mutant AR harboring T877A mutation) and 22RV- 1 (growth dependent on AR-SV lacking a LBD) cells.
  • Figure 23 presents degradation in 22RV-1 cells using 130. Using the methods described in the legend for Figure 12, compound 130 demonstrated SARD activity at least at the 10 ⁇ M concentration. (Example 8)
  • Figure 24 presents degradation in 22RV-1 cells using 134 and 130. Using the methods described in the legend for Figure 12, compounds 134 and 130 each demonstrated SARD activity at least at the 10 ⁇ M concentration. (Example 8)
  • Figure 25 presents degradation in LNCaP cells using 101, 105, 106, 107 and 108. Using the methods for Figure 11 above, 101, 105, 106, 107 and 108 each demonstrated the ability to degrade the AR in the nM range. (Example 8)
  • Figure 26 depicts degradation in LNCaP cells using 200 and ARN-509. LNCaP cells treated with 200 were lysed and subjected to Western blot analysis, as described above. (Example 13 and 14)
  • Figure 27 depicts degradation in 22RV-1 cells using 200 and 201.
  • 22RV-1 cells treated with 200 or 201 were lysed and subjected to Western blot analysis, as described above. (Example 13 and 14)
  • Figure 28 depicts degradation in 22RV-1 cells using 201.
  • 22RV-1 cells treated with 201 were lysed and subjected to Western blot analysis, as described above. (Example 13 and 14)
  • Figures 29A-29O depict transactivation data, binding, and AR-FL and AR-SV degradation for SARDs compounds of this invention.
  • Figures 30A-30D present Hershberger assay: Mice (6-7 weeks old) were treated with vehicle or indicated SARDs (100 mg/kg/day twice daily) for 14 days orally. Animals were sacrificed, and seminal vesicles weights were recorded and represented. Results: ( Figure 30A) and ( Figure 30D) SARDs demonstrated various degrees of decreased seminal vesicles (S.V.) weight, ( Figure 30B) increased in body weight (B.Wt.), and (Figure 30C) decreased prostate weight. This behavior is consistent with an in vivo antiandrogenic effect exerted by SARDs of this invention.
  • Figure 31 demonstrates that 103 slowed prostate cancer tumor growth in patient-derived xenografts (PDX) despite low levels in the plasma.
  • SARD 103 selectively accumulated in tumor.
  • NSG mice were implanted with patient-derived prostate cancer xenografts (PDX). Animals were treated for 14 days and tumor volumes were measured twice weekly, as shown in the graph. Animals were sacrificed, 103 was extracted from the serum and tumor and measured using LC-MS/MS metho
  • Example 16 Example 16
  • Figure 32 presents data in a mouse xenograft model treated with 103 and 36.
  • the % change in tumor volume is presented using 103 and 36.
  • LNCaP cells were implanted (5 million cells/mouse) in NSG mice. Once tumors reach 70-200 mm 3 , animals were randomized and treated with SARDs (100 mg/kg/ twice daily). Tumor volume was measured at regular intervals and represented as % change from baseline. 36 significantly inhibited tumor growth.
  • Figures 33A-33D present binding (Ki), transactivation (IC50), half-life in liver microsomes (MLM; t 1/2 (minutes)) and full-length AR degradation via Western blot of the androgen receptor with AD1 cells treated with: (Figure 33A) 76, ( Figure 33B) 75, ( Figure 33C) 96, and ( Figure 33D) 97. (Example 7)
  • Figure 34 presents the effect of known AR antagonists compared to SARD 96 on the AR-dependent gene FKBP5.
  • 96 suppressed the AR-responsive gene FKBP5 to a comparable extent as did enzalutamide, galeterone, and ARN-509, demonstrating that 96 is a potent AR antagonist in vitro. (Example 10)
  • Figure 35 presents the effect of known AR antagonists compared to SARD 96 on the AR-dependent gene PSA.
  • 96 suppressed the AR–responsive gene PSA to a comparable extent as did enzalutamide and greater than ARN-509.
  • galeterone potently suppressed at 100 nM but the effect was not dose responsive, reversing at higher doses.
  • Figure 36 presents the effect of known AR antagonists compared to SRB- LNCaP cell growth: LNCaP cells were plated in 96 well plates at 10,000 cells/well in RPMI + 1% csFBS without phenol red. Cells were treated as indicated in the figure in combination with 0.1 nM R1881 for 6 days with medium change on day 3. At the end of 6 days, the cells were fixed and stained with sulphorhodamine blue (SRB) stain. 96 demonstrated a robust and dose-dependent anti- proliferative effect whereas enzalutamide and ARN-509 only partially suppressed growth and galeterone did not exhibit dose-dependent effects. (Example 10).
  • SRB sulphorhodamine blue
  • FIGS 37A-37E depict inhibition of AR function by 11.
  • AR ligand binding assay was performed with GST-tagged purified human AR-LBD protein producing a Ki of 78.06 nM (data not shown).
  • 11 potently inhibits AR transactivation.
  • AR transactivation was performed by transfecting human AR cDNA, GRE-LUC, and CMV-renilla LUC into HEK-293 cells. Cells were treated 24 hrs after t
  • luciferase assay was performed 48 hrs after transfection. Values provided are IC50 ( Figure 37A).11, but not enzalutamide, comparably inhibits transactivation of wildtype and LBD-mutant AR. Transactivation assay with 11 or enzalutamide was performed with wildtype AR or AR carrying commonly known LBD mutants ( Figure 37B).11 cross-reacts with progesterone receptor (PR), but minimally with mineralocorticoid receptor (MR) or glucocorticoid receptor (GR). Transactivation was performed by transfecting human AR, PR, GR, or MR cDNA, GRE-LUC, and CMV-renilla LUC into HEK-293 cells.
  • PR progesterone receptor
  • MR mineralocorticoid receptor
  • GR glucocorticoid receptor
  • Figures 38A-38C 11 degrades AR and splice variant ARs.11 degrades AR full length in AD1 cells (left panel), AR-V567es in D567es cells (middle panel), and AR-SV in LNCaP-95 cells (lower panel).
  • AD1 cells expressing AR were maintained in charcoal-stripped serum containing medium, while D567es cells expressing AR-v567es and LNCaP-95 cells expressing AR and AR-SV were maintained in growth medium for 2 days. Cells were treated for 24 hrs, protein extracted, and Western blot for AR and actin was performed (Figure 38A).
  • Figures 40A-40E 11 inhibits the expression of AR-target genes and proliferation of prostate cancer cells.11 potently inhibits the expression of AR-target genes in LNCaP cells. LNCaP cells were maintained in charcoal stripped serum containing medium for two days and treated with vehicle or indicated compounds (11 or enzalutamide with dose of 1, 10, 100, 1000, and 10,000 nM) in the presence of 0.1 nM R1881 for 24 hours. RNA was isolated and expression of PSA (left) or FKBP5 (right) was quantified and normalized to GAPDH by realtime PCR (Figure 40A).11 inhibits expression of a subset of genes induced by AR-V7 in PC3 cells.
  • RNA was isolated ⁇ 16 hrs after treatment and RNA-Sequencing was performed in Ion Torrent next-generation sequencer.
  • Heatmap shows the top 50 genes differentially expressed in PC3-AR-V7 vehicle-treated but not in 11-treated cells compared to PC3 vehicle-treated cells.
  • Bar graph on the right shows representative genes that were differentially expressed in RNA (Figure 40B).11 inhibits AR-target gene expression in 22RV1 cells.
  • 22RV1 cells were plated in charcoal stripped serum, treated with vehicle (right-most bars of each chart) or indicated compounds (11 or enzalutamide with 10, 100, 1000, and 10,000 nM) for 3 days and the expression of AR-target genes was measured by realtime PCR (Figure 40C).
  • SARDs are potent inhibitors of prostate cancer cell proliferation.
  • LNCaP cells maintained in charcoal stripped serum containing medium were treated with vehicle or indicated compounds (1 pM-10 mM) in the presence of 0.1 nM R1881. Cells were re-treated three days later and the cell viability was measured after 6 days of treatment using SRB assay. Castration-resistant prosta
  • FIGS 41A-41B 11 inhibits transactivation of AD1 and D567es AR and cell proliferation. 11 inhibits AD1-AR-transactivation and cell growth. AR transactivation was performed by transfecting human GRE-LUC and CMV-renilla LUC into AD-1 cells. Cells were treated with vehicle, 0.1 nM R1881 alone or in combination with 10 mM 11 or enzalutamide 24 hrs after transfection and luciferase assay was performed 48 hrs after transfection (data not shown). AD1 cells maintained in charcoal stripped serum containing medium were treated with 10 mM UT-155 or enzalutamide in the presence of 0.1 nM R1881.
  • Figures 42A-42D 11 inhibits nuclear translocation and DNA binding of the AR. 11 inhibits recruitment of AR to the androgen response element (ARE).
  • Figure 42A 11 inhibits nuclear translocation of enzalutamide-resistant AR (EnzR AR).
  • EnzR LNCaP cells were maintained in charcoal-stripped serum (CSS) containing medium and treated with 10 mM 11 in the pr
  • Figure 43 The R-isomer of 11 (11R) was weaker in AR transactivation, but not in degradation. Structures of S- and R-isomers of 11 is shown. Transactivation IC50 and Western blot for the AR are shown in the figure.
  • FIG 44 Increasing concentrations of R1881 decreased enzalutamide’s, but not 11’s, potential to inhibit LNCaP cell proliferation.
  • LNCaP cells were plated in charcoal stripped serum containing medium and treated with a dose response of 11 (left panel) or enzalutamide (right panel) in combination with 0.1 or 10 nM R1881. Medium was changed and the cells were re-treated after 3 days. At the end of 6 days of treatment, cells were fixed and SRB assay, a measure of cell viability, was performed.
  • Figure 45 11 inhibited androgen-dependent and castration-resistant PCa growth in vivo.
  • 11 inhibited growth of patient-derived xenograft, Pr-3001. Pr- 3001 was implanted as 1 mm 3 fragment subcutaneously in castrated NSG mice (n 8-10/group) and the study was performed as described above. Tumor volume was measured thrice weekly. At sacrifice tumor weights were recorded (not shown). * significance from vehicle-treated mice at p ⁇ 0.05.
  • Figures 46A-46D 11 binds to the AR Activation Function Domain 1 (AF-1) between amino acids 244 and 360. Nuclear magnetic resonance (NMR) studies confirm the binding to AR- AF-1.
  • NMR Nuclear magnetic resonance
  • Figure 47 11 binds to AR AF-1 domain based on surface plasmon resonance. Biocore assay was performed with purified activation function domain 1 (AF-1) of the androgen receptor (AR) in the presence of 11.
  • AF-1 activation function domain 1
  • AR androgen receptor
  • Figure 48 11 is a full antagonist with no agonist activity in transactivation studies.
  • Figures 49A and 49B Degradation of FL AR and AR SV by selected SARDs.
  • LNCaP Figure 49A
  • 22RV1 Figure 49B
  • cells were plated in full-serum containing medium. Medium was changed to 1% charcoal-stripped serum containing medium and maintained in this medium for 2 days. Medium was changed again and the cells were treated with 0.1 nM R1881 (agonist) and either vehicle or a titration of SARD as indicated in the figure. Twenty-four hours after treatment, cells were harvested, protein extracted, and the proteins were blotted with AR-N20 antibody. Blots were stripped and re-probed with an actin antibody. AR- full length androgen receptor; AR-SV- androgen receptor splice variant.
  • Figures 50A and 50B SARDs antagonized transactivation of and degraded an enzalutamide resistance (Enz-R) conferring escape mutant AR.
  • Figure 50A AR with phenylalanine 876 mutated to leucine (F876L), GRE-LUC, and CMV-renilla LUC were transfected in COS cells. Cells were treated 24 h after transfection with 0.1 nM R1881 (agonist) and a dose response of antagonists. Luciferase assay was performed 48 h after transfection.
  • FIG. 50B Enzalutamide- resistant LNCaP cells (MR49F) were maintained in charcoal-stripped, serum containing medium for 2 d and treated with 0.1 nM R1881 (agonist) and a titration of the SARD as indicated in the figure.
  • Figure 51 Enzalutamide-resistant LNCaP (MR49F) cellular anti-proliferation: Enzalutamide-resistant LNCaP (MR49F) cells were plated in 1% charcoal-stripped, serum-containing maxim
  • Figures 52A and 52B SARDs inhibit androgen-dependent organs in mice and rats and inhibit growth of enzalutamide-resistant prostate cancer.
  • Androgens act in cells by binding to the AR, a member of the steroid receptor superfamily of transcription factors.
  • PCa prostate cancer
  • Treatment with AR antagonists such as enzalutamide, flutamide, bicalutamide or hydroxyflutamide to disrupt receptor activation has been successfully used in the past to reduce PCa growth.
  • All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repr
  • AR-SV AR splice variants
  • LBD ligand binding domain
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which inhibit the growth of prostate cancer (PCa) cells and tumors that are dependent on AR full length (AR-FL) including pathogenic and resistance-conferring mutation and/or wildtype, and/or AR splice variants (AR-SV) for proliferation.
  • SARD selective androgen receptor degrader
  • a“selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of causing degradation of a variety of pathogenic mutant variant AR’s and wildtype AR and hence are capable of exerting anti-androgenism is a wide variety of pathogenic altered cellular environments found in the disease states embodied in this invention.
  • the SARD is orally active.
  • the SARD is applied topically to the site of action.
  • a“selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist that is capable of inhibiting the growth of PCa cells and tumors that are dependent on AR-full length (AR-FL) and/or AR splice variants (AR-SV) for proliferation.
  • AR-FL AR-full length
  • AR-SV AR splice variants
  • the SARD compound binds to the N-terminal domain (NTD) of the AR. In another embodiment, the SARD compound binds to an alternate binding and degradation domain (BDD) of the AR. In another embodiment, the SARD compound binds both to the AR ligand binding domain (LBD) and to an alternate binding and degradation domain (BDD). In another embodiment, the SARD compound binds both to the N-terminal domain (NTD) and to the ligand binding domain (LBD) of the AR. In another embodiment, the SARD compound is capable of inhibiting growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV. In another embodiment, the SARD compound inhibits the AR through binding to a domain that is distinct from the AR LBD.
  • the SARD compound is a strong (i.e., highly potent and highly efficacious) selective androgen receptor antagonist, which antagonizes the AR more robustly than other known AR antagonists (e.g., enzalutamide, flutamide, bicalutamide and abiraterone).
  • the SARD compound is a selective androgen receptor antagonist, which targets AR- SVs, which cannot be inhibited by conventional antagonists.
  • the SARD compound exhibits AR-splice variant (AR-SV) degradation activity.
  • the SARD compound further exhibits AR-full length (AR-FL) degradation activity.
  • the SARD compound exhibits AR-splice variant (AR-SV) inhibitory activity (i.e., is an AR-SV antagonist). In another embodiment, the SARD compound further exhibits AR-full length (AR-FL) inhibitory activity (i.e., is an AR-FL antagonist). In another embodiment, the SARD compound possesses dual AR-SV degradation and AR-SV inhibitory functions. In another embodiment, the SARD compound further possesses dual AR-FL degradation and AR-FL inhibitory functions. In another embodiment, the SARD compound is a selective androgen receptor antagonist, which targets AR-SVs. In another embodiment, the SARD compound further targets AR-FLs. In another embodiment, the SARD compound inhibits the constitutive activation of AR-SVs.
  • AR-SV AR-splice variant
  • AR-FL AR-full length
  • the SARD compound possesses dual AR-SV degradation and AR-SV inhibitory functions. In another embodiment, the SARD compound further possesses dual AR-FL degradation and AR-FL inhibitory functions. In another embodiment, the SARD compound is
  • the SARD compound further inhibits the constitutive activation of AR-FLs.
  • the SARD compound is a selective androgen receptor antagonist, which degrades AR- full length (AR-FL) and AR splice variants (AR-SV).
  • AR-FL AR- full length
  • AR-SV AR splice variants
  • the SARD compound degrades the AR through binding to a domain that is distinct from the AR LBD.
  • the SARD compound possesses dual degradation and AR-SV inhibitory functions, that are distinct from any available CRPC therapeutics.
  • the SARD compound inhibits the re-activation of the AR by alternate mechanisms such as: intracrine androgen synthesis, expres
  • the SARD compound inhibits re-activated androgen receptors present in pathogenically altered cellular environments.
  • AR-splice variants are: AR-V7 and ARv567es (a.k.a. AR-V12).
  • AR mutations conferring antiandrogen resistance are: W741L, T877A, H874Y, T877S, or F876L.
  • AR-V7 is a splice variant of AR that lacks the LBD. It is constitutively active and has been demonstrated to be responsible for aggressive PCa and resistance to endocrine therapy.
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which bind to the AR through an alternate binding and degradation domain (BDD).
  • BDD alternate binding and degradation domain
  • the SARD further binds the AR ligand binding domain (LBD).
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which exhibit AR-splice variant (AR-SV) inhibitory activity (i.e., is an AR-SV antagonist).
  • novel selective androgen receptor degrader (SARD) compounds further exhibit AR-full length (AR-FL) inhibitory activity (i.e., is an AR-FL antagonist).
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which exhibit AR-splice variant (AR-SV) degradation activity.
  • the novel selective androgen receptor degrader (SARD) compounds further exhibit AR- full length (AR-FL) degradation activity.
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which possess dual AR-SV degradation and AR-SV inhibitory functions.
  • the SARDs further possess dual AR-FL degradation and AR-FL inhibitory functions.
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, which possess dual AR-SV and AR-FL degradation, and AR-SV and AR-FL inhibitory functions.
  • this invention is directed to novel selective androgen receptor degrader (SARD) compounds, for use in treating CRPC that cannot be treated with any other antagonist.
  • SARD selective androgen receptor degrader
  • this invention is directed to selective androgen receptor degrader (SARD) compounds, for use in treating CRPC, by degrading AR-SVs.
  • SARD selective androgen receptor degrader
  • novel SARD compounds according to this invention maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists.
  • the novel SARD compounds according to this invention maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists.
  • the SARD compounds elicit antagonistic activity within an altered cellular environment in which LBD- targeted agents are not effective. In another embodiment, the SARD compounds elicit antagonistic activity within an altered cellular environment in which NTD-dependent AR activity is constitutively active.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVII, XVIIa, XVIIb, XVIIc, or XVIId:
  • SARD selective androgen receptor degrader
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • X1, X2, X3, X4, and X5 are CH.
  • X1 or X5 is N.
  • at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is N.
  • X 2 or X 4 is N.
  • X3 is N.
  • X1 is N and X2, X3, X4, and X5 are CH.
  • X2 is N and X1, X3, X4, and X5 are CH.
  • X3 is N and X1, X2, X 4 , and X 5 are CH.
  • two of X 1 , X 2 , X 3 , X 4 , and X 5 are N.
  • X 1 and X 3 are both N.
  • X 1 and X 5 are both N.
  • X 2 and X 4 are both N.
  • X4 is N and X1, X2, X3, and X5 are CH.
  • W1, W2, W3, W4, W5, and W6 of formula XVII or XVIIa are each independently CH.
  • W 1 is N.
  • W 2 is N.
  • W1 is CH.
  • W2 is CH.
  • W3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W 1 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 2 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 3 is N and W1, W2, W4, W5, and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W 5 is N and W 1 , W 2 , W 3 , W 4 , and W 6 are CH.
  • W 6 is N and W 1 , W 2 , W 3 , W 4 , and W 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVII(1), XVIIa(1), XVIIb(1), XVIIc(1), or XVIId(1):
  • SARD selective androgen receptor degrader
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N;
  • T is OH, OR, -NHCOCH3, NHCOR or ;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 and R 4 are independently selected from hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted
  • substituted arylalkyl C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • X1, X2, X3, X4, and X5 are CH. In one embodiment, at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is N. In one embodiment, X 1 or X 5 is N. In one embodiment, X 2 or X 4 is N. In one embodiment, X3 is N. In one embodiment, X1 is N and X2, X3, X4, and X5 are CH. In one embodiment, X2 is N and X1, X3, X4, and X5 are CH. In one embodiment, X3 is N and X1, X2, X 4 , and X 5 are CH.
  • two of X 1 , X 2 , X 3 , X 4 , and X 5 are N.
  • X1 and X3 are both N.
  • X1 and X5 are both N.
  • X2 and X4 are both N.
  • X4 is N and X1, X2, X3, and X5 are CH.
  • W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 of formula XVII(1) or XVIIa(1) are each independently CH.
  • W 1 is N.
  • W 2 is N.
  • W1 is CH.
  • W2 is CH.
  • W3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W 1 is N and W 2 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W2 is N and W1, W3, W4, W5, and W6 are CH.
  • W3 is N and W1, W2, W4, W5, and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W 5 is N and W 1 , W 2 , W 3 , W 4 , and W 6 are CH.
  • W 6 is N and W 1 , W 2 , W 3 , W 4 , and W 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVII(2), XVIIa(2), XVIIb(2), XVIIc(2), or XVIId(2):
  • SARD selective androgen receptor degrader
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 and R 4 are independently selected from hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted pheny
  • substituted arylalkyl C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • X1, X2, X3, X4, and X5 are CH.
  • X1 or X5 is N.
  • at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is N.
  • X 2 or X 4 is N.
  • X3 is N.
  • X1 is N and X2, X3, X4, and X5 are CH.
  • X2 is N and X1, X3, X4, and X5 are CH.
  • X3 is N and X1, X2, X 4 , and X 5 are CH.
  • two of X 1 , X 2 , X 3 , X 4 , and X 5 are N.
  • X1 and X3 are both N.
  • X1 and X5 are both N.
  • X2 and X4 are both N.
  • X4 is N and X1, X2, X3, and X5 are CH.
  • W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 of formula XVII or XVIIa are each independently CH.
  • W 1 is N.
  • W 2 is N.
  • W1 is CH.
  • W2 is CH.
  • W3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W 1 is N and W 2 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 2 is N and W1, W3, W4, W5, and W6 are CH.
  • W3 is N and W1, W2, W4, W5, and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W 5 is N and W 1 , W 2 , W 3 , W 4 , and W 6 are CH.
  • W 6 is N and W 1 , W 2 , W 3 , W 4 , and W 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVIII:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CH, wherein if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCS
  • R 4 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, keto, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVIII(1):
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH 3 , NHCOR or Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 4 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, keto, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3; and or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XIX:
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl; substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XX:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CH, wherein if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH 3 , NHCOR or ;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched hetero
  • cycloalkyl optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R 4 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, keto, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula I, Ia, Ib, Ic, or Id:
  • W 1 and W 2 are each independently selected from N or CH;
  • W3, W4, W5 and W6 are each independently selected from CH or N; wherein if any one of W1, W2, W3, W4, W5, and W6 is CH, then the H is optionally replaced with R 4 , Q or R 3 in the respective position, and if any one of W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12- haloalkyl, -SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCO
  • R 3 and R 4 are independently selected from hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • W1, W2, W3, W4, W5, and W6 of formula I or Ia are each independently CH.
  • W 1 is N.
  • W 2 is N.
  • W 1 is CH.
  • W 2 is CH.
  • W 3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W1 is N and W1, W3, W4, W5, and W6 are CH.
  • W 2 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 3 is N and W1, W2, W4, W5, and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W5 is N and W1, W2, W3, W4, and W6 are CH.
  • W 6 is N and W 1 , W 2 , W 3 , W 4 , and W 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula I(1), Ia(1), Ib(1), Ic(1), or Id(1):
  • SARD selective androgen receptor degrader
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N; wherein if any one of W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is CH, then the H is optionally replaced with R4, Q or R3 in the respective position, and if any one of W1, W2, W3, W4, W5, and W6 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 - haloalkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R3 and R4 are independently selected from hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, option
  • NHCOOR OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • W1, W2, W3, W4, W5, and W6 of formula I(1) or Ia(1) are each independently CH.
  • W1 is N.
  • W2 is N.
  • W 1 is CH.
  • W 2 is CH.
  • W 3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W1 is N and W1, W3, W4, W5, and W6 are CH.
  • W 2 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 3 is N and W1, W2, W4, W5, and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W5 is N and W1, W2, W3, W4, and W6 are CH.
  • W 6 is N and W 1 , W 2 , W 3 , W 4 , and W 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula I(2), Ia(2), Ib(2), Ic(2), or Id(2):
  • SARD selective androgen receptor degrader
  • W1 and W2 are each independently selected from N or CH;
  • W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N; wherein if any one of W1, W2, W3, W4, W5, and W6 is CH, then the H is optionally replaced with R4, Q or R3 in the respective position, and if any one of W1, W2, W3, W4, W5, and W6 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12- haloalkyl, -SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R3 and R4 are independently selected from hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • W1, W2, W3, W4, W5, and W6 of formula I or Ia are each independently CH.
  • W 1 is N.
  • W 2 is N.
  • W 1 is CH.
  • W 2 is CH.
  • W 3 is N.
  • W4 is N.
  • W5 is N.
  • W6 is N.
  • W 1 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 2 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.
  • W 3 is N and W 1 , W 2 , W 4 , W 5 , and W6 are CH.
  • W4 is N and W1, W2, W3, W5, and W6 are CH.
  • W5 is N and W1, W2, W3, W4, and W6 are CH.
  • W6 is N and W1, W 2 , W 3 , W 4 , and W 5 are CH.
  • T is OH, OR, -NHCOCH 3 , NHCOR or
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R3 i
  • optionally substituted linear or branched alkyl optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula II(1):
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R4 is h
  • substituted linear or branched alkyl optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula III:
  • T is OH, OR, -NHCOCH 3 , NHCOR or ;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, al
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCO
  • n is an integer between 1-3;
  • n is an integer between 1-3
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula IV:
  • T is OH, OR, -NHCOCH3, NHCOR or
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substi
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXI:
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • X1, X2, X3, X4, and X5 are CH.
  • X1 or X5 is N.
  • at least one of X1, X2, X3, X4, and X5 is N.
  • X2 or X4 is N.
  • X 3 is N.
  • X 1 is N and X 2 , X 3 , X 4 , and X 5 are CH.
  • X 2 is N and X 1 , X 3 , X 4 , and X 5 are CH.
  • X 3 is N and X 1 , X 2 , X4, and X5 are CH.
  • X1, X2, X3, X4, and X5 are N.
  • X1 and X3 are both N.
  • X1 and X5 are both N.
  • X2 and X4 are both N.
  • X 4 is N and X 1 , X 2 , X 3 , and X 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXI(1):
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • X1, X2, X3, X4, and X5 are CH.
  • X1 or X5 is N.
  • at least one of X1, X2, X3, X4, and X5 is N.
  • X2 or X4 is N.
  • X 3 is N.
  • X 1 is N and X 2 , X 3 , X 4 , and X 5 are CH.
  • X 2 is N and X 1 , X 3 , X 4 , and X 5 are CH.
  • X 3 is N and X 1 , X 2 , X4, and X5 are CH.
  • X1, X2, X3, X4, and X5 are N.
  • X1 and X3 are both N.
  • X1 and X5 are both N.
  • X2 and X4 are both N.
  • X 4 is N and X 1 , X 2 , X 3 , and X 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXI(2):
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCS
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXII:
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXIII:
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl; substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, N
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CH, wherein if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCS
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXVa, XXVb, XXVc, XXVd, XXVe, XXVf, XXVg or XXVh:
  • SARD selective androgen receptor degrader
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; and or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXVI:
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; l is 0 or 1; and
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXVIIa, XXVIIb, XXVIIc, XXVIId, XXVIIe, XXVIIf, XXVIIg, or XXVIIh:
  • SARD selective androgen receptor degrader
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, option
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; and
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXVIII:
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, option
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXIXa, XXIXb, XXIXc, XXIXd, XXIXe, XXIXf, XXIXg, or XXIXh:
  • SARD selective androgen receptor degrader
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXX:
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCO
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXX(1):
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CH, wherein if any one of X 1 , X 2 , X 3 , X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl; substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3,
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXX(2):
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CH, wherein if any one of X 1 , X 2 , X 3 , X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloa
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXXI:
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; m is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XXXIIa, XXXIIb, XXXIIa(1), XXXIIb(1), XXXIIa(2), XXXIIb(2):
  • SARD selective androgen receptor degrader
  • X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X 4 , and X 5 is CH, then the H is optionally replaced with R 2 , Y, or Z in the respective position, and if any one of X 1 , X 2 , X 3 , X 4 , and X 5 is not CH, then the respective position is unsubstituted;
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, - SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula V:
  • T is OH, OR, -NHCOCH3, NHCOR or Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R3 is h
  • substituted linear or branched alkyl optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula V(1):
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalky
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula V(2):
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is h
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, CO
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula VI:
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH,
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR
  • optionally substituted heterocycloalkyl optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula VIII:
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, al
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula IXa, IXb, IXc, IXd, IXe, IXf, IXg or IXh:
  • SARD selective androgen receptor degrader
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy
  • n is an integer between 1-3;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, CO
  • n is an integer between 1-3;
  • l is 0 or 1
  • k 0, 1 or 2;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH,
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XII:
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2,
  • l is 0 or 1
  • k 0, 1 or 2;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XIV:
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; n is
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XIV(1):
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF3, F, I, Br, Cl, CN or C(R)3;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O-C 1 -C 12 -alkyl, O-C 1 -C 12 -haloalkyl, -SO 2 -aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R3 is h
  • substituted linear or branched alkyl optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XIV(2):
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy
  • R 4 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XV:
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN; R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, al
  • NHCOCH3, NHCOCF3, NHCOR NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • this invention is directed to a selective androgen receptor degrader (SARD) compound represented by the structure of formula XVIa, XVIb, XVIa(1), XVIb(1), XVIa(2), XVIb(2):
  • SARD selective androgen receptor degrader
  • T is OH, OR, -NHCOCH3, or NHCOR;
  • Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
  • R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O-C1-C12-alkyl, O-C1-C12-haloalkyl, -SO2-aryl, -SO 2 -phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
  • Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN; R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , SH, COOH, COOR, alkoxy
  • n is an integer between 1-3;
  • n is an integer between 1-3;
  • Q of compound of any one of the formulas as described herein is hydrogen.
  • Q is halogen.
  • Q is F.
  • Q is Br.
  • Q is Cl.
  • Q is I.
  • Q is CN.
  • Q is NO2.
  • Q is optionally substituted linear or branched alkyl. In one em
  • R 3 of compound of any one of the formulas as described herein is hydrogen. In one embodiment, R3 is halogen. In one embodiment, R3 is Cl. In one embodiment, R3 is Br. In one embodiment, R 3 is I. In one embodiment, R 3 is CN. In one embodiment, R 3 is COOH. In one embodiment, R 3 is NO 2 . In one embodiment, R 3 is CF 3 .
  • R4 of compound of any one of the fomulas as described herein is hydrogen. In one embodiment, R4 of compound of any one of the formulas as described herein is halogen. In one embodiment, R 4 of compound of any one of the formulas as described herein is F. In one embodiment, R4 of compound of any one of the formulas as described herein is Cl. In one embodiment, R4 of compound of any one of the formulas as described herein is Br. In one embodiment, R 4 of compound of any one of the formulas as described herein is I. In one embodiment, R4 of compound of any one of the formulas as described herein is CN. In one embodiment, R4 of compound of any one of the formulas as described herein is COOH.
  • R4 of compound of any one of the formulas as described herein is NO 2 . In one embodiment, R 4 of compound of any one of the formulas as described herein is CF 3 . In one embodiment, R 4 of compound of any one of the formulas as described herein is methyl. In one embodiment, R4 of compound of any one of the formulas as described herein is COOR.
  • Z of compound of any one of the formulas as described herein is CN.
  • Z is NO2.
  • Z is COOH.
  • Z is COR.
  • Z is NHCOR.
  • Z is CONHR.
  • Z is in the para position.
  • Y of compound of any one of the formulas as described herein is CF 3 .
  • Y is F.
  • Y is I.
  • Y is Br.
  • Y is Cl.
  • Y is CN.
  • Y is C(R) 3 .
  • Y is in the meta position.
  • Z of compound of any one of the formulas as described herein is CN and Y is CF3. In another embodiment, Z is NO2 and Y is CF3. In another embodiment, Z is NO2 and Y is halogen. In another embodiment, Z is CN and Y is halogen. In another embodiment, Z of compo
  • R 2 of compound of any one of the formulas as described herein is hydrogen. In one embodiment, R 2 is halogen. In one embodiment, R 2 is CN. In one embodiment, R 2 is NO2. In one embodiment, R2 is C1-C12-alkyl. In one embodiment, R2 is aryl. In one embodiment, R 2 is phenyl. In one embodiment, R 2 is COOH. In one embodiment, R 2 is COOR. In one embodiment, R 2 is COR. In one embodiment, R 2 is NHCOR. In one embodiment, R 2 is CONHR. In one embodiment, R2 is OH. In one embodiment, R2 is OR. In one embodiment, R2 is SH. In one embodiment, R2 is SR.
  • R2 is NH2. In one embodiment, R2 is NHR. In one embodiment, R 2 is N(R) 2 . In one embodiment, R 2 is C 1 -C 12 -haloalkyl. In one embodiment, R 2 is O- C1-C12-alkyl. In one embodiment, R2 is O-C1-C12-haloalkyl. In one embodiment, R2 is -SO2-aryl. In one embodiment, R2 is -SO2-phenyl. In one embodiment, R2 is -CO-aryl. In one embodiment, R2 is arylalkyl. In one embodiment, R 2 is benzyl. In one embodiment, R 2 is C 3 -C 7 -cycloalkyl.
  • R1 of compound of any one of the formulas as described herein is CH3. In another embodiment, R1 is CF3.
  • T of compound of any one of the formulas as described herein is OH.
  • T is OCH3. In another embodiment,
  • R of compound of any one of the formulas as described herein is alkyl.
  • R is haloalkyl.
  • R is dihaloalkyl.
  • R is trihaloalkyl.
  • R is CH 2 F.
  • R is CHF 2 .
  • R is CF3.
  • R is CF2CF3.
  • R is aryl.
  • R is phenyl.
  • R is F.
  • R is another embodiment, R
  • R is hydroxyl (OH).
  • m of compound of any one of the formulas as described herein is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n of compound of any one of the formulas as described herein is 1. In one embodiment, n is 2. In one embodiment, m is 3.
  • X 1 , X 2 , X 3 , X 4 , and X 5 are CH.
  • X 1 or X 5 is N.
  • at least one of X1, X2, X3, X4, and X5 is N.
  • X2 or X4 is N.
  • X3 is N.
  • X1 is N and X2, X3, X4, and X5 are CH.
  • X 2 is N and X 1 , X 3 , X 4 , and X 5 are CH.
  • X 3 is N and X 1 , X 2 , X4, and X5 are CH.
  • X1, X2, X3, X4, and X5 are N.
  • X1 and X3 are both N.
  • X1 and X5 are both N.
  • X2 and X4 are both N.
  • X 4 is N and X 1 , X 2 , X 3 , and X 5 are CH.
  • this invention is directed to a selective androgen receptor degrader (SARD) compound selected from the following structures: Indoles:
  • heterocycloalkyl refers, in one embodiment, to a cycloalkyl structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring.
  • the heterocycloalkyl is a 3-12 membered ring.
  • the heterocycloalkyl is a 6 membered ring.
  • the heterocycloalkyl is a 5- another embodiment, the heterocycloalkyl group may be unsubstituted or substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
  • the heterocycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring.
  • the heterocyclic ring is a saturated ring.
  • the heterocyclic ring is an unsaturated ring.
  • the heterocycloalkyl is piperidine, tetrahydrofuran, morpholine, pyrrolidine, or piperazine.
  • cycloalkyl refers to a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms.
  • a cycloalkyl group can have one or more carbon-carbon double bonds in the ring so long as the ring is not rendered aromatic by their presence.
  • cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C 3 -C 7 ) cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or substituted by one or two substituents.
  • the cycloalkyl group is a monocyclic ring or bicyclic ring.
  • alkyl refers, in one embodiment, to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups.
  • the alkyl group has 1-12 carbons.
  • the alkyl group has 1-7 carbons.
  • the alkyl group has 1-6 carbons.
  • the alkyl group has 1-4 carbons.
  • the cyclic alkyl group has 3-8 carbons.
  • the cyclic alkyl group has 3-12 carbons.
  • the branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons.
  • the branched alkyl is an alkyl substituted by haloalkyl side chains of 1 to 5 carbons.
  • the alkyl group may be unsubstituted or substituted by a halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
  • heteroalkyl refers to any alkyl as defined above wherein one or more of the carbons are being replaced by oxygen, nitrogen, sulfur, phosphorous or combination thereof.
  • An“arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined above.
  • An example of an arylalkyl group is a benzyl group.
  • alkenyl group may have one double bond, two double bonds, three double bonds, etc. In another embodiment, the alkenyl group has 2-12 carbons. In another embodiment, the alkenyl group has 2-6 carbons. In another embodiment, the alkenyl group has 2-4 carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl, etc.
  • the alkenyl group may be unsubstituted or substituted by a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
  • An“aryl” group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
  • Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
  • the aryl group is a 4-8 membered ring.
  • the aryl group is a 4-12 membered ring(s).
  • the aryl group is a 6 membered ring.
  • the aryl group is a 5 membered ring.
  • the aryl group is 2-4 fused ring system.
  • the aryl is phenyl.
  • A“haloalkyl” group refers, in another embodiment, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I.
  • A“hydroxyl” group refers, in another embodiment, to an OH group. It is understood by a person skilled in the art that when T, Q, R2 R3 or R4 in the compounds of the present invention is OR, then the corresponding R is not OH.
  • halogen refers to a halogen, such as F, Cl, Br or I.
  • this invention provides for the use of a compound as herein described and/or, its derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or combinations thereof.
  • the methods of this invention make use of“pharmaceutically acceptable salts” of the compounds, which may be produced, by reaction of a compound of this invention with an acid or base.
  • examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.
  • examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,
  • examples of inorganic salts of carboxylic acids or phenols may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.
  • organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines, N,N’- dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procaine, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.
  • the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.
  • the methods of this invention make use of a pharmaceutically acceptable salt of the compounds of this invention. In one embodiment, the methods of this invention make use of a pharmaceutically acceptable salt of compounds of this invention. In one embodiment, the methods of this invention make use of a salt of an amine of the compounds of this invention. In one embodiment, the methods of this invention make use of a salt of a phenol of the compounds of this invention.
  • the methods of this invention make use of a free base, free acid, non charged or non-complexed compounds of this invention and/or its isomer, pharmaceutical product, hydrate, polymorph, or combinations thereof.
  • the methods of this invention make use of an isomer of a compound of this invention. In one embodiment, the methods of this invention make use of a pharmaceutical product of a compound of this invention. In one embodiment, the methods of this invention make use of a hydrate of a compound of this invention. In one embodiment, the methods of this invention make use of a polymorph of a compound of this invention. In one embodiment, the methods of this invention make use of a metabolite of a compound of this invention. In another embodiment, the methods of this invention make use of a composition comprising a compound of this invention, as described herein, or, in another embodiment, a combination of isomer, metabolite, pharmaceutical product, hydrate, polymorph of a compound of this invention. [00207
  • the term“isomer” is meant to encompass optical isomers of the SARD compound. It will be appreciated by those skilled in the art that the SARDs of the present invention contain at least one chiral center. Accordingly, the SARDs used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of androgen-related conditions described herein. In one embodiment, the SARDs are the pure (R)-isomers.
  • the SARDs are the pure (S)-isomers. In another embodiment, the SARDs are a mixture of the (R) and the (S) isomers. In another embodiment, the SARDs are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • this invention further includes hydrates of the compounds.
  • the invention also includes use of N-oxides of the amino substituents of the compounds described herein.
  • the term“hydrate” refers to hemihydrate, monohydrate, dihydrate, trihydrate or others, as known in the art.
  • This invention provides, in other embodiments, use of metabolites of the compounds as herein described.
  • “metabolite” means any substance produced from another substance by metabolism or a metabolic process.
  • the compounds of this invention are prepared according to Examples 1- 4. Biological Activity of Selective Androgen Receptor Degraders
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically effective amount of a compound or its isomer, pharm
  • the prostate cancer is advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
  • the prostate cancer depends on AR-FL and/or AR-SV for proliferation.
  • the subject further receives androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the subject has failed androgen deprivation therapy (ADT).
  • the cancer is resistant to treatment with an androgen receptor antagonist.
  • the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof.
  • administering the compound to a subject reduces the levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR- splice variant (AR-SV), gene-amplified AR, or any combination thereof, in said subject.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, said compound selected from the following structures:
  • the prostate cancer is advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
  • the prostate cancer depends on AR- FL and/or AR-SV for proliferation.
  • the subject further receives androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the subject has failed androgen deprivation therapy (ADT).
  • the cancer is resistant to treatment with an androgen receptor antagonist.
  • the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof.
  • administering the compound to a subject reduces the levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), gene-amplified AR, or any combination thereof, in said subject.
  • the methods of this invention are directed to treating, suppressing, reducing the incidence, reducing the severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from prostate cancer. In one embodiment, the methods of this invention are directed to methods of treating, suppressing, reducing the incidence, reducing the severity, inhibiting, providing palliative care, or increasing the survival of advanced prostate cancer in a subject.
  • the methods of this invention are directed to treating, suppressing, reducing the incidence, reducing the severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from castration resistant prostate cancer (CRPC). In one embodiment, the methods of this invention are directed to treating, suppressing, reducing the incidence, reducing the severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from metastatic castration resistant prostate cancer (mCRPC). In one embodiment, the methods of this invention are directed to treating, suppressing, reducing the incidence, reducing the severity, inhibit
  • nmCRPC metastatic castration resistant prostate cancer
  • the nmCRPC is high- risk nmCRPC.
  • the subject has high or increasing prostate specific antigen (PSA) levels.
  • PSA prostate specific antigen
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically effective amount of a SARD compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, said compound is represented by a compound of any one of the formulas as describe herein or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205 and 300- 308 described herein.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of advanced prostate cancer and its symptoms, or increasing the survival of a male subject suffering from advanced prostate cancer comprising administering to said subject a therapeutically effective amount of a SARD compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, said compound is represented by a compound of any one of the formulas as described herein or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205 and 300-308 described herein.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of metastatic prostate cancer and its symptoms, or increasing the survival of a male subject suffering from metastatic prostate cancer comprising administering to said subject a therapeutically effective amount of a SARD compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, said compound is represented by a compound of any one of the formulas as described herein or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205 and 300-308 described herein.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of a male subject suffering from castration resista
  • CRPC castration resistant prostate cancer
  • a SARD compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof is represented by a compound of any one of the formulas as described herein or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205 and 300-308 described herein.
  • the SARD compounds as described herein and/or compositions comprising the same may be used for treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration resistant prostate cancer.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non- metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • the subject further receives androgen deprivation therapy.
  • the terms“increase” and“prolong” may be used interchangeably having all the same meanings and qualities, wherein these terms may in one embodiment refer to a lengthening of time.
  • the terms“increase”,“increasing”“increased” may be used interchangeably and refer to an entity becoming progressively greater (as in size, amount, number, or intensity), wherein for example the entity is sex hormone-binding globulin (SHBG) or prostate-specific antigen (PSA).
  • SHBG sex hormone-binding globulin
  • PSA prostate-specific antigen
  • the compounds as described herein and/or compositions comprising the same may be used for increasing metastasis-free survival (MFS) in a subject suffering from non- metastatic prostate cancer.
  • the non-metastatic prostate cancer is non-metastatic advanced prostate cancer.
  • the non-metastatic prostate cancer is non- metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • the SARD compounds as described herein and/or compositions comprising the same may be used to provide a dual action, for example treating prostate cancer and preventing metastases.
  • the prostate cancer being treated is advanced prostate cancer.
  • the prostate cancer being treated is castration resistant prostate cancer (CRPC).
  • the prostate cancer being treated is metastatic CRPC (mCRPC).
  • the prostate cancer being treated is non-metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • prostate cancer in one embodiment, are men on ADT with serum total testosterone concentrations greater than 20 ng/dL or in another embodiment, men with advanced prostate cancer who at the time of starting ADT had either (1) confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time ⁇ 3 months, (4) a PSA 320 ng/mL, or (5) a PSA relapse in ⁇ 3 years after definitive local therapy (radical prostatectomy or radiation therapy).
  • CRPC prostate cancer
  • Men with high risk non-metastatic castration resistant prostate cancer may include those with rapid PSA doubling times, having an expected progression-free survival of approximately 18 months or less (Miller K, Moul JW, Gleave M, et al.2013. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Canc Prost Dis. Feb; 16:187-192). This relatively rapid progression of their disease underscores the importance of novel therapies for these individuals.
  • the PSA levels are greater than 8 ng/mL in a subject suffering from high-risk nmCRPC.
  • the PSA doubling time is less than 8 months in a subject suffering from high-risk nmCRPC. In another embodiment, the PSA doubling time is less than 10 months in a subject suffering from high-risk nmCRPC. In one embodiment, the total serum testosterone levels are greater than 20 ng/mL in a subject suffering from high-risk nmCRPC. In one embodiment, the serum free testosterone levels are greater than those observed in an orchidectomized male in a subject suffering from high-risk nmCRPC.
  • the compounds as described herein and/or compositions comprising the same may be used in combination with LHRH agonist or antagonist for increasing the progression free survival or overall survival of a subject suffering from prostate cancer.
  • the prostate cancer is advanced prostate cancer.
  • the prostate cancer is castration resistant prostate cancer (CRPC).
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non-metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • the subject is surgically castrated.
  • the subject is chemically castrated.
  • the compounds as described herein and/or compositions comprising the same may be used in combination with anti-programmed death receptor 1 (anti-PD-1) drugs (e.g., AMP-224, nivolumab, pembrolizumab, pidilizumab, AMP-554, and the like) for increasing the progression free survival or overall survival of a subject suffering from prostate cancer.
  • anti-PD-1 drugs e.g., AMP-224, nivolumab, pembrolizumab, pidilizumab, AMP-554, and the like
  • cancer is castration resistant prostate cancer (CRPC).
  • CRPC is metastatic CRPC (mCRPC).
  • mCRPC metastatic CRPC
  • nmCRPC non-metastatic CRPC
  • the nmCRPC is high-risk nmCRPC.
  • the subject is surgically castrated.
  • the subject is chemically castrated.
  • the compounds as described herein and/or compositions comprising the same may be used in combination with anti- PD-L1 drugs or anti-CTLA-4 drugs (anti- PD-L1 drugs include, but are not limited to, BMS-936559, atezolizumab, durvalumab, avelumab, and MPDL3280A.
  • Anti-CTLA-4 drugs include, but are not limited to, ipilimumab and tremelimumab.) for increasing the progression free survival or overall survival of a subject suffering from prostate cancer.
  • the prostate cancer is advanced prostate cancer.
  • the prostate cancer is castration resistant prostate cancer (CRPC).
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non- metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, the subject is surgically castrated. In another embodiment, the subject is chemically castrated.
  • treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningful improvement in prostate cancer related symptoms, function and/or survival.
  • Clinically meaningful improvements include but are not limited to increasing radiographic progression free survival (rPFS) if cancer is metastatic, and increasing metastasis-free survival (MFS) if cancer is non-metastatic.
  • the compounds as described herein and/or compositions comprising the same may be used for increasing the survival of men with castration resistant prostate cancer (CRPC).
  • CRPC men with castration resistant prostate cancer
  • the CRPC is metastatic CRPC (mCRPC).
  • mCRPC metastatic CRPC
  • nmCRPC non-metastatic CRPC
  • the nmCRPC is high-risk nmCRPC.
  • the subject further receives androgen deprivation therapy.
  • levels of prostate specific antigen (PSA) considered normal are age dependent. In one embodiment, levels of prostate specific antigen (PSA) considered normal are dependent on the size of a male subject's prostate. In one embodiment, PSA levels in the range between 2.5-10 ng/mL are considered “borderline high”. In another embodiment, PSA levels above 10 ng/mL are considered “high”. [00234
  • this invention provides a method of lowering serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer, advanced prostate cancer, metastatic prostate cancer or castration resistant prostate cancer (CRPC), comprising administering a therapeutically effective amount of a SARD compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, said compound is represented by the structure of any one of the formulas as described herein or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205, or 300-308 described herein.
  • this invention is directed to treatment of a subject with high or increasing PSA levels comprising administering a SARD compound of this invention.
  • this invention is directed to treatment of a subject with high or increasing PSA levels despite ongoing ADT or a history of ADT, surgical castration or despite treatment with antiandrogens and/or LHRH agonist.
  • the treatment makes use of compounds of the invention or any one of compounds 11- 27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205, and 300-308 described herein.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration resistant prostate cancer comprising administering a therapeutically effective amount of a compound of the invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the compound is compound 11.
  • the compound is compound 11R.
  • the compound is compound 12.
  • the compound is compound 13.
  • the compound is compound 14.
  • the compound is compound 15.
  • the compound is compound 16.
  • the compound is compound 17.
  • the compound is compound 18.
  • the compound is compound 19. In another embodiment, the compound is compound 20. In another embodiment, the compound is compound 21. In another embodiment, the compound is compound 22. In another embodiment, the compound is compound 23. In another embodiment, the compound is compound 24. In another embodiment, the compound is compound 25. In another embodiment, the compound is compound 26. In another embodiment, the compound is compound 27. In another embodiment, the compound is compound 30. In
  • the compound is compound 32. In another embodiment, the compound is compound 33. In another embodiment, the compound is compound 34. In another embodiment, the compound is compound 35. In another embodiment, the compound is compound 36. In another embodiment, the compound is compound 37. In another embodiment, the compound is compound 38. In another embodiment, the compound is compound 39. In another embodiment, the compound is compound 40. In another embodiment, the compound is compound 41. In another embodiment, the compound is compound 42. In another embodiment, the compound is compound 43. In another embodiment, the compound is compound 44. In another embodiment, the compound is compound 45. In another embodiment, the compound is compound 46. In another embodiment, the compound is compound 45. In another embodiment, the compound is compound 47. In another embodiment, the compound is compound 70. In another embodiment, the compound is compound 71.
  • the compound is compound 72. In another embodiment, the compound is compound 73. In another embodiment, the compound is compound 74. In another embodiment, the compound is compound 75. In another embodiment, the compound is compound 76. In another embodiment, the compound is compound 77. In another embodiment, the compound is compound 78. In another embodiment, the compound is compound 79. In another embodiment, the compound is compound 80. In another embodiment, the compound is compound 90. In another embodiment, the compound is compound 91. In another embodiment, the compound is compound 92. In another embodiment, the compound is compound 93. In another embodiment, the compound is compound 94. In another embodiment, the compound is compound 95. In another embodiment, the compound is compound 96. In another embodiment, the compound is compound 97.
  • the compound is compound 98. In another embodiment, the compound is compound 99. In another embodiment, the compound is compound 300. In another embodiment, the compound is compound 301. In another embodiment, the compound is compound 302. In another embodiment, the compound is compound 303. In another embodiment, the compound is compound 304. In another embodiment, the compound is compound 211. In another embodiment, the compound is compound 305. In another embodiment, the compound is compound 306. In another embodiment, the compound is compound 307. In another embodiment, the compound is compound 308.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC).
  • CRPC castration resistant prostate cancer
  • the compound is compound 100.
  • the compound is compound 101.
  • the compound is compound 102.
  • the compound is compound 103.
  • the compound is compound 104.
  • the compound is compound 105.
  • the compound is compound 106.
  • the compound is compound 107.
  • the compound is compound 108.
  • the compound is compound 109.
  • the compound is compound 110.
  • the compound is compound 111.
  • the compound is compound 112.
  • the compound 113 is
  • the compound is compound 114. In another embodiment, the compound is compound 115. In another embodiment, the compound is compound 130. In another embodiment, the compound is compound 131. In another embodiment, the compound is compound 132. In another embodiment, the compound is compound 133. In another embodiment, the compound is compound 134. In another embodiment, the compound is compound 135. In another embodiment, the compound is compound 136. In another embodiment, the compound is compound 137.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration resistant prostate cancer comprising administering a therapeutically effective amount of a compound of this invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the compound is compound 200.
  • the compound is compound 201.
  • the compound is compound 202.
  • the compound is compound 203.
  • the compound is compound 204.
  • the compound is compound 205.
  • this invention provides a method of secondary hormonal therapy that reduces serum PSA in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of this invention or its isome
  • the castration is surgical castration.
  • the prostate cancer depends on AR-FL and/or AR-SV for proliferation.
  • the cancer is resistant to treatment with an androgen receptor antagonist.
  • the prostate cancer or other cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, apalutamide, darolutamide, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof.
  • administration of the compounds of this invention reduces the levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), gene-amplified AR, poly-Q AR, or any combination thereof, in the subject.
  • the castration is surgical castration.
  • the castration is chemical castration.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non-metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • the method further increases radiographic progression free survival (rPFS) in a subject suffering from a metastatic cancer. In another embodiment, the method further increases metastasis-free survival (MFS) in a subject suffering from non-metastatic cancer. In one embodiment, the method may be used to provide a dual action, for example treating prostate cancer and preventing metastases. In another embodiment, the subject has failed androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives LHRH agonist or antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject had undergone orchidectomy.
  • rPFS radiographic progression free survival
  • MFS metastasis-free survival
  • the method may be used to provide a dual action, for example treating prostate cancer and preventing metastases.
  • the subject has failed androgen deprivation therapy (ADT).
  • the subject further receives androgen depriv
  • the subject has high or increasing prostate specific antigen (PSA) levels.
  • PSA prostate specific antigen
  • the subject is a prostate cancer patient.
  • the subject is a prostate cancer patient on ADT.
  • the subject is a prostate cancer patient on ADT with castrate levels of total T.
  • the subject is an advanced prostate cancer patient.
  • the subject is an advanced prostate cancer patient on ADT.
  • the subject is an advanced prostate cancer patient on ADT with castrate levels of total T.
  • the subject is a CRPC patient.
  • the subject is a CRPC patient on ADT.
  • the subject is a CRPC patient on ADT with castrate levels of total T.
  • the subject is a mCRPC patient maintained on ADT. In another embodiment, the subject is a mCRPC patient maintained on ADT with castrate levels of total T. In another embodiment, the subject is a non-metastatic castration resistant prostate cancer (nmCRPC) patient. In another embodiment, the subject is an nmCRPC patient maintained on ADT. In another embodiment, the subject is an nmCRPC patient maintained on ADT with castrate levels of total T. In one embodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, the method further treats, suppresses, reduces the incidence, reduces the severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides palliative treatment of advanced prostate cancer.
  • this invention is directed to a method of reducing the levels of AR, AR- full length, AR-FL with antiandrogen resistance-conferring AR-LBD mutations, polyQ AR, and/or AR-splice variants in a subject, comprising administering to said subject a therapeutically effective amount of a SARD compound according to this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the reduction is achieved by degradation of said AR, AR-full length (AR-FL), polyQ AR, and/or AR- splice variants (AR-SV).
  • the reduction is achieved by inhibition of said AR, AR-full length (AR-FL) and/or AR-splice variants (AR-SV). In another embodiment, the reduction is achieved by dual AR-SV/AR-FL degradation and AR-SV/AR-FL inhibitory functions.
  • this invention is directed to a method of reducing the levels of AR-splice variants in a subject, comprising administering to said subject a therapeutically effective amount of a SARD compound according to this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the method further reduces the levels of AR-full length (AR-FL) in the subject.
  • the reduction is achieved by degradation of said AR-splice variants (AR-SV).
  • the reduction is further achieved by degradation of said AR-FL.
  • the reduction is achieved by inhibition of said AR-splice variants (AR-SV).
  • the reduction is further achieved by inhibition of said AR-FL.
  • the reduction is achieved by dual AR-SV degradation and AR-SV inhibitory functions.
  • the reduction is achieved by dual AR-FL degradation and AR-FL inhibitory functions.
  • a subject suffering from castration resistant prostate cancer refers to a subject which has been previously treated with androgen deprivation therapy (ADT), has responded to the
  • the term refers to a subject which despite being maintained on androgen deprivation therapy is diagnosed to have serum PSA progression.
  • the subject has a castrate level of serum total testosterone ( ⁇ 50 ng/dL).
  • the subject has a castrate level of serum total testosterone ( ⁇ 20 ng/dL).
  • the subject has rising serum PSA on two successive assessments at least 2 weeks apart.
  • the subject had been effectively treated with ADT.
  • the subject has a history of serum PSA response after initiation of ADT.
  • the subject has been treated with ADT and had an initial serum PSA response, but now has a serum PSA >2 ng/mL and a 25% increase above the nadir observed on ADT.
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non- metastatic CRPC (nmCRPC).
  • the nmCRPC is high-risk nmCRPC.
  • serum PSA response refers to, in one embodiment, at least 90% reduction in serum PSA value prior to the initiation of ADT, to ⁇ 10 ng/mL or undetectable level of serum PSA ( ⁇ 0.2 ng/mL) at any time, or in another embodiment to at least 50% decline from baseline in serum PSA, or in another embodiment to at least 90% decline from baseline in serum PSA, or in another embodiment to at least 30% decline from baseline in serum PSA, or in another embodiment to at least 10% decline from baseline in serum PSA.
  • serum PSA progression refers to in one embodiment, a 25% or greater increase in serum PSA and an absolute increase of 2 ng/ml or more from the nadir; or in another embodiment, to serum PSA >2 ng/mL, or >2 ng/mL and a 25% increase above the nadir after the initiation of androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the term "nadir" refers to the lowest PSA level while a patient is undergoing ADT.
  • Testosterone can be measured as “free” (that is, bioavailable and unbound) or as “total” (including the percentage which is protein bound and unavailable) serum levels.
  • total serum testosterone comprises free testosterone and bound testosterone.
  • forms of ADT include a LHRH agonist.
  • the LHRH agonist includes leuprolide acetate (Lupron®)(US 5,480,656; US 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 which are all incorporated by reference herein
  • forms of ADT include an LHRH antagonist.
  • the LHRH antagonist includes degarelix.
  • the LHRH antagonist includes abarelix.
  • forms of ADT include reversible antiandrogens.
  • the antiandrogens include bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, abiraterone or any combination thereof.
  • forms of ADT include bilateral orchidectomy.
  • this invention provides a method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of castration resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration resistant prostate cancer comprising administering a therapeutically effective amount of a combination of one or more forms of ADT and a compound of this invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the subject has failed androgen deprivation therapy (ADT).
  • this invention provides a method of lowering serum PSA levels in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a combination of one or more forms of ADT and a compound of this invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the subject has failed androgen deprivation therapy (ADT).
  • the methods of this invention comprise administering a therapeutically effective amount of an antiandrogen and a compound of this invention. In one embodiment, the methods of this invention comprise administering a therapeutically effective amount of an LHRH agonist and a compound of this invention. In one embodiment, the methods of this invention comprise administering a therapeutically effective amount of an antiandrogen, LHRH agonist and a compound of this invention. In another embodiment, the compound is a compound of this invention or any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205, or 300-308 described herein.
  • the methods of this invention comprise administering a therapeutically effective amount of a lyase inhibitor (e.g., abiraterone) and a compound of this invention.
  • a lyase inhibitor e.g., abiraterone
  • a compound of this invention e.g., abiraterone
  • this invention provides a method for androgen deprivation therapy (ADT) in a subject, comprising administering a therapeutically effective amount of a compound of this invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • said subject has prostate cancer.
  • the prostate cancer is castration resistant prostate cancer (CRPC).
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non- metastatic castration resistant prostate cancer (nmCRPC).
  • the nmCRPC is high- risk nmCRPC.
  • the compound is any one of compounds 11-27, 30-47, 11R, 70-79, 80, 90-99, 100-115, 130-137, 200-205, or 300-308 described herein.
  • the subject has failed androgen deprivation therapy (ADT).
  • the subject further receives androgen deprivation therapy (ADT).
  • this invention provides a method of treating prostate cancer or delaying the progression of prostate cancer comprising administering a SARD compound of this invention. In one embodiment, this invention provides a method of preventing and/or treating the recurrence of prostate cancer comprising administering a SARD compound of this invention.
  • the prostate cancer is castration resistant prostate cancer (CRPC).
  • the CRPC is metastatic CRPC (mCRPC).
  • the CRPC is non- metastatic castration resistant prostate cancer (nmCRPC).
  • the nmCRPC is high- risk nmCRPC.
  • this invention provides a method of increasing the survival of a subject having prostate cancer, advanced prostate cancer, castration resistant prostate cancer or metastatic castration resistant prostate cancer or non-metastatic castration resistant prostate cancer or high-risk non metastatic castration resistant prostate cancer, comprising administering a compound of this invention.
  • administering a compound of this invention in combination with LHRH analogs reversible antiandrogens (such as bicalutamide, flutamide, or enzalutamide), anti- estrogens, estrogens (such as estradiol, ethinyl estradiol, or capesaris), anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, selective androgen receptor modulators (SARMs) or agents acting through other nuclear hormone receptors.
  • the subject has failed androgen deprivation therapy (ADT).
  • the compound is a compo
  • the term“advanced prostate cancer” refers to metastatic cancer having originated in the prostate, and having widely metastasized to beyond the prostate such as the surrounding tissues to include the seminal vesicles the pelvic lymph nodes or bone, or to other parts of the body. Prostate cancer pathologies are graded with a Gleason grading from 1 to 5 in order of increasing malignancy. In another embodiment, patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and that any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has“advanced” disease. In another embodiment,“advanced prostate cancer” can refer to locally advanced prostate cancer.
  • prostate cancers which are male sex hormones that may help prostate tumors grow.
  • prostate cancers that initially respond to antiandrogen therapy eventually develop the ability to grow without androgens.
  • Such cancers are often referred to as hormone refractory, androgen independent, or castration resistant.
  • the advanced prostate cancer is castration resistant prostate cancer.
  • CRPC growth resistant prostate cancer
  • AR-SV AR splice variants
  • LBD ligand binding domain
  • CRPC is a result of expression of AR-LBD mutations with potential to resist antagonists.
  • castration resistant prostate cancer is an advanced prostate cancer which developed despite ongoing ADT and/or surgical castration.
  • castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), caboza
  • gonadotropin releasing hormone agonists e.g., leuprol
  • castration resistant prostate cancer is defined as hormone na ⁇ ve prostate cancer.
  • the tumor cells may have the ability to grow in the absence of androgens (hormones that promote the development and maintenance of male sex characteristics).
  • the term“androgen deprivation therapy” (ADT) or“traditional androgen deprivation therapy” is directed to orchidectomy (surgical castration) wherein the surgeon removes the testicles.
  • the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administering luteinizing hormone-releasing hormone (LHRH) analogs: these drugs lower the amount of testosterone made by the testicles.
  • LHRH analogs available in the United States include leuprolide (Lupron®, Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), and histrelin (Vantas®).
  • antiandrogen deprivation therapy or“traditional androgen deprivation therapy” is directed to administering antiandrogens: anti-androgens block the body's ability to use any androgens. Even after orchidectomy or during treatment with LHRH analogs, a small amount of androgens is still made by the adrenal glands.
  • antiandrogens drugs include enzalutamide (Xtandi®), apalutamide (Erleada®), flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®).
  • the term“androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administering luteinizing hormone-releasing hormone (LHRH) antagonists such as abarelix (Plenaxis ®) or degarelix (Firmagon®) (approved for use by the FDA in 2008 to treat advanced prostate cancer).
  • LHRH luteinizing hormone-releasing hormone

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Abstract

La présente invention concerne de nouveaux composés de dégradation sélectifs de récepteurs des androgènes (SARD) d'indole, dindazole, de benzimidazole, de benzotriazole, d'indoline, de quinolone, d'isoquinoléine et de carbazole, des compositions pharmaceutiques et leurs utilisations dans le traitement d'hyperproliférations de la prostate, notamment des pré-malignités et d'hyperplasie prostatique bénigne, du cancer de la prostate, du cancer avancé de la prostate, du cancer de la prostate résistant à la castration, d'autres cancers exprimant AR, de l'alopécie androgène ou d'autres maladies dermiques hyperandrogéniques, de la maladie de Kennedy, de la sclérose latérale amyotrophique (ALS), de l'anévrisme aortique abdominal (AAA), et des fibroïdes de l'utérus, ainsi que des méthodes permettant de réduire les niveaux (par dégradation) et ou l'activité (par inhibition) de tout récepteur des androgènes y compris des récepteur des androgènes pleine longueur (AR-FL), notamment des mutations pathogènes et/ou de résistance, des variants d'épissage AR (AR-SV), et des polymorphismes pathogènes de polyglutamine (polyQ) de AR chez un sujet.
PCT/US2019/049618 2018-09-05 2019-09-05 Ligands de composés de dégradation sélectifs de récepteurs des androgènes (sard) et procédés d'utilisation associés Ceased WO2020051260A1 (fr)

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