WO2024010815A2 - Antagonistes de récepteur des androgènes et des glucocorticoïdes non stéroïdiens doubles - Google Patents

Antagonistes de récepteur des androgènes et des glucocorticoïdes non stéroïdiens doubles Download PDF

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WO2024010815A2
WO2024010815A2 PCT/US2023/026940 US2023026940W WO2024010815A2 WO 2024010815 A2 WO2024010815 A2 WO 2024010815A2 US 2023026940 W US2023026940 W US 2023026940W WO 2024010815 A2 WO2024010815 A2 WO 2024010815A2
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cancer
compound
prostate cancer
cpd
androgen
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WO2024010815A3 (fr
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Ramesh Narayanan
Duane D. Miller
Thamarai PONNUSAMY
Yali He
Dong-Jin Hwang
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University of Tennessee Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles

Definitions

  • Compounds are provided for use as both an androgen receptor (AR.) and glucocorticoid receptor (GR) antagonists.
  • Prostate cancers extensively treated with AR antagonists develop resistance by increasing the expression and function of GR. These resistant cancers respond to GR antagonists.
  • several cancers including basal triple-negative breast cancers (TNBC), express GR and are dependent on GR for growth. Molecules that function as inhibitors of AR, AR splice variants (AR-SVs), and GR are useful in treating these cancers.
  • PCa Prostate cancer
  • ADT Androgen-deprivation therapy
  • LHRH luteinizing hormone releasing hormone
  • LHRH antagonists LHRH antagonists
  • bilateral orchiectomy a progressive orchiectomy
  • CRPC castration-resistant prostate cancer
  • mCRPC metastatic CRPC
  • Patients with CRPC have a median survival of 12-18 months.
  • AR androgen receptor
  • antiandrogens such as enzalutamide, bicalutamide and flutainide and androgen deprivation therapies (ADT) were approved for use in prostate cancer
  • ADT flutainide and androgen deprivation therapies
  • antiandrogens could also be used in a variety of other hormone 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.
  • breast cancer e.g., 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
  • PAIS partial androgen insensitivity syndromes
  • NSCLC non-small cell lung cancer
  • gastric cancer colon cancer
  • perianal adenoma or central nervous system cancer.
  • the AR gene has a polymorphism of glutamine repeats (polyQ) within exon 1 which when 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
  • GR glucocorticoid receptor
  • Prostate cancers and other cancers when treated with androgen receptor antagonists can develop resistance by increasing the expression and function of glucocorticoid receptor (GR).
  • GR glucocorticoid receptor
  • Such resistant cancers respond to glucocorticoid receptor antagonists.
  • compounds that are both AR antagonists (including AR splice variants (AR-SVs) antagonists) and GR antagonists are desirable in treating such cancers.
  • methods of treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by one of the structures provided in TABLE 1 herein, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, whereby androgen receptor and glucocorticoid receptor are antagonized.
  • a method is provided of treating cancer in a subject, wherein the cancer exhibits upregulation of androgen receptor and glucocorticoid receptor, comprising administering to the subject a therapeutically effective amount of a compound represented by one of the structures provided in TABLE 1 herein, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, whereby androgen receptor and glucocorticoid receptor are antagonized.
  • the mineralcorticoid receptor activity is not inhibited.
  • the compound is of one of the following formulas:
  • the compound is of formula:
  • the cancer is at least one of 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, melanoma, or central nervous system cancer.
  • the breast cancer can be triple negative breast cancer, e.g., basal triple negative breast cancer.
  • the cancer is prostate cancer (PCa), wherein the survival of a male subject suffering from prostate cancer is increased.
  • the prostate cancer can be at least one of advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.
  • the method can further comprise administering androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the prostate cancer can be resistant to treatment with an androgen receptor antagonist(s).
  • the androgen receptor antagonist can be at least one of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.
  • the cancer is enzalutamide resistant prostate cancer.
  • the cancer is abiraterone resistant prostate cancer.
  • the cancer is basal triple negative breast cancer.
  • levels of AR-splice variants in the subject are reduced.
  • the levels of AR-full length (AR- FL) in the subject can further be reduced.
  • a method of treating Cushing’s syndrome comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by one of the structures of TABLE 1, whereby whereby androgen receptor and glucocorticoid receptor are antagonized.
  • the compound is represented by one of the following structures:
  • the compound is selected from of one of the following formulas:
  • the compound is of fomiuia:
  • FIG. 1 GR antagonist activity of selected compounds in a 0.1 nM Dex solution was determined based on measured luciferase light emissions and reported as relative light unit intensity (RLU). RLU is reported on the y-axis and for each of the compounds tested (x axis) at a concentration of 3 ⁇ M, Compounds tested included CPD. 6, CPD. 7, CPD. 9, CPD. 10, CPD. 4, CPD. 13, CPD. 12, and CPD. 11.
  • RLU relative light unit intensity
  • FIG. 4 GR antagonist activity of selected compounds in a 0.1 nM Dex solution was determined based on measured luciferase light emissions and reported as relative light unit intensity (RLU). RLU is reported on the y-axis and for each of the compounds tested (x axis) at a concentration of 3 ⁇ M.
  • Compounds tested included CPD. 30, CPI). 31, CPD. 32, CPD. 36, CPD. 35, CPD. 41, and CPD. 33.
  • FIG. 6 The GR transactivation results for dexamethasone were reported based on measured luciferase light emissions and reported as relative light unit intensity (RLU). The results are plotted with RLU reported on the y-axis and concentration (log M) on the x-axis.
  • FIG. 8 illustrates the Western blot of the glucocorticoid receptor degradation assays for Compound Cpd. 33 with LNCaP cells and LNCaP-AR-V7 cells.
  • FIG. 10 FKBP5 expression in PC3 cells for CPD. 33 compared to RU486 is plotted at concentrations of 0 pM, 0.1 pM, 0.3 pM, 1 pM, and 3 pM (Cpd. 33) and concentrations of 0.1 ⁇ M, 0.3 ⁇ M, and 0 ⁇ M (RU486).
  • FIG. 11 provides a Western blot of GR degradation assays for CPD. 33.
  • 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, bicalutamide or hydroxyflutamide to disrupt receptor activation has been successfully used m the past to reduce PCa growth.
  • All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repress transcription of target genes.
  • corepressors such as NCoR and SMRT
  • mutation of W741 and T877 within .AR converts bicalutamide and hydroxyflutamide, respectively, to agonists.
  • increased intracellular cytokines recruit coactivators instead of corepressors to AR- responsive promoters subsequently converting bicalutamide to an agonist.
  • mutations that have been linked to enzalutamide resistance include F876, H874, T877, and di-mutants T877/S888, T877/D890, F876/T877 (i.e., MR49 cells), and H874/T877 (Genome Biol. (2006) 17:10 (dor 10.1186/sl 3059-015-0864-1)).
  • CRPC castration-resistant prostate cancer
  • AR androgen receptor
  • AR-SV AR splice variants
  • LBD ligand binding domain
  • Prostate cancers and other cancers when treated with androgen receptor antagonists can develop resistance by increasing the expression and function of glucocorticoid receptor (GR).
  • GR glucocorticoid receptor
  • Such resistant cancers respond to glucocorticoid receptor antagonists.
  • compounds that are both androgen receptor antagonists (including AR splice variants (AR-SVs) antagonists) and glucocorticoid receptor antagonists are desirable in treating such cancers.
  • SARD selective androgen receptor degrader
  • a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist 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.
  • the SARD compound may not bind to ligand binding domain (LBD).
  • 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 disclosure.
  • the SARD is orally active.
  • the SARD is applied topically to the site of action.
  • the SARD compound may bind to the N-terminal domain (NTD) of the AR; to an alternate binding and degradation domain (BDD) of the AR; to both the AR ligand binding domain (LBD) and to an alternate binding and degradation domain (BDD); or to both the N- terminal domain (NTD) and to the ligand binding domain (LBD) of the AR.
  • the BDD may be located in the NTD.
  • the BDD is located in the AF-1 region of the NTD.
  • the SARD compound may be capable of: inhibiting growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV; or inhibiting the AR through binding to a domain that is distinct from the AR LBD.
  • the SARD compound may be a strong (i.e., highly potent and highly efficacious) selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide, and abiraterone).
  • a strong androgen receptor antagonist e.g., highly potent and highly efficacious selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide, and abiraterone).
  • the SARD compound may be a selective androgen receptor antagonist, which targets AR-SVs, which cannot be inhibited by conventional antagonists.
  • the SARD compound may exhibit one of several activities including, but not limited to: AR-SV degradation activity; AR- FL degradation activity, AR-SV inhibitory activity (i.e., is an AR-SV antagonist), AR-FL inhibitory activity (i.e., is an AR-FL antagonist); inhibition of the constitutive activation of AR- SVs; or inhibition of the constitutive activation of AR-FLs.
  • the SARD compound may possess dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions; or alternatively possess all four of these activities.
  • the SARD compound may also degrade AR-FL and AR-SV.
  • the SARD compound may degrade the AR through binding to a domain that is distinct from the AR LBD.
  • the SARD compound may possess dual degradation and AR-SV inhibitory functions that are distinct from any available CRPC therapeutics.
  • the SARD compound may inhibit the re-activation of the AR by alternate mechanisms such as: intra crine androgen synthesis, expression of AR-SV that lack ligand binding domain (LBD) and AR-LBD mutations with potential to resist antagonists, or inhibit re-activated androgen receptors present in pathogenic altered cellular environments.
  • Examples of AR-splice variants include, but are not limited to, AR-V7 and ARv567es (a.k.a.
  • AR-V12 S. Sun, etal. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. (2010) 120(8), 2715- 2730), Nonlimiting examples of AR mutations conferring antiandrogen resistance are: W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. (2013) 3(9), 1020-1029) mutations. Many other LBD resistance conferring mutations are known in the art and will continue to be discovered, AR-V7 is a splice variant of AR that lacks the LBD (A. H.
  • the SARD compounds can bind to the AR through an alternate binding and degradation domain (BDD).
  • BDD alternate binding and degradation domain
  • the SARDs may further bind the AR ligand binding domain (LBD).
  • the SARD compounds may be used in treating CRPC that cannot be treated with any other antagonist.
  • the SARD compounds may treat CRPC by degrading AR-SVs.
  • the SARD compounds may maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists. For instance, the SARD compounds maintain their antagonistic activity to AR mutants W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN- 509. Cancer Discov. (2013) 3(9): 1020-1029).
  • the SARD compounds elicit antagonistic activity within an altered cellular environment in which LBD-targeted agents are not effective or in which NTD-dependent AR activity is constitutively active.
  • One embodiment of the disclosure encompasses a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:
  • T is H, OH, OR, OCOR, CH?, -NHCOCH?, or NHCOR;
  • Ri is H, CH3. CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or I' and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • Y is H. CH3, F, I, Br. Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR,
  • X is CH or N
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • this disclosure is directed to a SARD compound represented by the structure of formula IA:
  • T is H, OH, OR, OCOR. CH 3, -NHCOCHi, or NHCOR, or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • Y is H, CF3, F, I, Br, Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR,
  • X is CH or N
  • Ris H alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH, and
  • A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hy drate or any combination thereof.
  • this disclosure is directed to a SARD compound represented by the structure of formula IB:
  • T is H, OH, OR, OCOR, CH 3 , -NHCOCHy or NHCOR;
  • Ri is H, CH 3 , CH 2 F, CHF2, CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • Y is H. CF 3 , F, I, Br, Cl, CN, or C( R) 3;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a SARD compound represented by the structure of formula IT:
  • RI is H, CH 3 , CH2F, CHF2, CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CFbCl, CH 2 CH 2 C1, aryl, F, Cl, Br, I, or OH; and
  • A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazdidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q ⁇ or Q ⁇ each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalky l, haloalkyl, CF 3 , substituted or unsubstituted ary l, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, malemnde, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical
  • RI is H, CH 3 , CHZF, CHF2, CF 3 , CH2CH3, or CF2CF3;
  • Y is H, CF 3 , F, I, Br, Cl, CN, or C( R) 3;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • Ris H alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q 3 , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer
  • this disclosure is directed to a SARD compound represented by the structure of formula IIB: wherein
  • Ri is H, CH 3 , CEbF, CHF2, CH. CH 2CH3, or CF2CF3;
  • Y is H, CP';. F, I, Br, Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N; Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2.OH, CF 3 , CH2CI, CH2.CH2CI, aryl, F, Cl, Br, I, or OH; and
  • A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q J , or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONFER, COOR or COR; or its isomer
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula III:
  • T is FI, OH, OR, OCOR. Cl b. -NHCOCH?, or NHCOR;
  • Ri is H, Ci h. CI I2F, CHF2, CF 3 , Ci bCI b. or CF 2 CF 3 ; or I' and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • Y is H. CF .. F, I, Br, Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONI IR,
  • X is CH or N;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and
  • Q 2 , Q J , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IIIA: wherein
  • T is H, OH, OR. OCOR, CFI3, -NHCOCFI3, or NHCOR;
  • Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3, or T and Ri form a 3-8 carbocyclic or heterocyclic ring:
  • Y is H, CF3, F, I, Br, Cl, CN, or C(R)i;
  • Z is NO2, CN, ( OOH. ( OR NHCOR, or CONFIR;
  • X is CH or N
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and Q ⁇ Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof,
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IIIB:
  • T is H, OH, OR, OCOR. CH?, -NHCOCH?, or NHCOR;
  • Ri is H, Ci h. CI-bF, CHF2, CF 3 , Ci -I2CH 3, or CF2CF3; or I' and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • Y is H, OF?, F, I, Br, Cl, CN, or C(R) 3 ;
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR,
  • X is CH or N
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 , Q 3 , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)?., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IV : wherein
  • Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • Ri is H, CH3, CH 2 F, CHF?, CFa, CH2CH3, or CF2CF3;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 , Q ⁇ or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVA:
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
  • Ri is H, CH 3 , CH2F, CHF2, CF 3 , CH-CH r or CF 2 CF 3 ;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH2CI, CH 2 CH 2 C1, aryl, F, Cl, Br, I, or OH; and
  • Q 2 , QC or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, arylalkyl, NCS, rnaleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVB: wherein
  • X is CH or N
  • Y is H, CFs, F, I, Br, Cl, CN, or C(R)s;
  • Ri is H, CH 3 , CH?F, CHF?, CF 3 , CH?CH 3 , or CF.-Clw
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF 3 , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 , Q J , or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)?, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula V: wherein
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR,
  • X is CH or N
  • Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
  • T is H, OH, OR, OCOR, CH 3 , -NHCOCHy or NHCOR;
  • Ri is H, CH 3 , CH2F, CHF?, CF 3 , CH2CH3, or CF?CF 3 , or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2.CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalky 1, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VA: wherein
  • Z is NO2, CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • Y is I I. CF3, F. I, Br, Cl, CN, or C(R) 3 ;
  • T is H, OH, OR, OCOR, CH3, -NHCOCH3, or NHCOR; 1 or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VB: wherein
  • Z is NO?., CN, COOH, COR, NHCOR, or CONHR;
  • X is CH or N
  • Y is H, CF .. F, I, Br, Cl, CN, or C(R) 3 ;
  • T is H, OH, OR, OCOR, CH 3 , -NHCOCHs, or NHCOR;
  • Ri is H, CH 3 , CH 2 F, CHF?, CF 3 , CH 2 CH 3 , or CF 2 CT . or T and Ri form a 3-8 carbocyclic or heterocyclic ring;
  • R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 C1, CH2CH2CI, aryl, F, Cl, Br, I, or OH;
  • Q 2 or Q 4 are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or un substituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NOz, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • Antagonists of Both .Androgen Receptor and Glucorticoid Receptor Antagonists of Both .Androgen Receptor and Glucorticoid Receptor
  • the compound and/or its derivative, optical isomer, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, prodrug, polymorph, crystal or combinations thereof is employed.
  • the methods make use of “pharmaceutically acceptable salts” of a compound, which may be produced, by reaction of the compound with an acid or base.
  • a compound may be converted into pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt may be produced by reaction of a compound with an acid or base.
  • Suitable pharmaceutically acceptable salts of amines may be prepared from an inorganic acid or from an organic acid.
  • inorganic salts of amines include, but are not limited to, bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfamlates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates, or 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, caniphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decano
  • Examples of inorganic salts of carboxylic acids or phenols may be selected from ammonium, alkali metals, and alkaline earth metals.
  • Alkali metals include, but are not limited to, lithium, sodium, potassium, or cesium.
  • Alkaline earth metals include, but are not limited to, calcium, magnesium, aluminium; zinc, barium, cholines, or quaternary ammoniums.
  • organic salts of carboxylic acids or phenols may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylammes, benethamines (A-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, A-methyl-D-glu camines, N,N ’-d ibenzy lethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, procaine, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylaniines, tromethamines and ureas.
  • organic amines to
  • 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 may use an uncharged compound or a pharmaceutically acceptable salt of the compound as described herein.
  • the pharmaceutically acceptable salt may be an amine salt or a salt of a phenol of the compound as described herein.
  • the methods make use of a free base, free acid, non charged or non-complexed compound, and/or its isomer, pharmaceutical product, hydrate, polymorph, or combinations thereof.
  • the methods make use of an optical isomer of a compound. In one embodiment, the methods make use of an isomer of a compound. In one embodiment, the methods of this disclosure make use of a pharmaceutical product of a compound. In one embodiment, the methods make use of a hydrate of a compound. In one embodiment, the methods make use of a polymorph of a compound. In one embodiment, the methods make use of a metabolite of a compound. In another embodiment, the methods make use of a composition comprising a compound, or, in another embodiment, a combination of isomer, metabolite, pharmaceutical product, hydrate, polymorph a compound.
  • the term “isomer” includes, but is not limited to, optical isomers, structural isomers, or conformational isomers.
  • the term “isomer” is meant to encompass optical isomers of the compound. It will be appreciated by those skilled in the art that the compounds may contain at least one chiral center. Accordingly, the compounds may exist as optically-active (such as an (/?) isomer or (S) isomer) or racemic forms. Optically active compounds may exist as enantiomerically enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that any racemic, optically active, polymorphic, or stereroisonieric form, or mixtures thereof are encompassed. Thus, compounds as pure (A)-isomers or as pure (S)-isomers are encompassed.
  • 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.
  • Compounds may be hydrates of the compounds.
  • the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, or trihydrate.
  • Use of A-oxides of the amino substituents of the compounds described herein is also contemplated,
  • metabolites of the compound means any substance produced from another substance by metabolism or a metabolic process.
  • the compounds are prepared according to known synthetic routes, e.g., such as those described in U.S. Patent No. 10,314,797, the contents of which are hereby incorporated herein in their entirety.
  • a method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of TABLE 1 or any one of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • a method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of TABLE I or any one of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the prostate cancer may be advanced prostate cancer, refractory’ prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.
  • CRPC castration resistant prostate cancer
  • mCRPC metastatic CRPC
  • nmCRPC non-metastatic CRPC
  • high-risk nmCRPC or any combination thereof.
  • the prostate cancer may depend on AR-FL and/or AR-S V for proliferation.
  • the prostate or other cancer may be resistant to treatment with an androgen receptor antagonist.
  • a method is provided of treating enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of TABLE 1 or any one of formulas I, TA, IB, II, IIA, IIB, III, III A, IIIB, IV, IVA, TVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • a method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of TABLE 1 or any one of formulas I, TA, IB, II, IIA, TIB, HI, IIIA, IIIB, IV, IVA, TVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • a method of treating a basal triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a c compound of TABLE 1 or any one of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • the method may further comprise a second therapy such as androgen deprivation therapy (ADT) or LHRH agonist or antagonist.
  • ADT androgen deprivation therapy
  • LHRH agonists include, but are not limited to, leuprolide acetate.
  • a method is provided of treating or inhibiting the progression of prostate cancer
  • PCa or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • a method is provided of treating or inhibiting the progression of refractory prostate cancer (PCa) or increasing the survival of a male subject suffering from refractory/ prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • the disclosure encompasses a method of treating or increasing the survival of a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • CRPC castration resistant prostate cancer
  • the method may further comprise administering androgen deprivation therapy to the subject.
  • a method is provided of treating or inhibiting the progression of enzalutamide resistant prostate cancer (PCa) or increasing the survival of a male subject suffering from enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • the method may further comprise administering androgen deprivation therapy to the subject.
  • the disclosure encompasses a method of treating or inhibiting the progression of basal triple negative breast cancer (TNBC) or increasing the survival of a female subject suffering from basal triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • TNBC basal triple negative breast cancer
  • the terms “increase”, increasing” and “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 and compositions may be used for increasing metastasis-free survival (MFS) in a subject suffering from non-metastatic prostate cancer.
  • the non-metastatic prostate cancer may be non-metastatic advanced prostate cancer, non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.
  • the compounds may be used to provide a dual action. For example, the compounds may treat prostate cancer and prevent metastasis.
  • the prostate cancer may be refractory prostate cancer; advanced prostate cancer; castration resistant prostate cancer (CRPC); metastatic CRPC (mCRPC); non-metastatic CRPC (nmCRPC); or high-risk nmCRPC.
  • the compounds may be used to provide a dual action.
  • the compounds may treat TNBC and prevent metastasis.
  • Men with advanced prostate cancer who are at high risk for progression to castration resistant prostate cancer are men on ADT with serum total testosterone concentrations greater than 20 ng/dL or 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 >20 ng/mL, or (5) a PSA relapse in ⁇ 3 years after definitive local therapy (radical prostatectomy or radiation therapy).
  • PSA prostate specific antigen
  • 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- control led study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer,” Prostate Cane Prost Dis. Feb; 16: 187-192). This relatively rapid progression of their disease underscores the importance of novel therapies for these individuals.
  • the methods may treat subjects with PSA levels greater than 8 ng/mL where the subject suffers from high-risk nmCRPC.
  • the patient population includes subjects suffering from nmCRPC where PSA doubles in less than 8 months or less than 10 months.
  • the method may also treat patient populations where the total serum testosterone levels are greater than 20 ng/mL in a subject suffering from high-risk nmCRPC. In one case, the serum free testosterone levels are greater than those observed in an orchiechtomized male in a subject suffering from high-risk nmCRPC.
  • LHRH antagonists include, but are not limited to, degarelix or abarelix.
  • Antiandrogens include, but are not limited to, bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, abiraterone, or any combination thereof.
  • Anti-PD-1 drugs include, but are not limited to, AMP-224, nivolumab, pembrolizumab, pidilizumab, and AMP-554.
  • Anti-PD-Ll 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.
  • 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 improvement can be determined by an increase in radiographic progression free survival (rPFS) if cancer is metastatic, or an increase metastasis-free survival (MFS) if cancer is non-metastatic, among others.
  • rPFS radiographic progression free survival
  • MFS metastasis-free survival
  • Methods are provided 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 to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • PSA prostate specific antigen
  • CRPC castration resistant prostate cancer
  • a method is provided of secondary hormonal therapy that reduces serum PSA in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering to the subject a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt.
  • the method may increase radiographic progression free survival (rPFS) or metastasis-free survival (MFS).
  • rPFS radiographic progression free survival
  • MFS metastasis-free survival
  • Subjects may have non-metastatic cancer; failed androgen deprivation therapy (ADT), undergone orchidectomy, or have high or increasing prostate specific antigen (PSA) levels; subjects may be a patient with prostate cancer, advanced prostate cancer, refractory prostate cancer, CRPC patient, metastatic castration resistant prostate cancer (mCRPC) patient, or non-metastatic castration resistant prostate cancer (nmCRPC) patient.
  • the refractory may be enzalutamide resistant prostate cancer.
  • the nmCRPC may be high-risk nmCRPC.
  • the subject may be on androgen deprivation therapy (ADT) with or without castrate levels of total T.
  • a subject suffering from castration resistant prostate cancer refers to a subject with at least one of the following characteristics: has been previously treated with androgen deprivation therapy (ADT); has responded to the ADT and currently has a serum PSA > 2 ng/mL or >2 ng/mL and representing a 25% increase above the nadir achieved on the ADT; a subject which despite being maintained on androgen deprivation therapy is diagnosed to have serum PSA progression; a castrate level of serum total testosterone ( ⁇ 50 ng/dL) or a castrate level of serum total testosterone ( ⁇ 20 ng/dL).
  • the subject may have rising serum PSA on two successive assessments at least 2 weeks apart; been effectively treated with ADT; or has a history of serum PSA response after initiation of ADT,
  • serum PSA progression refers to a 25% or greater increase in serum PSA and an absolute increase of 2 ng/ml or more from the nadir; or 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
  • nadir refers to the lowest PSA level while a patient is undergoing ADT.
  • serum PSA response refers to at least one of the following: at least 90% reduction in serum PSA value prior to the initiation of ADT; to ⁇ 10 ng/mL undetectable level of serum PSA ( ⁇ 0.2 ng/mL) at any time; at least 50% decline from baseline in serum PSA; at least 90% decline from baseline in serum PSA; at least 30% decline from baseline in serum PSA; or at least 10% decline from baseline in serum PSA.
  • the methods can comprise administering a combination of forms of ADT and a compound of TABLE 1 or any one of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.
  • forms of ADT include a LHRH agonist.
  • LHRH agonist includes, but is not limited to, 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 hereby incorporated by reference) or goserehn acetate (Zoladex®) (US 7,118,552; 7,220,247; 7,500,964 hereby incorporated by reference).
  • Forms of ADT include, but are not limited to LHRH antagonists, reversible antiandrogens, or bilateral orchidectomy.
  • LHRH antagonists include, but are not limited to, degarelix and abarelix.
  • Antiandrogens include, but are not limited to, bicalutamide, flutamide, finasteride, dutastende, enzalutannde, ARN-509, ODM-201, nilutamide, chlormadinone, abiraterone, or any combination thereof.
  • the methods can encompass administering at least one compound of TABLE 1 or any one of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, or VB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof and a lyase inhibitor (e.g., abiraterone).
  • 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. Patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has “advanced” disease. “Advanced prostate cancer” can refer to locally advanced prostate cancer. Similarly, “advanced breast cancer” refers to metastatic cancer having originated in the breast, and having widely metastasized to beyond the breast to surrounding tissues or other parts of the body such as the liver, brain, lungs, or bone.
  • refractory may refer to cancers that do not respond to treatment.
  • prostate or breast cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
  • Refractory cancer may also be referred to herein as “resistant cancer”. Upregulation of GR is one of the resistance mechanisms to AR antagonists in castration resistant prostate cancer and certain other cancers.
  • CRPC growth hormone refractory, hormone naive, androgen independent or chemical or surgical castration resistant.
  • CRPC may be the result of AR activation by intracrine androgen synthesis; expression of AR splice variants ( AR- SV) that lack ligand binding domain (LBD); or expression of AR-LBD mutations with potential to resist antagonists.
  • AR- SV AR splice variants
  • LBD ligand binding domain
  • 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 (u.g., degarelix or abarelix), antiandrogens (u.g., bicalutamide, flutamide, enzaiutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, nntoxantrone, estramu stine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitmib (Iressa®), cabozantimb (CometriqTM, also known as XI/184)) or other prostate cancer therapies (e.g., vaccines (sipuleu
  • Castration resistant prostate cancer may be defined as hormone naive 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).
  • ADT may include orchiectomy; administering luteinizing hormone-releasing hormone (LHRH) analogs; administering luteinizing hormone-releasing hormone (LHRH) antagonists; administering 5a-reductase inhibitors; administering antiandrogens; administering inhibitors of testosterone biosynthesis; administering estrogens; or administering 17a ⁇ hydroxylase/C 17,20 lyase (CYP17A1) inhibitors.
  • LHRH 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®).
  • Antiandrogens block the body's ability to use any androgens.
  • antiandrogens drugs include enzalutamide (Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®).
  • Luteinizing hormone- releasing hormone (LHRH) antagonists include abarelix (Plenaxis®) or degarelix (Finnagon®) (approved for use by the FDA in 2008 to treat advanced prostate cancer).
  • 5a-Reductase inhibitors block the body’s ability to convert testosterone to the more active androgen, 5a- dihydrotestosterone (DHT) and include drugs such as finasteride (Proscar®) and dutasteride (Avodart®).
  • Inhibitors of testosterone biosynthesis include drugs such as ketoconazole (Nizoral®).
  • Estrogens include diethylstilbestrol or 17p-estradiol.
  • 17a-Hydroxylase/C 17,20 lyase (CYP17A1) inhibitors include abiraterone (Zytiga®).
  • the disclosure encompasses a method of treating antiandrogen-resistant prostate cancer.
  • the antiandrogen may include, but is not limited to, bicalutamide, hydroxyflutamide, flutamide, enzalutamide or abiraterone.
  • TNBC Triple Negative Breast Cancer
  • TNBC Triple negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 receptor kinase a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase.
  • HER2 receptor kinase lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers.
  • chemotherapy is often the initial pharmacotherapy for TNBC.
  • AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy.
  • ER-positive breast cancer AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors.
  • AR in the absence of ER,
  • TNBC TNBC
  • SARDs which are capable of destroying AR-SVs through a binding site in the NTD of AR can antagonize AR in these TNBC’s and provide an anti-tumor effect.
  • compositions means either the compound or pharmaceutically acceptable salt of the active ingredient with a pharmaceutically acceptable carrier or diluent.
  • a “therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.
  • administering refers to bringing a subject in contact with a compound of the present disclosure.
  • administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans. The subjects may be a male or female subject or both.
  • the mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
  • compositions of the disclosure can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracan cerally, transmucosally, transdennally, intramuscularly, mtranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intraventricularly, intracranially, intravaginally, by inhalation, rectally, or intratumorally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces.
  • compositions may be administered topically to body surfaces, and are thus formulated in a form suitable for topical administration.
  • Suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
  • the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdernial, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for systemic delivery of active ingredients. Depending on the indication, formulations suitable for oral or topical administration are preferred.
  • the active ingredient may be mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • carrier or diluents are well known to those skilled in the art.
  • the carrier or diluent may be a solid carrier or diluent for solid formuations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
  • Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregel etanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a gum e.g., corn starch, pregel etanized starch
  • a sugar e.g., lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g., microcrystalline cellulose
  • an acrylate e.g., polymethylacrylate
  • calcium carbonate e.g., magnesium oxide, talc, or mixtures thereof.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may- be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
  • the active agent in a vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient.
  • a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
  • a tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
  • Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
  • a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients).
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
  • Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose form.
  • Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
  • Nasal and other mucosal spray formulations inhalable forms can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes.
  • formulations can be in the form of finely divided solid powders suspended in a gas carrier.
  • Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
  • Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
  • Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g, methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g, methyl cellulose or hydroxyethyl cellulose
  • formulations of this disclosure may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, dismtegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
  • the physician wall determine the actual dosage and duration of treatment.
  • the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.
  • the methods comprise administration of a compound at a therapeutically effective amount.
  • the theraperutically effective amount may include various dosages.
  • a compound is administered at a dosage of 1-3000 mg per day.
  • a compound is administered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-2.6 mg per day, 15-60 mg per day, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 nig per day, 200-500 nig per day, 125-500 nig per day, 500-1000 nig per day, 200- 1000 mg per day, 1000-2000 nig per day, 1000-3000 mg per day, 125-3000 mg per day, 2.000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day.
  • a dosage of 300 mg per day In one embodiment, a compound is administered at a dosage of 500 mg per day. In one embodiment, a compound is administered at a dosage of 600 mg per day. In one embodiment, a compound is administered at a dosage of 1000 mg per day. In one embodiment, a compound is administered at a dosage of 1500 mg per day. In one embodiment, a compound is administered at a dosage of 2000 mg per day. In one embodiment, a compound is administered at. a dosage of 2500 mg per day. In one embodiment, a compound is administered at a dosage of 3000 mg per day.
  • the methods may comprise administering a compound at various dosages.
  • the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.
  • the compound may be administered at a dosage of 0.1 mg/kg/day.
  • the compound may administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
  • the pharmaceutical composition may be a solid dosage form, a solution, or a transdermal patch.
  • Solid dosage forms include, but are not limited to, tablets and capsules.
  • FIG. 1 through FIG. 5 provide GR antagonist activity of selected compounds in a 0. 1 nM Dex solution. Activity was determined based on measured luciferase light emissions and reported as relative light unit intensity 7 (RLU). RLU is reported on the y-axis for each of the compounds tested (x axis) at a concentration of 3 ⁇ M.
  • Compounds tested included CPD, 6, CPD. 7, CPD. 9, CPD. 10, CPD. 4, CPD. 13, CPD. 12, and CPD. 1 1 (FIG. 1); CPD. 14, CPD. 15, CPD. 20, CPD. 21, CPD. 19, CPD. 18, and CPD. 17 (FIG. 2); CPD. 22, CPD. 23, CPD. 24, CPD. 28, CPD.
  • CPD. 33, CPD. 23, CPD. 24, CPD. 31, and CPD. 37 are potent antagonists of glucocorticoid receptor.
  • the GR transactivation results for dexamethasone are compared to those of RU486 (Mifepristone, closed circle, 3.99 nM), CPD. 33 (closed square, 67.6 nM), CPD. 38 (closed upright triangle), CPD. 39 (closed upside-down triangle, 213.5 nM), CPD. 40 (closed diamond, 256.2 nM), and CPD. 31 (open circle, 247.7 nM) (FIG. 7).
  • the results were reported based on measured luciferase light emissions and reported as relative light unit intensity (RLU). Curves were fitted to the each set of points. The data demonstrate that CPD. 33 exhibits satisfactory
  • FIG. 8 provides Western blot of the glucocorticoid receptor degradation assays for Compound HY-II-39 with with LNCaP cells and LNCaP-AR-V7 cells. The data demonstrate that CPD. 33 is a potent degrade of AR and AR-V7. It antagonizes AR at -2.50 nM.
  • FKBP5 expression in PC3 cells for CPD. 33 was compared to that of RU486 (FIG. 10) and a Western blot of GR degradation assays for CPD. 33 was obtained.
  • TABLE 2 includes test results for a number of synthesized compounds.
  • M.W. molecular weight
  • GR Ki (nM) and IC50 (nM) GR Ki (nM) and IC50 (nM)
  • SARD Activity Full Length degradation at 1 , 10 ⁇
  • the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like;
  • the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;
  • the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desi
  • a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise.
  • a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

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Abstract

L'invention concerne des composés destinés à être utilisés à la fois en tant qu'antagonistes du récepteur des androgènes (AR) et du récepteur des glucocorticoïdes (GR). Les cancers de la prostate traités de manière extensive avec des antagonistes AR développent une résistance en augmentant l'expression et la fonction de GR. Lesdits cancers résistants répondent à des antagonistes de GR. De plus, plusieurs cancers, notamment des cancers du sein triple-négatif basaux (TNBC), et des indications non oncologiques telles que celles de Cushing expriment le GR et dépendent du GR pour la croissance. Des molécules qui fonctionnent en tant qu'inhibiteurs d'AR, de variants d'épissage AR (AR-SV), et de GR sont utiles dans le traitement desdits cancers.
PCT/US2023/026940 2022-07-07 2023-07-05 Antagonistes de récepteur des androgènes et des glucocorticoïdes non stéroïdiens doubles Ceased WO2024010815A2 (fr)

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EP4110327A4 (fr) * 2020-02-25 2024-03-13 University of Tennessee Research Foundation Ligands de composés de dégradation sélectifs de récepteurs des androgènes (sard) et procédés d'utilisation associés
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