Pharmaceutical compositions and methods of use for treating breast cancer

Abstract

The present invention relates to treating breast cancer in a subject, including a method of treating by first determining 18F-16 beta-fluoro-5 alpha-dihydrotestosterone (18F-DHT) tumor uptake and identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, the method comprising administering to the subject a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

Description

[Technical Field]

[0001] The present invention relates to the treatment of androgen receptor positive breast cancer in a subject, for example, a male or female subject. Thus, the present invention provides a) treating a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without expression of estrogen receptor (ER), progesterone receptor (PR), and / or human epidermal growth factor receptor 2 (HER2), i) treating a subject with triple negative breast cancer (TNBC), j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SMR). gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (SERMs) (tamoxifen, toremifene, raloxifene),inhibitors (AI) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), poly(ADP-ribonucleotide-binding protein (PAB) inhibitors), PARP inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2 ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Av m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER mutant-expressing breast cancer; s) treating a subject with Y537S ER mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer that has not been treated with HER2-positive breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18F-16β-fluoro-5α-dihydrotestosterone, 18 F-DHT) tumor uptake was determined, 18 Provided is a method of treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, the method comprising administering to the subject a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound. [Background technology]

[0002] Breast cancer is a disease that kills more than 45,000 women each year in the United States alone. It is estimated that more than 180,000 new cases of breast cancer are diagnosed each year, and one in eight women will develop breast cancer. These figures indicate that breast cancer is one of the most dangerous diseases facing women today. Breast cancer also occurs in men, but at a much lower incidence. Cancer research has not been able to determine the cause of breast cancer, nor has it identified a suitable method of treatment or prevention.

[0003] Genotyping has long been used to screen women who may have a genetic predisposition to developing breast cancer. This is another diagnostic or prognostic tool that can be used to determine the availability of therapy. Certain women are predisposed to developing breast cancer based on the presence of germline (i.e., inherited) mutations in the breast cancer susceptibility gene (BRCA) type 1 (BRCA1) or BRCA2. Several SERMs, including tamoxifen in 1999 and raloxifene in 2007, were approved for the primary prevention of breast cancer in patient populations at high risk based on family history and / or genotype considerations. However, hysterectomy or prophylactic mastectomy have often been considered as more definitive prevention in these patients. In 2018 and 2019, talazoparib (Talzenna) and olaparib (Lynparza), inhibitors of poly ADP ribose polymerase (PARP), were approved for patients with metastatic ER-positive and HER2-negative breast cancer who have certain inherited BRCA mutations and have received chemotherapy (and hormone therapy if ER-positive). In 2019, alpelisib (Piqray), a phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity primarily against PI3Kα, was approved for patients with certain gain-of-function mutations in the gene encoding the catalytic α subunit of PI3K (PIK3CA). These mutations lead to activation of PI3Kα and Akt signaling, cell transformation, and tumor development in in vitro and in vivo models. PI3K inhibition by alpelisib treatment has been shown to induce increased estrogen receptor (ER) transcription in breast cancer cells. In xenograft models derived from ER-positive, PIK3CA-mutated breast cancer cell lines, the combination of alpelisib and fulvestrant demonstrated increased antitumor activity compared with either treatment alone. PIK3CA mutations are present in approximately 30–40% of breast cancer tumors and are most commonly found in ER-positive patients.

[0004] Standard treatment currently involves screening tumors for expression levels of hormone receptors, estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor 2 (HER2) kinase. Currently, women diagnosed with breast cancer may be preliminarily treated with surgery, chemotherapy (optional), and radiation before targeted therapy is initiated. Hormone receptor-positive breast cancer is sensitive to hormone therapy (also called endocrine therapy) with selective estrogen receptor modulators or SERMs (e.g., tamoxifen, toremifene, raloxifene), aromatase inhibitors or AIs (e.g., anastrozole, letrozole, exemestane), or selective estrogen receptor degraders or SERDs (e.g., fulvestrant). Hormone therapies, such as gonadotropin-releasing hormone (GnRH) agonists (typically used in pre- and peri-menopausal women) and aromatase inhibitors (AIs) (typically used in postmenopausal women or together with GnRH agonists in pre- or peri-menopausal women), block the body's production of estrogen, while SERMs and SERDs block the proliferative effects of estrogen on breast cancer cells. While the prognosis for most patients with early-stage ER-positive breast cancer is relatively good compared to non-hormonal cancers, adjuvant hormonal therapy often fails, resulting in recurrence, including distant metastasis (i.e., advanced breast cancer). Metastatic or advanced breast cancer, whether hormone-naive or advanced despite endocrine therapy, often remains ER-positive and remains dependent on the ER axis for growth. The treatment of advanced breast cancer has rapidly evolved from the use of endocrine monotherapy, such as SERMs or AIs or fulvestrant, to the combination of endocrine therapy with recently approved kinase inhibitors, including cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (approved in 2015), ribociclib (approved in 2017), abemaciclib (approved in 2017), trilaciclib, and relociclib), or mechanistic target of rapamycin (mTOR) inhibitors (everolimus (approved in 2012)).These combination therapies delay the progression of advanced breast cancer compared with endocrine therapy alone and have replaced the use of endocrine therapy alone in late-stage breast cancer.

[0005] Herein, we propose the use of tumor genotyping (deep DNA sequencing) as a means to determine the mutational status of estrogen receptors in breast cancer patients as a basis for rational therapy selection. Certain common mutations in estrogen receptor alpha may arise during treatment and confer resistance to approved endocrine therapies, even when combined with various kinase therapies discussed above. We have discovered at least one mutation described herein (e.g., Y537S) that remains sensitive to the androgen agonists of the present invention despite resistance to SERMs, AIs, and fulvestrant. As a result, even patients with late-stage ER-positive and AR-positive breast cancer who have been exposed to a fully endocrine- and oriented therapy environment may still have additional hormonal treatment options before being committed to chemotherapy. If screening reveals certain ER mutations, their treatment can be personalized to include the use of SARMs to delay disease progression and / or cause tumor regression.

[0006] HER2-positive breast cancer is sensitive to HER2 kinase inhibitors (e.g., trastuzumab, lapatinib, neratinib, and tucatinib), which are commonly used in metastatic disease. Antiangiogenic therapy (bevacizumab) was also approved for metastatic disease, but the FDA removed it in 2011. Despite these multiple rounds of targeted therapy, patients often have or develop refractory forms of breast cancer. Examples of refractory breast cancer include primary tumors that are triple-negative (lacking ER, PR, and HER2), hormone-resistant (SERM, SERD, or AI-resistant), or kinase inhibitor-resistant (e.g., inhibitors of CDK4 / 6, mTor, and / or HER2), or metastatic breast cancer tumors. When all targeted therapies fail, for example, when metastatic tumors reactivate or further metastasize, radiation and high-dose chemotherapy are required to remove refractory breast cancer tumors. Current chemotherapy available for the treatment of refractory breast cancer includes anthracyclines, taxanes, and epothilones, which are toxic, risky, expensive, administered intravenously, and often ineffective, especially in the treatment of metastatic disease.

[0007] Ample clinical evidence suggests that androgens normally inhibit breast growth. For example, women with androgen deficiency are at increased risk for developing breast cancer. Androgen signaling plays a critical role in breast homeostasis, counteracting the proliferative effects of estrogen signaling in the breast. However, when steroidal androgens biotransform into estrogens (via the aromatase pathway), they increase cell proliferation and the risk of breast carcinogenesis. Historically, the steroidal androgen receptor agonists testosterone, fluoxymesterone, and calcitonin were used for advanced breast cancer. These agents suffered from side effects such as excessive virilization, cross-reactivity with estrogen receptors, and aromatization to estrogens. The use of steroidal androgens in advanced breast cancer predates breast cancer screening for hormone and kinase receptors. Recently, the AR has been found to be expressed in 50–90% of breast tumors, providing a mechanism for using androgens as targeted therapy for AR-positive breast cancer.

[0008] Although the majority of breast cancers are considered hormone receptor-positive (ER, PR, or HER2), 15–20% of women diagnosed with breast cancer have triple-negative breast cancer (TNBC), characterized by the lack of expression of ER, PR, or HER2. TNBC occurs more frequently in younger patients (under 50 years of age) and generally exhibits more aggressive behavior. Until recently, these patients with advanced TNBC were limited to standard supportive treatment options, such as cytotoxic chemotherapy. The efficacy of chemotherapy has been improved with the use of sacituzumab govitecan (Trodelvy), an antibody-directed conjugate therapy that delivers SN-38, the active metabolite of the topoisomerase inhibitor irinotecan, to TNBC patients who express Trop-2 (human trophoblast cell-surface antigen 2) on their breast cancer cells. Topoisomerases I and II are normal host enzymes found in the nuclei of mammalian cells and are required for normal DNA replication and cell division. The enzyme creates and then repairs single-stranded nicks in cellular DNA. The nicks untangle and relax the supercoiled double-stranded DNA, allowing replication to proceed. Once the torsional strain of the DNA is relieved, topoisomerase reseals the relaxed double helix. Topoisomerase activity is particularly increased in rapidly dividing cells and cancer cells. When topoisomerase is inhibited, the accumulation of DNA breaks leads to DNA replication inhibition and cell death. This makes it an appropriate, but non-selective, target for anti-cancer therapy.

[0009] The experimental microtubule-disrupting agent, sabizabrin [(2-(1H-indol-3-yl)imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone and its alternative resonance form, (2-(1H-indol-3-yl)imidazol-5-yl)(3,4,5-trimethoxyphenyl)methanone], has been shown to bind to the colchicine-binding site of tubulin and inhibit (CBSI) tubulin dynamics. These agents are orally active, and unlike colchicine, these CBSIs are not substrates for the efflux channels that pump anticancer drugs out of cancer cells, allowing CBSIs to overcome taxane resistance. CBSI-based inhibition of tubulin dynamics leads to apoptotic cell death by arrest in the G2 / M phase of mitosis. Deng et al. recently characterized sabizablin in various in vitro and in vivo models of TNBC and confirmed potent and highly effective tumor growth inhibition in primary and metastatic tumors, as well as prevention of metastasis to distant organs, including the liver, lung, pancreas, and brain, in taxane-sensitive (MDA-MB-231) and taxane-resistant models of TNBC, including patient-derived xenografts.

[0010] However, even after an initial response to chemotherapy, the duration of response may be short, and there is a higher likelihood of visceral metastasis, aggressive disease, and reduced survival compared with hormone receptor-positive breast cancer. Therefore, research is focused on identifying therapeutic targets in TNBC.

[0011] A novel approach to treating TNBC using antibodies that block programmed death ligand 1 (PD-L1) has been approved in PD-LI-positive patients. One such antibody is atezolizumab (Tecentriq, approved for TNBC in 2019), and another is pembrolizumab (Keytruda, approved for TNBC in 2020). A median progression-free survival (PFS) of 7.4 months was observed with atezolizumab and nab-paclitaxel compared with 4.8 months with placebo and nab-paclitaxel, leading to the approval of atezolizumab. With pembrolizumab, the median PFS was 9.7 months in the pembrolizumab plus chemotherapy group and 5.6 months in the placebo group.

[0012] One hormone receptor target still available in ER-positive, HER2-positive, and triple-negative breast cancer is the androgen receptor (AR). AR is the most highly expressed steroid receptor in breast cancer, with up to 95% of ER-positive breast cancers expressing AR (see Example 9 below). In TNBC, up to 30% of cancers may express AR. Historically, AR has been considered antiproliferative and beneficial in hormone receptor-positive breast cancer. Data indicates that the presence of AR and androgen synthase in TNBC is associated with lower proliferation, lower tumor grade, better overall survival, and more favorable clinical outcomes compared with patients with TNBC that do not express AR. Furthermore, evidence suggests that the AR target gene prostate-specific antigen (PSA) is a favorable prognostic marker in breast cancer (not just TNBC). Based on these findings, research is focusing on AR as a potential therapeutic target.

[0013] Long-term cancer treatment with estrogen synthesis inhibitors (AIs or GnRH agonists) or ER antagonists (SERMs or SERDs) leads to mutations in target proteins and activation of resistance pathways. For example, continued treatment of ER-positive breast cancer with ER antagonists or aromatase inhibitors (AIs) leads to resistance due to mutations in the ER ligand-binding domain (LBD). Clinical studies have estimated that more than 30% of breast cancers treated with tamoxifen become refractory and recur as resistant cancers, and more than 40% of recurrent breast cancers express mutated ERs. Mutant ERs that arise during treatment escape the inhibition of the hormonal axis, rendering these patients unable to respond to endocrine therapy. Therefore, these patients must be treated with chemotherapeutic agents. Such cancers require new, non-toxic, or less toxic, effective endocrine therapies. One possibility is pharmacogenomic screening of tumors or circulating tumor cells for the presence of mutated ERs that confer resistance to current endocrine therapies. This can be done upon molecular phenotyping as ER-positive (i.e., early stage disease), or alternatively in patients who have failed endocrine therapy such as SERMs, AIs, SERDs, and / or GnRH agonists, whether or not combined with CDK4 / 6 or mTor inhibitors (i.e., late stage disease).

[0014] Selective androgen receptor modulators (SARMs) are compounds that exhibit AR-mediated tissue-selective activity. Unlike their steroid precursors, SARMs are non-aromatizable, generally do not exhibit activity at other steroid receptors, including ER and PR, and are non-androgenic. Furthermore, SARMs may be beneficial in refractory breast cancer patients due to their hypermyoanabolic effects, which should improve resistance to high-dose chemotherapy. Furthermore, SARMs have beneficial osteogenic and anti-osteoclastic effects in bone, which may reduce the risk of bone metastasis during endocrine and / or chemotherapy, or reduce the risk of osteoporosis.

[0015] New innovative approaches are being developed to treat subjects with a) breast cancer, b) metastatic breast cancer, c) refractory breast cancer, d) AR-positive breast cancer, e) AR-positive refractory breast cancer, f) AR-positive metastatic breast cancer, g) AR-positive and ER-positive breast cancer, h) AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) triple-negative breast cancer, j) advanced breast cancer, and k) selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastomosis), and other therapeutic agents. Trozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (PA RP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2Treating subjects with breast cancer who have failed treatment with ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; and / or p) prolonging progression-free survival of a subject with breast cancer; q) treating, preventing, suppressing or inhibiting AR-positive triple-negative breast cancer; r) treating a subject with HER2-positive breast cancer; s) treating a subject with ER-mutant-expressing breast cancer; t) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or u) initially 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 There is an urgent need, at both the basic science and clinical levels, to develop compounds that are useful for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake. Summary of the Invention

[0016] In one aspect, the present invention provides a pharmaceutical composition comprising a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor, wherein the SARM compound has the structure of Formula I:

[0017] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0018] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0019] [ka] n is an integer from 1 to 4, m is an integer from 1 to 3; or Pharmaceutical compositions are provided that are optical isomers, racemic mixtures, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or crystals thereof.

[0020] In some embodiments, the SARM compound of the compositions of the invention is represented by the structure of formula VIII, IX, X, XI, XII, XIII, or XIV:

[0021] [ka]

[0022] [ka]

[0023] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and a CDK4 / 6 inhibitor.

[0024] [ka] In some embodiments of the compositions of the present invention, the CDK4 / 6 inhibitor is palbociclib, ribociclib, trilaciclib, relociclib, or abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and palbociclib.

[0026] [ka]

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and ribociclib.

[0028] [ka]

[0029] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and trilaciclib.

[0030] [ka]

[0031] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and relociclib.

[0032] [ka]

[0033] In another aspect, the present invention provides a pharmaceutical composition comprising compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and abemaciclib.

[0034] [ka]

[0035] In yet another aspect, the present invention provides a method for treating a subject suffering from breast cancer, comprising administering to said subject a pharmaceutical composition of the present invention described herein.

[0036] In some embodiments of the methods of the invention, the breast cancer is AR-positive breast cancer, ER-positive breast cancer, triple-negative breast cancer, HER2-positive breast cancer, advanced breast cancer, refractory breast cancer, metastatic breast cancer, or breast cancer treated with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), a gonadotropin-releasing hormone (GnRH) agonist (goserelin), an aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), fulvestrant, a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relocilib, ribo ... rib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (PARP) inhibitor (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitor (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2 Breast cancer that has not been treated with ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin).

[0037] In some embodiments, the breast cancer has not been treatable with a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the subject in the methods of the present invention is resistant or non-responsive to a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, or abemaciclib (Vorzenio). In certain embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance). In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio).

[0038] In some embodiments, the compositions of the present invention described herein resensitize the breast cancer to treatment with a CDK4 / 6 inhibitor. In some embodiments, the compositions of the present invention described herein overcome estrogen endocrine resistance. In some embodiments, the compositions of the present invention described herein overcome resistance to estrogen endocrine and CDK4 / 6 inhibitor combination therapy. In some embodiments, the estrogen endocrine therapy includes at least one of tamoxifen, toremifene, raloxifene, exemestane, letrozole, anastrozole, and fulvestrant. In some embodiments of the methods of the present invention, the CDK4 / 6 inhibitor is at least one of palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, and abemaciclib (Vorzenio). [Brief explanation of the drawings]

[0039] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, the invention, both as to the organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in connection with the accompanying drawings. [Figure 1A]Figure 1 shows that DHT and the compound of formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figure 1A shows MDA-MB-231 cell expression of AR after transfection. [Figure 1B] Figure 1B shows that DHT and the compound of formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figure 1B shows the IC50 in AR-positive MDA-MB-231 cells. [Figure 1C] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1D] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1E]Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1F] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1G] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1H]Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1I] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 1J] Figures 1C-1J show that DHT and the compound of Formula IX inhibit MDA-MB-231 triple-negative breast cancer cell growth. Figures 1C-1J show the effects of DHT, Formula IX, bicalutamide, and the (R) enantiomer of Formula IX on percent cell viability. (Cells in Figures 1C, 1E, 1G, and 1I were treated in charcoal-stripped FBS. Cells in Figures 1D, 1F, 1H, and 1J were treated in full serum.) ● MDA-MB-231 and lacZ, ○ MDA-MB-231 and AR (200 μL), Ψ MDA-MB-231 and AR (500 μL). [Figure 2A] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figure 2A shows HCC-38 cell expression of AR after transfection. [Figure 2B] Figure 2B shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figure 2B shows the IC50 in AR-positive HCC-38 cells. [Figure 2C] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 2D] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 2E] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 2F] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 2G]Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 2H] Figure 2 shows that DHT and Formula IX inhibit HCC-38 triple-negative breast cancer cell growth. Figures 2A-2H show the effects of DHT, Formula IX, and bicalutamide on percent cell viability (%). (Cells in Figures 2C, 2E, and 2G were treated in charcoal-stripped FBS. Cells in Figures 2D, 2F, and 2H were treated in full serum.) ● HCC-38 with lacZ, ○ HCC-38 and AR (200 μL), Ψ HCC-38 and AR (500 μL). [Figure 3A] Figures 3A-3D show the effect of DHT or Formula IX on MDA-MB-231 cells, reversed by bicalutamide. Figures 3A-3D show the effect of DHT or Formula IX on percent cell viability (%) in the presence or absence of bicalutamide. (Cells in Figures 3A and 3C were treated in charcoal-stripped FBS. Cells in Figures 3B and 3D were treated in full serum.) lacZ and 10 μM bicalutamide; lacZ, ΨAR and 10 μM bicalutamide, ΔAR. [Figure 3B] Figures 3A-3D show the effect of DHT or Formula IX on MDA-MB-231 cells, reversed by bicalutamide. Figures 3A-3D show the effect of DHT or Formula IX on percent cell viability (%) in the presence or absence of bicalutamide. (Cells in Figures 3A and 3C were treated in charcoal-stripped FBS. Cells in Figures 3B and 3D were treated in full serum.) lacZ and 10 μM bicalutamide; lacZ, ΨAR and 10 μM bicalutamide, ΔAR. [Figure 3C]Figures 3A-3D show the effect of DHT or Formula IX on MDA-MB-231 cells, reversed by bicalutamide. Figures 3A-3D show the effect of DHT or Formula IX on percent cell viability (%) in the presence or absence of bicalutamide. (Cells in Figures 3A and 3C were treated in charcoal-stripped FBS. Cells in Figures 3B and 3D were treated in full serum.) lacZ and 10 μM bicalutamide; lacZ, ΨAR and 10 μM bicalutamide, ΔAR. [Figure 3D] Figures 3A-3D show the effect of DHT or Formula IX on MDA-MB-231 cells, reversed by bicalutamide. Figures 3A-3D show the effect of DHT or Formula IX on percent cell viability (%) in the presence or absence of bicalutamide. (Cells in Figures 3A and 3C were treated in charcoal-stripped FBS. Cells in Figures 3B and 3D were treated in full serum.) lacZ and 10 μM bicalutamide; lacZ, ΨAR and 10 μM bicalutamide, ΔAR. [Figure 3E] Figure 3E shows that the effects of DHT and Formula IX on MDA-MB-231 cells were reversed by bicalutamide. Figure 3E shows IC50 values ​​in AR-positive cells in the presence or absence of bicalutamide pretreatment. [Figure 4A] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell viability percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4B] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figure 4A, Figure 4B, Figure 4E, Figure 4F, Figure 4G, Figure 4H, Figure 4K, Figure 4L, Figure 4M, Figure 4N, Figure 4O, and Figure 4P show the effect of AR agonists on cell survival percentage (%). Figure 4B, Figure 4D, Figure 4F, Figure 4H, Figure 4J, Figure 4L, Figure 4N, and Figure 4P cells were treated in complete serum. Figure 4Q shows the EC50 and IC50 values ​​in AR-positive cells. [Figure 4C] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4C and 4D show the effect of AR antagonists on cell survival percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4D] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4C and 4D show the effect of AR antagonists on cell survival percentage (%). Cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4E] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell viability percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4F] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell survival percentage (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4G] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell viability percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4H]Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell survival percentage (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4I] Figures 4A, 4B, 4C, 4E, 4G, 4I, 4M, and 4O show the effect of AR non-binding agents on percent cell viability. Figures 4A ... [Figure 4J] Figures 4A, 4B, 4C, 4D, 4F, 4H, 4J, 4L, 4N, and 4P show the effect of AR non-binding agents on percent cell viability (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in full serum. [Figure 4K] Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on percent (%) cell survival. [Figure 4L] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell survival percentage (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4M]Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell viability percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4N] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell survival percentage (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4O] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell viability percentage (%). The cells in Figures 4A, 4C, 4E, 4G, 4I, 4M, and 4O were treated in charcoal-treated FBS. [Figure 4P] Figure 4 shows that AR agonists inhibit triple-negative breast cancer cell growth. Figures 4A, 4B, 4E, 4F, 4G, 4H, 4K, 4L, 4M, 4N, 4O, and 4P show the effect of AR agonists on cell survival percentage (%). The cells in Figures 4B, 4D, 4F, 4H, 4J, 4L, 4N, and 4P were treated in complete serum. [Figure 4Q] Figure 4Q shows that AR agonists inhibit triple-negative breast cancer cell growth. Figure 4Q shows EC50 and IC50 values ​​in AR-positive cells. [Figure 5] 1 shows that growth inhibitory ligands are AR agonists in MDA-MB-231 cells. [Figure 6A]Figures 6A and 6B show the expression of ERα or ERβ in MDA-MB-231 cells after transfection, indicating that the growth inhibitory effect in MDA-MB-231 cells is selective for AR. [Figure 6B] Figures 6A and 6B show the expression of ERα or ERβ in MDA-MB-231 cells after transfection, indicating that the growth inhibitory effect in MDA-MB-231 cells is selective for AR. [Figure 6C] The growth inhibitory effect in MDA-MB-231 cells is selective for AR. Figures 6C, 6D, and 6E show the effect of estradiol (E2) or ICI 182,780 (ICI) on percent cell viability (%). (Cells in Figure 6C were treated in charcoal-treated serum.) [Figure 6D] The growth inhibitory effect in MDA-MB-231 cells is selective for AR. Figures 6C, 6D, and 6E show the effect of estradiol (E2) or ICI 182,780 (ICI) on percent cell survival (%). (Cells in Figures 6D and 6E were treated in full serum.) [Figure 6E] The growth inhibitory effect in MDA-MB-231 cells is selective for AR. Figures 6C, 6D, and 6E show the effect of estradiol (E2) or ICI 182,780 (ICI) on percent cell survival (%). (Cells in Figures 6D and 6E were treated in full serum.) [Figure 7] 1 shows that DHT alters the morphology of MDA-MB-231 cells. [Figure 8] 1 shows the effect of Formula VIII on steroid receptor transactivation (agonist mode). [Figure 9]1 illustrates dose-response curves of PR activity (antagonist mode) for compounds of Formula VIII, Formula IX, the R-enantiomer of Formula IX, and RU486. Black circles (●) correspond to the data point for Formula VIII (IC50=17.05 nM), white circles (○) correspond to Formula IX (IC50=162.9 nM), black triangles (▼) correspond to the R-enantiomer of Formula IX (IC50=1689 nM), and white triangles (Δ) correspond to RU486 (IC50=0.048 nM). [Figure 10A] Figure 10 shows that SARM (Formula VIII) inhibits MDA-MB-231-AR tumor growth. Intact female nude mice bearing 150-200 mm tumors derived from MDA-MB-231-AR triple-negative breast cancer cells were administered vehicle () or 30 mg / kg of Formula VIII (●) orally for 35 days after measuring body weight (10A) and tumor size (10B). [Figure 10B] Figure 10 shows that SARM (Formula VIII) inhibits MDA-MB-231-AR tumor growth. Intact female nude mice bearing 150-200 mm tumors derived from MDA-MB-231-AR triple-negative breast cancer cells were administered vehicle () or 30 mg / kg of Formula VIII (●) orally for 35 days after measuring body weight (10A) and tumor size (10B). [Figure 11] Figure 1 shows that SARM (Formula VIII) inhibits MDA-MB-231-AR tumor growth. In intact female nude mice bearing 150-200 mm tumors from MDA-MB-231-AR triple-negative breast cancer cells, and then receiving an oral dose of vehicle or 30 mg / kg of Formula VIII, tumor size (mm) (left panel) and % change in tumor size (center panel), as well as tumor weight (right panel) were measured after 35 days. [Figure 12]Figure 1 shows the morphology of MDA-MB-231 breast cancer cells (MDA-MB-231-AR cells) stably transfected with AR. The results show that AR agonists, DHT, Formula IX and Formula VIII, compared with vehicle, bicalutamide, or the inactive isomer of Formula IX, change the morphology to a more rigid phenotype. This may indicate a less metastatic breast cancer phenotype. [Figure 13A] Figure 16 shows the binding and transactivation of the indicated ligands to HEK-293 (13A) or MDA-MB-231 (13B and 13C) cells. DHT, Formula IX, and Formula VIII are agonists of AR in breast cancer cells. (Example 16) [Figure 13B] Figure 16 shows the binding and transactivation of the indicated ligands to HEK-293 (13A) or MDA-MB-231 (13B and 13C) cells. DHT, Formula IX, and Formula VIII are agonists of AR in breast cancer cells. (Example 16) [Figure 13C] Figure 16 shows the binding and transactivation of the indicated ligands to HEK-293 (13A) or MDA-MB-231 (13B and 13C) cells. DHT, Formula IX, and Formula VIII are agonists of AR in breast cancer cells. (Example 16) [Figure 14] Figure 1 shows the antiproliferative activity of DHT and SARMs in MDA-MB-231 breast cancer cells stably transfected with AR. MDA-MB-231 cells stably transfected with AR using lentivirus were treated with the indicated ligands for 6 days, and cell numbers were counted using a Coulter counter. DHT and SARMs (VIII and IX) inhibited the growth of MDA-MB-231 triple-negative breast cancer cells stably transfected with AR, but the AR antagonist bicalutamide did not. [Figure 15] Microarray results are presented showing that activated AR (AR activated by the compound of Formula VIII) suppressed the expression of more genes than induced in MDA-MB-231-AR xenograft breast cancer cells. [Figure 16]Illustrates validation of microarray results. [Figure 17] Figure 1 shows that Formula VIII inhibited the growth of MCF-7-AR triple positive xenografts. [Figure 18] 1 shows inhibition of uterine weight gain in estrogen-supplemented animals treated with Formula VIII, demonstrating the ability of the SARM to counteract estrogen stimulation in vivo. [Figure 19] 1 shows that the AR expression pattern in response to an AR agonist (Formula VIII) is similar to that observed in prostate cancer cells. [Figure 20] Illustrates validation of microarray results. [Figure 21] 10 shows upregulation of JNK phosphorylation in MCF7-AR tumors using Formula VIII. [Figure 22] Figure 1 shows the inhibition of triple-negative breast cancer (TNBC) growth using Formulas VIII and IX. Formula VIII and Formula IX showed approximately 85% TGI in a TNBC model using MDA-MB-231-AR cells in nude mice at all doses tested (5 and 10 mg per kg for Formula VIII, and 5, 10, and 30 mg per kg for Formula IX). [Figure 23] Figure 1 shows the inhibition of triple-negative breast cancer using Formulas VIII and IX. Tumor weight was similarly reduced for all doses of Formula VIII and Formula IX. Spleen enlargement (680 mg vs. 200-300 mg in normal mice) was only seen in vehicle-treated mice, likely indicating prevention of tumor metastasis to the spleen by the SARM. [Figure 24] All doses of the SARMs of Formula VIII and Formula IX showed weight gain, indicating healthy growth and a lack of toxicity. In comparison, vehicle-treated animals grew less robustly. [Figure 25A]Figure 25B and Figure 25D illustrate the antagonism by SARM of estradiol's ability to activate ER target genes in MCF-7-AR cells. Figures 25B and 25D show that adding AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effect of estradiol (unopposed) on the ER target genes PR and PS2, respectively. Addition of AR to MCF-7-AR cells suppressed activation of these ER targets in the presence of SARM alone or SARM plus estradiol (E2) compared to GFP-transfected cells (i.e., without AR, Figures 25A and 25C). [Figure 25B] Figure 25B and Figure 25D illustrate the antagonism by SARM of estradiol's ability to activate ER target genes in MCF-7-AR cells. Figures 25B and 25D show that adding AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effect of estradiol (unopposed) on the ER target genes PR and PS2, respectively. Addition of AR to MCF-7-AR cells suppressed activation of these ER targets in the presence of SARM alone or SARM plus estradiol (E2) compared to GFP-transfected cells (i.e., without AR, Figures 25A and 25C). [Figure 25C]Figure 25B and Figure 25D illustrate the antagonism by SARM of estradiol's ability to activate ER target genes in MCF-7-AR cells. Figures 25B and 25D show that adding AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effect of estradiol (unopposed) on the ER target genes PR and PS2, respectively. Addition of AR to MCF-7-AR cells suppressed activation of these ER targets in the presence of SARM alone or SARM plus estradiol (E2) compared to GFP-transfected cells (i.e., without AR, Figures 25A and 25C). [Figure 25D] Figure 25B and Figure 25D illustrate the antagonism by SARM of estradiol's ability to activate ER target genes in MCF-7-AR cells. Figures 25B and 25D show that adding AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effect of estradiol (unopposed) on the ER target genes PR and PS2, respectively. Addition of AR to MCF-7-AR cells suppressed activation of these ER targets in the presence of SARM alone or SARM plus estradiol (E2) compared to GFP-transfected cells (i.e., without AR, Figures 25A and 25C). [Figure 25E]Figure 25B and Figure 25D show that the addition of AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effect of estradiol (unopposed) on the ER target genes PR and PS2, respectively. Addition of AR to MCF-7-AR cells suppressed activation of these ER targets in the presence of SARM alone or SARM plus estradiol (E2), compared to GFP-transfected cells (i.e., without AR, Figures 25A and 25C). Figure 25E shows that AR target genes are enhanced by SARM even in the presence of estradiol. [Figure 26A] Immunohistochemistry of two regions of the same BR-0001 tumor, a triple-negative breast cancer (TNBC), is shown, demonstrating that AR expression is consistent throughout this formalin-fixed, paraffin-embedded (FFPE) tissue stained with an AR antibody (AR N20 from SCBT). [Figure 26B] Immunohistochemistry of two regions of the same BR-0001 tumor, a triple-negative breast cancer (TNBC), is shown, demonstrating that AR expression is consistent throughout this formalin-fixed, paraffin-embedded (FFPE) tissue stained with an AR antibody (AR N20 from SCBT). [Figure 26C] Immunohistochemical staining of an AR-negative TNBC FFPE tumor is depicted as a negative control. [Figure 27A]The inhibition of BR-0001 tumor xenograft growth by Formula IX compared to enzalutamide (Enza) or vehicle is illustrated in terms of breast cancer tumor volume (Figures 27A and 27B) and weight (Figure 27C) over time. Experiments 1 and 2 were duplicate experiments performed at different times with n=5 and n=10 animals, respectively. Figure 27A provides the results for Experiment 1, Figure 27B provides the results for Experiment 2, and Figure 27C provides the results for Experiment 2. BR-0001 TNBC fragments of 1 mm (approximately) were implanted subcutaneously into NOD scid gamma (NSG) mice. When tumors reached 100-200 mm, animals were randomized and orally treated with vehicle, 10 mg / kg / day Formula IX, or enzalutamide. Tumor volumes were measured three times weekly. Animals were sacrificed, and tumors were weighed. [Figure 27B] The inhibition of BR-0001 tumor xenograft growth by Formula IX compared to enzalutamide (Enza) or vehicle is illustrated in terms of breast cancer tumor volume (Figures 27A and 27B) and weight (Figure 27C) over time. Experiments 1 and 2 were duplicate experiments performed at different times with n=5 and n=10 animals, respectively. Figure 27A provides the results for Experiment 1, Figure 27B provides the results for Experiment 2, and Figure 27C provides the results for Experiment 2. BR-0001 TNBC fragments of 1 mm (approximately) were implanted subcutaneously into NOD scid gamma (NSG) mice. When tumors reached 100-200 mm, animals were randomized and orally treated with vehicle, 10 mg / kg / day Formula IX, or enzalutamide. Tumor volumes were measured three times weekly. Animals were sacrificed, and tumors were weighed. [Figure 27C]The inhibition of BR-0001 tumor xenograft growth by Formula IX compared to enzalutamide (Enza) or vehicle is illustrated in terms of breast cancer tumor volume (Figures 27A and 27B) and weight (Figure 27C) over time. Experiments 1 and 2 were duplicate experiments performed at different times with n=5 and n=10 animals, respectively. Figure 27A provides the results for Experiment 1, Figure 27B provides the results for Experiment 2, and Figure 27C provides the results for Experiment 2. BR-0001 TNBC fragments of 1 mm (approximately) were implanted subcutaneously into NOD scid gamma (NSG) mice. When tumors reached 100-200 mm, animals were randomized and orally treated with vehicle, 10 mg / kg / day Formula IX, or enzalutamide. Tumor volumes were measured three times weekly. Animals were sacrificed, and tumors were weighed. [Figure 28A] Figure 28A illustrates immunohistochemistry of BR-0001 tumors from animals treated with vehicle or Formula IX and stained for Ki-67. Ki-67 was reduced in tumors from animals treated with Formula IX. Quantification of Ki-67 showed that Ki-67 staining was reduced by approximately 50% after two weeks of treatment. Tumors from Experiment 2 were fixed in formalin and paraffin-embedded. Slides were sectioned and stained with Ki-67 antibody (Figure 28A). Ki-67 staining was reduced in tumors from animals treated with Formula IX. Ki-67-positive cells (200 cells total per field) in each slide were counted and expressed as % stained cells (Figure 28B). For reference, insets to the graphics are bars measuring 200 microns (μm) in length. [Figure 28B]Figure 28A illustrates immunohistochemistry of BR-0001 tumors from animals treated with vehicle or Formula IX and stained for Ki-67. Ki-67 was reduced in tumors from animals treated with Formula IX. Quantification of Ki-67 showed that Ki-67 staining was reduced by approximately 50% after two weeks of treatment. Tumors from Experiment 2 were fixed in formalin and paraffin-embedded. Slides were sectioned and stained with Ki-67 antibody (Figure 28A). Ki-67 staining was reduced in tumors from animals treated with Formula IX. Ki-67-positive cells (200 cells total per field) in each slide were counted and expressed as % stained cells (Figure 28B). For reference, insets to the graphics are bars measuring 200 microns (μm) in length. [Figure 29] The Z-score (PAM50) of the 50 genes used to identify BR-0001 is shown. PAM50 is a 50-gene set used to classify breast cancer. PAM50 gene expression data indicated that BR-0001 tumor belongs to the basal-like breast cancer (BLBC) subtype of TNBC. The expression (Z-score) of the 50 genes required to classify breast cancer is shown here. [Figure 30A] This figure illustrates gene expression data compared with published genes (Pietenpol group) that are useful for subclassifying basal-like breast cancer (BLBC). Subclassification showed that BR-0001 belongs to the luminal androgen receptor (LAR) and mesenchymal stem-like (MSL) subtypes. The six TNBC subtypes according to the Pietenpol group include two basal-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) subtypes. GE-gene expression. [Figure 30B]This figure illustrates gene expression data compared with published genes (Pietenpol group) that are useful for subclassifying basal-like breast cancer (BLBC). Subclassification showed that BR-0001 belongs to the luminal androgen receptor (LAR) and mesenchymal stem-like (MSL) subtypes. The six TNBC subtypes according to the Pietenpol group include two basal-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) subtypes. GE-gene expression. [Figure 31] 1 depicts gene expression changes in BR-0001 tumors treated with Formula IX. [Figure 32] 1 illustrates the reduction in tumor growth of ER-positive, PR-positive, HER2-positive, and AR-positive tumors composed of HCI-007 cells using Formula IX. [Figure 33A] Figure 33A illustrates the potent tumor growth reduction using Formula IX in xenografts composed of HCI-013 cells. HCI-013 phenotype is triple positive and also expresses AR. Figure 33A: Tumor volume change (%). [Figure 33B] Figure 33B illustrates the potent tumor growth reduction using Formula IX in xenografts composed of HCI-013 cells. HCI-013 phenotype is triple positive and also expresses AR. Figure 33B: Tumor weight (g). [Figure 34A] Figure 34A illustrates that ER agonists inhibited the growth of ER- and AR-positive breast cancer cells. Figure 34B illustrates that Formula IX inhibited the growth of ZR-75-1 cells. ZR-75-1 breast cancer cells (n=4 / treatment) seeded in growth medium were treated with the indicated doses of Formula IX for 6 days, the medium was changed, and re-treated on day 3. After 6 days of treatment, the cells were harvested and counted. [Figure 34B]Figure 34B illustrates that ER agonists inhibited the growth of ER- and AR-positive breast cancer cells. Figure 34B illustrates that Formula IX inhibited the growth of AR-expressing MCF-7 cells. MCF-7 cells stably transfected with GFP (MCF-7-GFP) or AR (MCF-7-AR) were seeded in growth medium in a 96-well plate (n=4 / treatment) and treated with the indicated doses of Formula IX. The medium was replaced after 3 days and the cells were re-treated. After 6 days of treatment, the cells were fixed and cell viability was measured by SRB assay. [Figure 34C] This figure illustrates that ER agonists inhibited the growth of ER- and AR-positive breast cancer cells. Figure 34C illustrates that breast cancer fibroblasts treated with AR agonists secreted factors that inhibited MCF-7-GFP cells lacking supplemental AR. Primary fibroblasts obtained from breast cancer patients were cultured in growth medium and treated in triplicate with vehicle, 10 nM DHT, 1 μM enzalutamide, or 1 μM Formula IX. The medium was replaced, and cells were re-treated on days 4 and 7. The medium was collected, pooled from the triplicates, and stored at -80°C. After 10 days of treatment, cells were fixed, and cell viability was measured using SRB. MCF-7 cells stably transfected with GFP (MCF-7-GFP) were seeded in growth medium. 24 hours after seeding, the cells were fed with conditioned medium obtained from patient-derived fibroblasts as described above. Cells were fed with conditioned medium for 10 days, with medium changes on days 4 and 7. After 10 days of treatment, cells were fixed and viability was measured by SRB assay. [Figure 34D] Figure 34D illustrates that ER agonists inhibited the growth of ER- and AR-positive breast cancer cells. Figure 34D illustrates that AR ligands did not inhibit the growth of ER-negative, AR-positive HCI-9 PDXs. AR-positive, but ER-negative HCI-9 PDXs were surgically implanted as 1 mm fragments under the mammary fat pad of NSG mice (n = 8-10 per group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle (DMSO:PEG-300 (15%:85%)), Formula IX (10 mpk p.o.), or enzalutamide (30 mpk p.o.). Tumor volumes were measured three times weekly. [Figure 34E] This figure illustrates that ER agonists inhibited the growth of ER- and AR-positive breast cancer cells. Figure 34E illustrates that HCI-13 ER-α was resistant to the ER antagonists fulvestrant and tamoxifen (right panel) compared to wild-type ER-α (left panel). ER-α from HCI-13 was cloned into the pCR3.1 vector. Wild-type ER-α and HCI-13 ER-α, ERE-LUC, and CMV-LUC were transfected into COS-1 cells using lipofectamine. 24 hours after transfection, the cells were treated with vehicle, 0.1 nM estradiol, 10 nM fulvestrant, or 1 μM tamoxifen in combination with 0.1 nM estradiol. 24 hours after treatment, the cells were harvested and luciferase assays were performed. ER antagonist treatment in wt-ER-α was significantly different from vehicle-treated wt-ER-α as indicated by *p<0.05. AR - androgen receptor, GFP - green fluorescent protein, DHT - 5α - dihydrotestosterone, E2 - 17β - estradiol, ER - estrogen receptor, SARM - selective androgen receptor modulator, SRB - sulforhodamine B, mpk - milligrams per kilogram of body weight. Values ​​are expressed as mean ± SE from n = 3-4 per data point. [Figure 35A] Figure 35A illustrates that AR agonists inhibit the proliferation and growth of wild-type and mutant ER and AR positive xenografts. Figure 35A illustrates that proteins from HCI PDX (HCI-7, 9 or 13) tumor fragments are extracted, fractionated on SDS-PAGE, and Western blotted for AR.AR is also quantified at the mRNA level and expressed as the fold change from LNCaP prostate cancer cell AR (numbers are provided below the blot). [Figure 35B]Figure 35B (same as Figure 32) and Figure 35C illustrate that AR agonists inhibited the proliferation and growth of wild-type and mutant ER and AR-positive xenografts. Figure 35B (same as Figure 32) and Figure 35C illustrate that Formula IX inhibited HCI-7 tumor growth. AR-positive HCI-7 PDX expressing wild-type ER were surgically implanted as 1 mm fragments under the mammary fat pad of NSG mice (n = 8-10 / group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle (DMSO:PEG-300 (15%:85%)), Formula IX (10 mpk po), or enzalutamide (30 mpk po). Tumor volumes were measured weekly. At sacrifice, tumors were removed, weighed (Figure 35C), and stored for further analysis. [Figure 35C] Figure 35B (same as Figure 32) and Figure 35C illustrate that AR agonists inhibited the proliferation and growth of wild-type and mutant ER and AR-positive xenografts. Figure 35B (same as Figure 32) and Figure 35C illustrate that Formula IX inhibited HCI-7 tumor growth. AR-positive HCI-7 PDX expressing wild-type ER were surgically implanted as 1 mm fragments under the mammary fat pad of NSG mice (n = 8-10 / group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle (DMSO:PEG-300 (15%:85%)), Formula IX (10 mpk po), or enzalutamide (30 mpk po). Tumor volumes were measured weekly. At sacrifice, tumors were removed, weighed (Figure 35C), and stored for further analysis. [Figure 35D]Figure 35D illustrates that AR agonists inhibited the proliferation and growth of wild-type and mutant ER- and AR-positive xenografts. Figure 35D illustrates that MCF-7 cells stably expressing AR (MCF-7-AR) (3 million cells / mouse) were subcutaneously implanted into ovariectomized mice supplemented with 17β-estradiol (n=8 / group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle or Formula IX (10 mpk po). Tumor volumes were measured twice weekly. *=p<0.05, HCI—Huntsman Cancer Institute; AR—androgen receptor; ER—estrogen receptor; NSG—NOD SCID gamma; PDX—patient-derived xenograft; OVX—ovariectomized; PR—progesterone receptor; mpk—milligrams per kilogram of body weight. [Figure 36A] Figure 36A illustrates that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figure 36B illustrates that HCI-13 PDX growth was independent of circulating estrogen. HCI-13 PDX tumor fragments were surgically implanted as 1 mm3 fragments under the mammary fat pad of sham-operated or ovariectomized NSG mice (n=6 / group). Tumor volumes were measured weekly. [Figure 36B] Figures 36B and 36C illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36B and 36C illustrate that AR agonists (Formula IX) inhibited the growth of HCI-13 PDXs. AR-positive HCI-13 PDXs expressing mutant ER were surgically implanted as 1 mm fragments under the mammary fat pad of NSG mice (n = 8-10 per group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle (DMSO:PEG-300 (15%:85%)) or Formula IX (10 mpk po). Tumor volumes were measured weekly. At sacrifice, tumors were removed, weighed (Figure 36C), and stored for further analysis. [Figure 36C]Figures 36B and 36C illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36B and 36C illustrate that AR agonists (Formula IX) inhibited the growth of HCI-13 PDXs. AR-positive HCI-13 PDXs expressing mutant ER were surgically implanted as 1 mm fragments under the mammary fat pad of NSG mice (n = 8-10 per group). When tumors reached 100-200 mm, mice were randomized and treated with vehicle (DMSO:PEG-300 (15%:85%)) or Formula IX (10 mpk po). Tumor volumes were measured weekly. At sacrifice, tumors were removed, weighed (Figure 36C), and stored for further analysis. [Figure 36D] Figures 36D-36G illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36D-36G illustrate that AR agonists, but not AR or ER antagonists, inhibited ER target genes in HCI-13 ex vivo sponge cultures. HCI-13 tumors (1 mm3) were cultured on gelatin sponges in growth medium (n = 3 / group, each n obtained by pooling five fragments). Tissues were treated with vehicle, 10 nM DHT, 1 μM Formula IX, 1 μM enzalutamide, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36E] Figures 36D-36G illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36D-36G illustrate that AR agonists, but not AR or ER antagonists, inhibited ER target genes in HCI-13 ex vivo sponge cultures. HCI-13 tumors (1 mm3) were cultured on gelatin sponges in growth medium (n = 3 / group, each n obtained by pooling five fragments). Tissues were treated with vehicle, 10 nM DHT, 1 μM Formula IX, 1 μM enzalutamide, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36F] Figures 36D-36G illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36D-36G illustrate that AR agonists, but not AR or ER antagonists, inhibited ER target genes in HCI-13 ex vivo sponge cultures. HCI-13 tumors (1 mm3) were cultured on gelatin sponges in growth medium (n = 3 / group, each n obtained by pooling five fragments). Tissues were treated with vehicle, 10 nM DHT, 1 μM Formula IX, 1 μM enzalutamide, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36G] Figures 36D-36G illustrate that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. Figures 36D-36G illustrate that AR agonists, but not AR or ER antagonists, inhibited ER target genes in HCI-13 ex vivo sponge cultures. HCI-13 tumors (1 mm3) were cultured on gelatin sponges in growth medium (n = 3 / group, each n obtained by pooling five fragments). Tissues were treated with vehicle, 10 nM DHT, 1 μM Formula IX, 1 μM enzalutamide, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36H] Figures 36H-36J illustrate the effect of Formula IX on ER-positive breast cancer patient specimens. Breast cancer specimens obtained from patients were cultured on gelatin sponges (n=1, each n was obtained from 5 tumor fragments). Tissues were treated with vehicle, 1 μM Formula IX, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36I]Figure 36A illustrates that AR agonists inhibited the proliferation and growth of mutant ER- and AR-positive xenografts. Figure 36A illustrates that HCI-13 PDX growth was independent of circulating estrogen. HCI-13 PDX tumor fragments were surgically implanted as 1 mm3 fragments under the mammary fat pad of sham-operated or ovariectomized NSG mice (n=6 / group). Tumor volume was measured weekly. Figures 36H-36J illustrate the effect of Formula IX on ER-positive breast cancer patient specimens. Breast cancer specimens obtained from patients were cultured on gelatin sponges (n=1, each n was obtained from 5 tumor fragments). Tissues were treated with vehicle, 1 μM Formula IX, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36J] Figures 36H-36J illustrate the effect of Formula IX on ER-positive breast cancer patient specimens. Breast cancer specimens obtained from patients were cultured on gelatin sponges (n=1, each n was obtained from 5 tumor fragments). Tissues were treated with vehicle, 1 μM Formula IX, or 100 nM fulvestrant for 3 days. RNA was extracted from the tissues, and gene expression was measured by real-time PCR and normalized to GAPDH. [Figure 36K] Figure 36 illustrates that AR agonists inhibited the proliferation and growth of mutant ER and AR-positive xenografts. The table in Figure 36K shows the fold difference in AR and ER expression at the mRNA level compared to HCI-13 tumors. *=p<0.05, HCI - Huntsman Cancer Institute, AR - androgen receptor, ER - estrogen receptor, NSG - NOD SCID gamma, PDX - patient-derived xenograft, MKI67 - Ki67 proliferation indicator protein mRNA, OVX - ovariectomized, PR - progesterone receptor, mpk - milligrams per kilogram of body weight. [Figure 37A]37A-37C illustrate gene expression studies in HCI-13 PDX demonstrating inhibition of the ER pathway by AR agonists. RNA was isolated from vehicle- or Formula IX-treated HCI-13 PDX xenografts (Figures 36B-36C), and microarrays were performed (n=4 / group). Genes differentially differentiated in the Formula IX-treated group (q<0.05) are represented in a heatmap (the top 1 / 5 of the left column of the heatmap (vehicle-treated) is primarily upregulated (originally red), while the bottom 4 / 5 of the heatmap is primarily downregulated (originally green). In contrast, the Formula IX-treated column is the exact opposite (green on top, red on bottom)) (Figure 37A). [Figure 37B] Figure 36 illustrates gene expression studies in HCI-13 PDX demonstrating inhibition of the ER pathway by AR agonists. RNA was isolated from vehicle- or Formula IX-treated HCI-13 PDX xenografts (Figures 36B-36C), and microarrays were performed (n=4 / group). Genes that differed in the Formula IX-treated group (q<0.05) are represented in a heatmap (the top 1 / 5 of the left column of the heatmap (vehicle-treated) are primarily up-regulated (originally red), while the bottom 4 / 5 of the heatmap are primarily down-regulated (originally green). The log fold change in expression of the top up- and down-regulated genes is presented in panel Figure 37B. [Figure 37C] Gene expression studies in HCI-13 PDXs are shown to demonstrate inhibition of the ER pathway by AR agonists. RNA was isolated from vehicle- or Formula IX-treated HCI-13 PDX xenografts (Figures 36B-36C), and microarrays were performed (n=4 / group). Genes differentially differentiated in the Formula IX-treated group (q<0.05) are represented in a heatmap (the top 1 / 5 of the left column of the heatmap (vehicle-treated) are primarily upregulated (originally red), while the bottom 4 / 5 of the heatmap are primarily downregulated (originally green). Canonical pathways, upstream regulators, and diseases represented by enriched genes obtained from Ingenuity Pathway Analysis (IPA) are shown in panel Figure 37C. [Figure 37D]Figure 37 illustrates gene expression studies in HCI-13 PDXs showing inhibition of the ER pathway by AR agonists. Representative ER and AR target genes and the most up- and down-regulated genes are shown in panels Figure 37D-Figure 37G. [Figure 37E] Figure 37 illustrates gene expression studies in HCI-13 PDXs showing inhibition of the ER pathway by AR agonists. Representative ER and AR target genes and the most up- and down-regulated genes are shown in panels Figure 37D-Figure 37G. [Figure 37F] Figure 37 illustrates gene expression studies in HCI-13 PDXs showing inhibition of the ER pathway by AR agonists. Representative ER and AR target genes and the most up- and down-regulated genes are shown in panels Figure 37D-Figure 37G. [Figure 37G] Figure 37 illustrates gene expression studies in HCI-13 PDXs showing inhibition of the ER pathway by AR agonists. Representative ER and AR target genes and the most up- and down-regulated genes are shown in panels Figure 37D-Figure 37G. [Figure 37H] Figure 37H illustrates gene expression studies in HCI-13 PDXs showing inhibition of the ER pathway by AR agonists. Figure 37H illustrates that GSEA KEGG pathway analysis provided ERBB2 (ERBB is abbreviated from erythroblastic oncogene B, often referred to as the HER2 (from human epidermal growth factor receptor 2) or HER2 / neu) pathway as one of the pathways highly correlated with Formula IX treatment (the bottom four rows of the left column (vehicle-treated) are down-regulated genes (original color blue), while the majority of rows are up-regulated genes (original color red). In contrast, the Formula IX-treated column (right) is the exact opposite). *=q<0.05, ER - estrogen receptor, AR - androgen receptor, PDX - patient-derived xenograft, GSEA - gene set enrichment analysis, KEGG - Kyoto Encyclopedia of Genes and Genomes. [Figure 38A]Figure 38A illustrates that ChIP sequencing showed rearrangements of ER and AR binding to DNA. Chromatin immunoprecipitation (ChIP) assays were performed with ER in tumors (tumors from animals shown in Figures 36B-36C) treated with vehicle (n=4) or 10 mg / kg / day Formula IX (n=3) or AR (n=1). Next-generation sequencing was performed to determine genome-wide binding of ER and AR to DNA. A heatmap of significantly different peaks (q<0.05 for ER and corresponding AR peaks) is shown. [Figure 38B] Figure 38B illustrates that ChIP-sequencing revealed rearrangements of ER and AR binding to DNA. Figure 38B shows representative peaks from KLK3 regulatory regions from ER and AR ChIP-Seq. [Figure 38C] Figure 38C shows a Principal Component Analysis (PCA) plot of vehicle- and Formula IX-treated samples corresponding to ER-ChIP peaks. [Figure 38D] Figure 38D illustrates that ChIP sequencing showed rearrangement of ER and AR binding to DNA. ChIP assays were performed using AR or ER antibodies in HCI-13 samples treated with vehicle or Formula IX, and real-time PCR was performed using primers and Taqman probes for the indicated regions. [Figure 38E] This figure shows that ChIP sequencing revealed rearrangement of ER and AR binding to DNA. Figure 38E shows a pie chart showing the distribution of ER enrichment in HCl-13 samples treated with Formula IX. For downregulated sites (left circle), "distal regulatory regions" represent 56%, introns 38%, exons 5%, and promoters 2%. For enriched sites (right circle), "distal regulatory proteins" represent 53%, introns 36%, exons 8%, and promoters 3%. [Figure 38F]Figure 38F illustrates that ChIP-sequencing showed rearrangements of ER and AR binding to DNA. Figure 38F shows a Venn diagram showing the overlap between depleted FOXA1RE and ERE regions and enriched ARE, GRE, and FOXA1RE. [Figure 38G] Figure 38G illustrates that ChIP sequencing showed rearrangement of ER and AR binding to DNA. Figure 38G illustrates that SRC-1 interacted with both AR and ER in response to Formula IX. Protein extracts from HCI-13 tumor samples treated with vehicle or Formula IX were immunoprecipitated with AR or ER antibodies and Western blotted for SRC-1. AR - androgen receptor, ER - estrogen receptor, ChIP - chromatin immunoprecipitation, ARE - androgen response element, ERE - estrogen response element, GRE - glucocorticoid response element, SRC-1 - steroid receptor coactivator-1, FOXA1RE - forkhead box A1 response element. [Figure 38H] Figure 38 illustrates that ChIP sequencing showed rearrangements of ER and AR binding to DNA. The top enriched motif is shown in Figure 38H. Figure 38H illustrates the upregulated motif (ER). [Figure 39] Illustrates co-localization of AR and ER-α in luminal B breast cancer specimens. [Figure 40] Representative ChIP-Seq peaks in the regulatory regions of genes are color-coded. The top panel is primarily upregulated (red), the second panel is downregulated (blue), the third panel (CERS3) is downregulated except for the last line (IX(AR)), and the bottom panel (miR4471) is also downregulated except for the last line (IX(AR)). [Figure 41A]Phosphoproteome analysis of HCI-13 PDX is illustrated. Figures 41A-41C show that lysates from HCI-13 tumor specimens (n=4) from PDX (as shown in Figures 36B-36C) were printed onto nitrocellulose-coated slides. Arrays were probed with a total of 174 antibodies targeting a wide range of protein kinases and their activation via phosphorylation. Arrays were stained with anti-rabbit or anti-mouse biotinylated secondary antibodies. Signals were amplified, and streptavidin-conjugated IRDye680 was used as a secondary signal detector. Images were acquired and quantified. [Figure 41B] Phosphoproteome analysis of HCI-13 PDX is illustrated. Figures 41A-41C show that lysates from HCI-13 tumor specimens (n=4) from PDX (as shown in Figures 36B-36C) were printed onto nitrocellulose-coated slides. Arrays were probed with a total of 174 antibodies targeting a wide range of protein kinases and their activation via phosphorylation. Arrays were stained with anti-rabbit or anti-mouse biotinylated secondary antibodies. Signals were amplified, and streptavidin-conjugated IRDye680 was used as a secondary signal detector. Images were acquired and quantified. [Figure 41C] Phosphoproteome analysis of HCI-13 PDX is illustrated. Figures 41A-41C show that lysates from HCI-13 tumor specimens (n=4) from PDX (as shown in Figures 36B-36C) were printed onto nitrocellulose-coated slides. Arrays were probed with a total of 174 antibodies targeting a wide range of protein kinases and their activation via phosphorylation. Arrays were stained with anti-rabbit or anti-mouse biotinylated secondary antibodies. Signals were amplified, and streptavidin-conjugated IRDye680 was used as a secondary signal detector. Images were acquired and quantified. [Figure 41D]Phosphoproteome analysis of HCI-13 PDX is illustrated. Figures 41D-41E illustrate that PKC activation overcame inhibition by Formula IX. HCI-13 tissue fragments were cultured on gelatin sponges and treated with 100 nM phorbol 12-myristate 13-acetate (PMA) or 100 ng / mL EGF for 30 minutes, followed by the addition of 1 μM Formula IX. EGF was treated twice daily due to its short stability. After 3 days of treatment, tissues were harvested, RNA was isolated, and the expression of various genes was measured by real-time PCR. *p<0.05 from vehicle-treated samples. #p<0.05 from Formula IX-treated samples. n=3 / group (each sample derived from 5 individual fragments). PMA - phorbol 12-myristate 13-acetate; EGF - epidermal growth factor; PDX - patient-derived xenograft; HCI - Huntsman Cancer Institute. [Figure 41E] Phosphoproteome analysis of HCI-13 PDX is illustrated. Figures 41D-41E illustrate that PKC activation overcame inhibition by Formula IX. HCI-13 tissue fragments were cultured on gelatin sponges and treated with 100 nM phorbol 12-myristate 13-acetate (PMA) or 100 ng / mL EGF for 30 minutes, followed by the addition of 1 μM Formula IX. EGF was treated twice daily due to its short stability. After 3 days of treatment, tissues were harvested, RNA was isolated, and the expression of various genes was measured by real-time PCR. *p<0.05 from vehicle-treated samples. #p<0.05 from Formula IX-treated samples. n=3 / group (each sample derived from 5 individual fragments). PMA - phorbol 12-myristate 13-acetate; EGF - epidermal growth factor; PDX - patient-derived xenograft; HCI - Huntsman Cancer Institute. [Figure 42] Illustrates a model showing regulation of ER function by AR agonists. [Figure 43A]Figure 43A shows baseline [18F]-16β-fluoro-5α-dihydrotestosterone (FDHT) SUVmax (FDHT uptake) versus AR. Figure 43A illustrates that baseline FDHT uptake (baseline FDHT-SUVmax) was higher for AR-positive (n=7) tumors compared to AR-negative (n=2) tumors, as determined by biopsy. ND-AR status was not determined, and UNK-AR status was unknown. [Figure 43B] Figure 43B shows baseline [F]-16β-fluoro-5α-dihydrotestosterone (FDHT) SUVmax (FDHT uptake) versus AR. Figure 43B illustrates the correlation between baseline SUVmax and AR levels, as determined by biopsy. The correlation is 0.41 (p-value = 0.27). With the exception of one outlier (shown in the figure with AR = 64,1946 and baseline SUVmax = 1), a trend for higher baseline FDHT SUVmax was seen with higher quantitative AR expression levels (r = 0.71, p = 0.046). [Figure 44A] The correlation between baseline FDHT uptake (baseline FDHT-SUVmax) and best response (clinical benefit (CB) or no CB) is presented. Figure 44A illustrates that the median baseline FDHT-SUVmax was 2.93 (range 1-4.38) for the seven patients with CB (defined as complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST criteria) after 12 weeks of therapy, and 2.15 (range 0.96-3.77) for the four patients with progressive disease (PD). [Figure 44B] The correlation between baseline FDHT uptake (baseline FDHT-SUVmax) and best response (clinical benefit (CB) or no CB) is presented. Figure 44B illustrates that the change in FDHT uptake from baseline to week 6 (change in SUVmax from baseline to week 6) decreased for those with CB at week 12, but not for those with PD. Disc(AE) - discontinued due to adverse event, Disc - discontinued. [Figure 45A]Figure 45A shows that Formula IX (SARM) resensitized human breast cancer models to CDK4 / 6 inhibition in a model of CDK4 / 6 resistance. Figure 45A illustrates the growth curves of PDX GAR15-13 treated with vehicle (n=8), Formula IX (denoted as SARM) (n=8), Palbo (n=7), or the combination of SARM and Palbo (n=11). Asterisks indicate significantly different tumor volumes at the ethical endpoints as determined by a two-tailed, unpaired Student's t-test for Palbo vs. Combo (t=3.7246, df=14, P=0.0022) and SARM vs. Combo (t=4.094, df=15, P=0.0010). Data are presented as mean ± sem. [Figure 45B] Figure 45B shows that Formula IX (SARM) resensitized a human breast cancer model to CDK4 / 6 inhibition in a model of CDK4 / 6 resistance. Figure 45B illustrates the proliferation of PalbR cells in response to an AR agonist (Formula IX 100 nM) and Palb (125 nM), alone or in combination. Data represent the mean ± sem of four replicate cell culture wells per condition. Data were analyzed using one-way ANOVA (F = 79.71, df = 23, P < 0.0001) followed by Tukey's multiple comparison test. P values ​​are indicated by gray asterisks, where ****P < 0.0001 for all highlighted comparisons. DETAILED DESCRIPTION OF THE INVENTION

[0040] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject. Accordingly, the present invention provides a) treating a subject suffering from breast cancer, b) treating a subject suffering from metastatic breast cancer, c) treating a subject suffering from refractory breast cancer, d) treating a subject suffering from AR-positive breast cancer, e) treating a subject suffering from AR-positive refractory breast cancer, f) treating a subject suffering from AR-positive metastatic breast cancer, g) treating a subject suffering from AR-positive and ER-positive breast cancer, h) treating a subject suffering from ER, PR, and / or HER2-positive breast cancer. i) treating subjects with AR-positive breast cancer with or without AR expression; j) treating subjects with triple-negative breast cancer; k) treating subjects with advanced breast cancer; k) treating subjects with selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), tan), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (PARP) inhibitor agents (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2Breasts that have failed treatment with ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating, preventing, suppressing, or inhibiting AR-positive triple-negative breast cancer; r) treating a subject with HER2-positive breast cancer; s) treating a subject with ER-mutant-expressing breast cancer; t) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or u) initially treating a subject with ER-mutant-expressing breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 The present invention provides a method for treating breast cancer in a subject by administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake. In one embodiment, the subject is male. In one embodiment, the subject is female.

[0041] In one embodiment of the present invention, there is provided a method for treating a subject suffering from breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0042] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with metastatic breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0043] In another embodiment of the present invention, there is provided a method for treating a subject suffering from refractory breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0044] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0045] In one embodiment, the AR-positive breast cancer is ER-, PR-, and HER2-positive. In another embodiment, the AR-positive breast cancer is ER-, PR-, and HER2-negative. In one embodiment, the AR-positive breast cancer is ER-positive and PR- and HER2-negative. In another embodiment, the AR-positive breast cancer is ER- and PR-positive and HER2-negative. In yet another embodiment, the AR-positive breast cancer is ER- and HER2-positive and PR-negative. In yet another embodiment, the AR-positive breast cancer is ER-negative and PR- and HER2-positive. In a further embodiment, the AR-positive breast cancer is ER- and PR-negative and HER2-positive. In a still further embodiment, the AR-positive breast cancer is ER- and HER2-negative and PR-positive. In one embodiment, the AR-positive breast cancer is ER-negative. In another embodiment, the AR-positive breast cancer is ER-positive.

[0046] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive refractory breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0047] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive metastatic breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0048] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with AR-positive and ER-positive breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0049] In another embodiment of the present invention, there is provided a method for treating a subject suffering from ER-positive breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat ER-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0050] In one embodiment, the ER-positive breast cancer is AR-positive. In another embodiment, the ER-positive breast cancer is AR-negative. In one embodiment, the ER-positive breast cancer is triple-positive (ER, PR, HER2) breast cancer. In another embodiment, the ER-positive breast cancer is not triple-positive breast cancer.

[0051] In another embodiment of the present invention, there is provided a method for treating a subject suffering from triple-negative breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat triple-negative breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0052] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive triple-negative breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the AR-positive triple-negative breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0053] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with advanced breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat advanced breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0054] In another embodiment of the present invention, selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol-3-carboxylates), ribosomal acid dehydrogenase inhibitors (RIDM1 ... inhibitors of PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro) or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Ava A method for treating a subject suffering from breast cancer that has failed to be treated with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), a gonadotropin-releasing hormone (GnRH) agonist (gossereli), a steroid hormone receptor modulator (SRM), a steroid hormone receptor antagonist (SHR ... ), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), polyAD P-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) are administered to a subject in an amount effective to treat breast cancer that has failed to be treated with trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)). In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0055] In another embodiment, the present invention provides a method for treating a subject afflicted with HER2-positive breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat HER2-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0056] In one embodiment, the HER2-positive breast cancer is HER2-positive refractory breast cancer. In another embodiment, the HER2-positive breast cancer is HER2-positive metastatic breast cancer. In one embodiment, the HER2-positive breast cancer is ER-negative. In another embodiment, the HER2-positive breast cancer is ER-positive. In one embodiment, the HER2-positive breast cancer is PR-positive. In another embodiment, the HER2-positive breast cancer is PR-negative. In one embodiment, the HER2-positive breast cancer is AR-positive. In another embodiment, the HER2-positive breast cancer is AR-negative.

[0057] In certain embodiments, the HER2-positive breast cancer is ER-positive, PR-positive, and AR-positive. In another embodiment, the HER2-positive breast cancer is ER-positive, PR-negative, and AR-positive. In another embodiment, the HER2-positive breast cancer is ER-positive, PR-negative, and AR-negative. In another embodiment, the HER2-positive breast cancer is ER-positive, PR-positive, and AR-negative. In another embodiment, the HER2-positive breast cancer is ER-negative, PR-negative, and AR-positive. In another embodiment, the HER2-positive breast cancer is ER-negative, PR-positive, and AR-positive. In another embodiment, the HER2-positive breast cancer is ER-negative, PR-positive, and AR-negative. In certain embodiments, the HER2-positive breast cancer is ER-negative, PR-negative ... triple-positive HER2 breast cancer.

[0058] In another embodiment, the present invention provides a method for treating a subject afflicted with ER mutant-expressing breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the ER mutant-expressing breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0059] In certain embodiments, the ER mutant-expressing breast cancer is a Y537S mutation-expressing breast cancer.

[0060] In certain embodiments, the ER mutant-expressing breast cancer is a D351Y mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is an E380Q mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a V422del mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a S432L mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a G442A mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a S463P mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a L469V mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a L536R mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a L536H mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a L536P mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a L536Q mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a Y537N mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a Y537C mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a Y537D mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is a D538G mutation-expressing breast cancer. In certain embodiments, the ER mutant-expressing breast cancer is an E542G mutation-expressing breast cancer. In one embodiment, the ER mutant-expressing breast cancer refers to a mutant of ER-alpha.

[0061] In certain embodiments, the ER mutant-expressing breast cancer is as described in Cancer Cell 2018, 33, 173-186 or Nat Rev Cancer 2018, 18(6):377-388 (incorporated herein by reference). In one embodiment, ER mutant-expressing breast cancer refers to a mutant of ER-alpha.

[0062] In one aspect, the present invention provides a pharmaceutical composition comprising a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor, wherein the SARM compound has the structure of Formula I:

[0063] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0064] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0065] [ka] n is an integer from 1 to 4, m is an integer from 1 to 3; or Pharmaceutical compositions are provided that are optical isomers, racemic mixtures, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or crystals thereof.

[0066] In some embodiments, the SARM compound in the compositions of the present invention has the structure of formula II:

[0067] [ka] During the ceremony, X is a bond, O, CH, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0068] [ka] R is C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C1-C4 haloalkyl, halogen, or haloalkenyl; R1 is CH3, CF3, CH2CH3, or CF2CF3.

[0069] In some embodiments, the SARM compound of the compositions of the invention has the structure of formula VIII, IX, X, XI, XII, XIII, or XIV:

[0070] [ka]

[0071] [ka]

[0072] In another aspect, the present invention provides a pharmaceutical composition comprising the following formula IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and a CDK4 / 6 inhibitor:

[0073] [ka]

[0074] In some embodiments of the compositions of the present invention, the CDK4 / 6 inhibitor is palbociclib, ribociclib, trilaciclib, relociclib, or abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0075] In another aspect, the present invention provides a pharmaceutical composition comprising the following compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and palbociclib:

[0076] [ka]

[0077] In another aspect, the present invention provides a pharmaceutical composition comprising the following compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and ribociclib:

[0078] [ka]

[0079] In another aspect, the present invention provides a pharmaceutical composition comprising the following compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and trilaciclib:

[0080] [ka]

[0081] In another aspect, the present invention provides a pharmaceutical composition comprising the following compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and relociclib:

[0082] [ka]

[0083] In another aspect, the present invention provides a pharmaceutical composition comprising the following compound IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and abemaciclib:

[0084] [ka]

[0085] In some embodiments, the compositions of the present invention are in the form of pellets, tablets, capsules, liquids, suspensions, emulsions, elixirs, gels, creams, suppositories, or parenteral formulations.

[0086] Another aspect of the present invention is that the pharmaceutical compositions of the present invention may be used in the treatment of breast cancer.

[0087] In one aspect, the present invention provides a method for treating a subject suffering from breast cancer, the method comprising administering to the subject a pharmaceutical composition of the present invention described herein.

[0088] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor, wherein the SARM compound has the structure of Formula I:

[0089] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0090] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0091] [ka] n is an integer from 1 to 4, m is an integer from 1 to 3; or It may be an optical isomer, a racemic mixture, a pharmaceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or a crystal thereof.

[0092] In some embodiments of the methods of the present invention, the SARM compound has the structure of formula II:

[0093] [ka] During the ceremony, X is a bond, O, CH, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0094] [ka] R is C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C1-C4 haloalkyl, halogen, or haloalkenyl; R1 is CH3, CF3, CH2CH3, or CF2CF3.

[0095] In some embodiments of the methods of the present invention, the SARM compound is represented by the structure of formula VIII, IX, X, XI, XII, XIII, or XIV:

[0096] [ka]

[0097] [ka]

[0098] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises Formula IX below, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and a CDK4 / 6 inhibitor:

[0099] [ka]

[0100] In some embodiments of the methods of the present invention, the CDK4 / 6 inhibitor is palbociclib, ribociclib, trilaciclib, relociclib, or abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0101] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises palbociclib and Formula IX below, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof:

[0102] [ka]

[0103] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises ribociclib and Formula IX below, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof:

[0104] [ka]

[0105] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises the following formula IX, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and trilaciclib:

[0106] [ka]

[0107] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises lerociclib and Formula IX below, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof:

[0108] [ka]

[0109] In some embodiments of the methods of the present invention, the pharmaceutical composition comprises a compound of Formula IX below, or an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and abemaciclib:

[0110] [ka]

[0111] In some embodiments of the methods of the invention, the breast cancer is AR-positive breast cancer, ER-positive breast cancer, triple-negative breast cancer, HER2-positive breast cancer, advanced breast cancer, refractory breast cancer, metastatic breast cancer, or breast cancer treated with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), a gonadotropin-releasing hormone (GnRH) agonist (goserelin), an aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), fulvestrant, a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relocilib, ribo ... rib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (PARP) inhibitor (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitor (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2 Breast cancer that has not been treated with ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin).

[0112] In some embodiments, the breast cancer is AR-positive metastatic breast cancer. In certain embodiments, the breast cancer is AR-positive refractory breast cancer.

[0113] In some embodiments, the ER-positive breast cancer is AR-positive and ER-positive breast cancer, or AR-negative and ER-positive breast cancer.

[0114] In some embodiments, the AR-positive breast cancer is ER-negative, ER-negative, PR-negative and HER2-negative, ER-negative, PR-negative and HER2-positive, ER-negative, PR-positive and HER2-negative, ER-negative, PR-positive and HER2-positive, ER-positive, PR-negative and HER2-negative, ER-positive, PR-positive and HER2-negative, ER-positive, PR-negative and HER2-positive, or ER-positive, PR-positive and HER2-positive.

[0115] In some embodiments, the breast cancer has not been treatable with a selective estrogen receptor modulator (SERM), hi some embodiments, the SERM is tamoxifen, toremifene, or raloxifene.

[0116] In some embodiments, the breast cancer has not been treatable with a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the subject is resistant or non-responsive to a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, or abemaciclib (Vorzenio). In certain embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance). In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0117] In some embodiments of the methods of the present invention, the compositions of the present invention described herein resensitize the breast cancer to treatment with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is at least one of palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, and abemaciclib (Vorzenio). In certain embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali). In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0118] In some embodiments of the methods of the present invention, the compositions of the present invention described herein overcome estrogen endocrine resistance. In some embodiments, the estrogen endocrine therapy comprises at least one of tamoxifen, toremifene, raloxifene, exemestane, letrozole, anastrozole, and fulvestrant. In some embodiments, the estrogen endocrine therapy comprises tamoxifen. In some embodiments, the estrogen endocrine therapy comprises toremifene. In some embodiments, the estrogen endocrine therapy comprises raloxifene. In some embodiments, the estrogen endocrine therapy comprises exemestane. In some embodiments, the estrogen endocrine therapy comprises letrozole. In some embodiments, the estrogen endocrine therapy comprises anastrozole. In some embodiments, the estrogen endocrine therapy comprises fulvestrant.

[0119] Another aspect of the present invention is that the compositions of the present invention described herein overcome resistance to combination therapy with estrogen endocrine therapy and a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is at least one of palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, and abemaciclib (Vorzenio). In certain embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali). In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the estrogen endocrine therapy includes at least one of tamoxifen, toremifene, raloxifene, exemestane, letrozole, anastrozole, and fulvestrant. In some embodiments, the estrogen endocrine therapy includes tamoxifen. In some embodiments, the estrogen endocrine therapy includes toremifene. In some embodiments, the estrogen endocrine therapy includes raloxifene. In some embodiments, the estrogen endocrine therapy includes exemestane. In some embodiments, the estrogen endocrine therapy includes letrozole. In some embodiments, the estrogen endocrine therapy includes anastrozole. In some embodiments, the estrogen endocrine therapy includes fulvestrant.

[0120] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Ibrance) and the estrogen endocrine therapy comprises fulvestrant.

[0121] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen endocrine therapy comprises fulvestrant.

[0122] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes fulvestrant.

[0123] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes fulvestrant.

[0124] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Vorzenio) and the estrogen endocrine therapy comprises fulvestrant.

[0125] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Kisqali) and the estrogen endocrine therapy comprises fulvestrant.

[0126] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib and the estrogen therapy includes fulvestrant.

[0127] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is relociclib and the estrogen therapy includes fulvestrant.

[0128] In some embodiments, when the compositions of the present invention described herein overcome resistance to combined estrogen and CDK4 / 6 inhibitor therapy, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes tamoxifen. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes toremifene. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes raloxifene. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes exemestane. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes letrozole. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes anastrozole. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib and the estrogen therapy includes fulvestrant.

[0129] In some embodiments of the methods of the present invention, the breast cancer has not been treatable with an mTOR inhibitor, hi some embodiments, the mTOR inhibitor is everolimus, sirolimus, temsirolimus, or ridafarolimus.

[0130] In some embodiments, the methods of the present invention further extend the survival of a subject with breast cancer or extend the progression-free survival of a subject with breast cancer.

[0131] In some embodiments, compositions of the present invention are administered intravenously, intraarterially, intramuscularly, subcutaneously, orally, or topically, hi some embodiments, compositions of the present invention are administered orally.

[0132] In some embodiments, the selective androgen receptor modulator is administered at 1 mg to 50 mg per day. In some embodiments, the selective androgen receptor modulator is administered at about 1 mg to about 5 mg, or about 5 mg to about 50 mg, or about 5 mg to about 10 mg, or about 5 mg to about 15 mg, or about 5 mg to about 20 mg, or about 5 mg to about 30 mg, or about 10 mg to about 50 mg, or about 10 mg to about 40 mg, or about 10 mg to about 30 mg, or about 10 mg to about 20 mg, or about 15 mg to about 50 mg, or about 20 mg to about 50 mg, or about 25 mg to about 50 mg, or about 30 mg to about 50 mg, or about 30 mg to about 40 mg per day. In some embodiments, the selective androgen receptor modulator is administered at about 9 mg per day or 18 mg per day.

[0133] As used herein, in one embodiment, the term "treating" may refer to treating, delaying progression, preventing recurrence, or treating recurrence. In one embodiment, the term "treating" refers to reducing morbidity, mortality, or a combination thereof associated with breast cancer.

[0134] The term "preventing" can refer to preventing the initial occurrence of a disorder, reducing risk factors, minimizing the disability or potential health threat of a disorder.

[0135] As used herein, the term "breast cancer" includes breast cancer, advanced breast cancer, metastatic breast cancer, AR-positive breast cancer, ER-positive breast cancer, AR-positive breast cancer with or without ER, PR, and / or HER2 expression, triple-positive breast cancer (ER-, PR-, and HER2-positive), AR-positive breast cancer with or without ER expression, ER-positive breast cancer with or without AR expression, AR-positive and ER-positive breast cancer, refractory breast cancer, AR-positive refractory breast cancer, ER-positive refractory breast cancer, AR-positive metastatic breast cancer, ER-positive metastatic breast cancer, selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, etoposide), and HER2-positive breast cancer. xemestane), cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), mTOR inhibitors (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), alpelisib (Piqray) (inhibitors of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (inhibitors of the enzyme poly ADP-ribose polymerase (PARP)), bevacizumab (Avastin), and / or fulvestrant; breast cancer that has not been treated with these inhibitors; triple-negative breast cancer; or 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 This may refer to breast cancers that take up NF-DHT, or any combination thereof.

[0136] In one embodiment, the term "breast cancer" refers to a condition characterized by the abnormally rapid growth of abnormal cells in one or both breasts of a subject. The abnormal cells are often referred to as "neoplastic cells," which, in some embodiments, refer to transformed cells that can form solid tumors. The term "tumor," in some embodiments, refers to an abnormal mass or population of cells (i.e., two or more cells), whether malignant or benign, resulting from excessive or abnormal cell division and precancerous and cancerous cells. Malignant tumors are distinguished from benign growths or tumors in that, in addition to uncontrolled cell growth, they can invade surrounding tissues and metastasize.

[0137] In breast cancer, neoplastic cells may be identified in only one or both breasts but not in another tissue or organ, in one or both breasts and one or more adjacent tissues or organs (e.g., lymph nodes), or in the breast and one or more non-adjacent tissues or organs to which the breast cancer cells have metastasized.

[0138] The term "metastasis," in some embodiments, refers to the process by which cancer cells migrate from one organ or tissue to another, non-adjacent organ or tissue. Cancer cells in the breast(s) can spread to tissues and organs of interest; conversely, cancer cells from other organs or tissues can invade or metastasize to the breast. Cancerous cells from the breast(s) can invade or metastasize to any other organ or tissue in the body. Breast cancer cells often invade lymph node cells and / or metastasize to the liver, brain, and / or bone, spreading cancer to these tissues and organs. The term "invasion," in some embodiments, refers to the spread of cancerous cells to adjacent surrounding tissues.

[0139] As used herein, the term "advanced breast cancer" refers to cancer that has spread elsewhere in the body and usually cannot be cured or controlled with current treatments.

[0140] As used herein, the term "AR-positive breast cancer" may refer to breast cancer in which at least a portion of the cancer cells express at least the androgen receptor (AR).

[0141] As used herein, the term "ER-positive breast cancer" may refer to breast cancer in which at least a portion of the cancer cells express at least the estrogen receptor (ER).

[0142] As used herein, the term "triple-negative breast cancer" may refer to breast cancer cells that do not have estrogen receptors (ER), progesterone receptors (PR), or large amounts of HER2 / neu protein. "Triple-negative breast cancer" may also be referred to herein as "ER-negative, PR-negative, HER2 / neu-negative breast cancer."

[0143] As used herein, the term "triple-positive breast cancer" may refer to breast cancer cells that express estrogen receptor (ER), progesterone receptor (PR), and high amounts of HER2 / neu (HER2) protein. "Triple-positive breast cancer" may also be referred to herein as "ER-positive, PR-positive, HER2 / neu-positive breast cancer" or "ER, PR, and HER2 breast cancer."

[0144] As used herein, the term "refractory" may refer to breast cancer that does not respond to treatment. The breast cancer may be resistant at the start of treatment or may become resistant during treatment. "Refractory breast cancer" may also be referred to herein as "resistant cancer."

[0145] As used herein, the term "HER2-positive breast cancer" can refer to breast cancer in which at least some of the cancer cells express elevated levels of the HER2 protein (HER2 (from human epidermal growth factor receptor 2) or HER2 / neu), which promotes rapid cell growth.

[0146] As used herein, the term "ER mutant-expressing breast cancer" may refer to breast cancer that expresses estrogen receptor alpha (ER-α) with therapy-resistance-conferring mutations. Often, these mutations are located within the ligand-binding domain of ER-α, arise during treatment, and / or confer resistance to certain or all endocrine therapies, such as SERMs, AIs, SERDs, and / or GnRH agonists. As used herein, the term "Y537S ER mutant-expressing breast cancer" may refer to breast cancer that expresses estrogen receptor alpha (ER-α) with the point mutation Y537S.

[0147] In another embodiment of the present invention, there is provided a method for treating, preventing, suppressing, or inhibiting metastasis in a subject afflicted with breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat, prevent, suppress, or inhibit metastasis in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0148] In another embodiment of the present invention, there is provided a method for prolonging the survival of a subject with breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to prolong the survival of the subject with breast cancer. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0149] In another embodiment of the present invention, there is provided a method for slowing the progression of breast cancer in a subject, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to slow the progression of breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0150] In another embodiment of the present invention, there is provided a method for extending progression-free survival of a subject with breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to extend progression-free survival of the subject with breast cancer. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0151] In one embodiment, the breast cancer of the present invention refers to, in one embodiment, ER-positive metastatic breast cancer, and in another embodiment, ER-positive refractory breast cancer, and in another embodiment, ER-positive, PR-positive, HER2-negative breast cancer, and in another embodiment, AR-positive, ER-positive breast cancer, and in another embodiment, AR-positive, ER-positive refractory breast cancer, and in another embodiment, AR-positive, ER-positive metastatic breast cancer, and in another embodiment, triple-positive breast cancer, and in another embodiment, advanced ER-positive breast cancer, and in another embodiment, AR-positive, and in another embodiment, ER-positive breast cancer, and in another embodiment, selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, sarcolemmal steroids, and the like. Icrin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (an inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (PARP) inhibitor (olaparib) (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin).

[0152] In another embodiment of the present invention, a method for reducing biomarker levels in a subject having breast cancer is provided, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to reduce biomarker levels in the subject. In another embodiment, the method comprises administering a compound of Formulas I-XIV of the present invention. As used herein, the term "biomarker" may refer to a substance used as an indicator of a process, event, or condition. A biomarker may be a biological molecule, such as a nucleic acid molecule (e.g., microRNA, genomic DNA, etc.), a protein, or a polysaccharide. Biomarkers include tumor antigens and tumor markers. In one embodiment, a biomarker indicates the presence of cancer, e.g., breast cancer. In one embodiment, a biomarker may be used to determine the effectiveness of a treatment. In one embodiment, a biomarker may be used to determine the progression of a condition, e.g., breast cancer.

[0153] MUC-1-associated antigen or CA27.29 is a cancer antigen highly associated with breast cancer. As used herein, the term "CA27.29 biomarker" refers to a biomarker for breast cancer. In one embodiment, CA27.29 is a biomarker for aggressive breast cancer.

[0154] The "PSA (prostate-specific antigen) biomarker" is used as a biomarker for prostate cancer, but PSA has also been found in the blood of women with breast cancer at higher levels than women without breast cancer. PSA is also useful as a biomarker for breast cancer.

[0155] The "CTX biomarker" and "NTX biomarker" are the C-telopeptide and N-telopeptide of type I collagen, respectively, which are used as biomarkers of bone metabolism. The NTX and CTX biomarkers can be sensitive indicators of the presence of bone metastasis in breast cancer patients.

[0156] In one embodiment, the method of the present invention reduces the CA27.29 biomarker in a subject. In one embodiment, the method of the present invention reduces PSA in a subject. In one embodiment, the method of the present invention reduces the CTX biomarker in a subject. In one embodiment of the present invention, the method of the present invention reduces the NTX biomarker in a subject. In another embodiment, the method of the present invention maintains the level of CA27.29 in a subject. In another embodiment, the method of the present invention maintains the level of PSA in a subject. In another embodiment, the method of the present invention maintains the level of the CTX biomarker in a subject. In another embodiment, the method of the present invention maintains the level of the NTX biomarker. In one embodiment, the subject has breast cancer. In one embodiment, the subject has advanced breast cancer. In another embodiment, the subject has refractory breast cancer. In yet another embodiment, the subject has AR-positive breast cancer. In yet another embodiment, the subject has ER-positive breast cancer.

[0157] In one embodiment, the present invention provides a method of treating breast cancer in a subject, comprising: 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18The present invention is directed to a method for determining whether a subject has AR-positive breast cancer, comprising the steps of: identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake; and subsequently administering to the subject with AR-positive breast cancer a selective androgen receptor modulator (SARM) compound.

[0158] In another embodiment, the selective androgen receptor modulator compound is a compound of Formulas I-XIV.

[0159] In one embodiment, the tumor is a metastatic breast cancer tumor. In one embodiment, the tumor is an ER-positive metastatic breast cancer tumor. In one embodiment, the tumor is an ER-positive metastatic breast cancer tumor that has not been treated with FDA-approved hormones and / or kinases.

[0160] In one embodiment, the AR-positive breast cancer is ER-positive. In another embodiment, the AR-positive breast cancer is metastatic.In another embodiment, the breast cancer is selected from the group consisting of refractory breast cancer, AR-positive breast cancer, AR-positive refractory breast cancer, AR-positive metastatic breast cancer, AR-positive and ER-positive breast cancer, AR-positive breast cancer with or without estrogen receptor (ER), progesterone receptor (PR), and / or human epidermal growth factor receptor 2 (HER2) expression, triple-negative breast cancer (TNBC), advanced breast cancer, selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib ( Kisqali, abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (inhibitors of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2 The patients with breast cancer have either: breast cancer that has failed treatment with ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin); ER-positive breast cancer; HER2-positive breast cancer; ER-mutant-expressing breast cancer; or Y537S ER-mutant-expressing breast cancer.

[0161] In another embodiment, the breast cancer is estrogen receptor positive (ER+) metastatic breast cancer.

[0162] In one embodiment, the compound of the present invention is an antagonist. In another embodiment, the compound of the present invention is an agonist. In yet another embodiment, the compound of the present invention is a partial agonist / partial antagonist. In one embodiment, the compound of the present invention is an AR agonist. In another embodiment, the compound is an AR antagonist. In yet another embodiment, the compound is a partial AR agonist and an AR antagonist. In one embodiment, the compound of the present invention is a PR agonist. In another embodiment, the compound is a PR antagonist. In yet another embodiment, the compound is a partial PR agonist and a PR antagonist.

[0163] In one embodiment, the compounds of the invention are AR agonists and PR antagonists.

[0164] The SARM compounds of the present invention may, in some embodiments, be useful for a) treating, preventing, delaying the onset of, increasing the time to, suppressing or inhibiting, or reducing the risk of developing a first skeletal-related event (SRE), such as pathological fracture, bone surgery, bone radiation, spinal cord compression, new bone metastasis, and / or bone loss in a subject; b) treating, preventing, suppressing or inhibiting, or reducing the risk of developing various hormone-related conditions in a subject, for example, to increase libido; and / or c) improving the quality of life in a subject.

[0165] Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture. In the United States, this condition affects over 25 million people and causes over 1.3 million fractures annually, including 500,000 spinal fractures, 250,000 hip fractures, and 240,000 wrist fractures. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year and over 50% of survivors being incapacitated. Elderly individuals are at highest risk for osteoporosis, and the problem is predicted to increase significantly with the aging population. Global fracture incidence is predicted to triple over the next 60 years, with one study estimating there will be 4.5 million hip fractures worldwide by 2050.

[0166] Women are at higher risk for osteoporosis than men. They experience a rapid acceleration of bone loss during the five years following menopause. Other factors that increase risk include smoking, alcohol abuse, a sedentary lifestyle, and low calcium intake. However, osteoporosis also occurs frequently in men. It is well established that bone mineral density in men decreases with age. Decreases in bone mineral content and density correlate with decreased bone strength and increased susceptibility to fractures. While the molecular mechanisms underlying the pleiotropic effects of sex hormones in non-reproductive tissues are only beginning to be understood, it is clear that physiological concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the life cycle. Consequently, androgen or estrogen deficiency results in an increased rate of bone remodeling, tilting the balance between resorption and formation in favor of resorption, contributing to an overall loss of bone mass. In men, the natural decline in sex hormones during maturation (direct decline in androgens as well as reduced levels of estrogen resulting from peripheral aromatization of androgens) is associated with bone fragility, an effect also observed in castrated men.

[0167] In one embodiment, the present invention provides the use of a compound as described herein, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate, or any combination thereof, for a) treating a bone-related disorder, b) preventing a bone-related disorder, c) suppressing a bone-related disorder, d) inhibiting a bone-related disorder, e) increasing bone strength in a subject, f) increasing bone mass in a subject, g) for use in inhibiting osteoclast formation, and / or h) for use in stimulating osteoblast formation.

[0168] In one embodiment, the present invention provides the use of a compound as described herein, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate, or any combination thereof, for a) accelerating bone repair, b) treating a bone disorder, c) treating bone mineral loss, d) treating low bone mineral density (BMD), e) treating reduced bone mass, f) treating metabolic bone disease, g) promoting bone growth or regrowth, h) promoting bone repair, i) promoting fracture repair, j) promoting bone remodeling, k) treating bone injury after reconstructive surgery involving the face, hip, or joints, l) enhancing bone strength and function, m) increasing cortical bone mass, n) increasing trabecular connectivity, o) preventing, inhibiting, or delaying metastasis to bone, and / or p) preventing, inhibiting, or delaying metastatic tumor growth in bone.

[0169] In one embodiment, the bone-related disorder is a genetic disorder, or in another embodiment, is induced as a result of a treatment regimen for a given disease. For example, and in one embodiment, the compounds described herein are useful for treating bone-related disorders that arise as a result of cancer metastasis to bone, or in another embodiment, as a result of androgen deprivation therapy administered in response to, for example, prostate carcinogenesis in a subject.

[0170] As used herein, "estrogen deprivation therapy" may refer to therapy administered in response to breast cancer in a subject. Known treatments include treatment with a GnRH agonist, a SERM, a SERD, or an aromatase inhibitor (AI). For example, and in one embodiment, the compounds described herein are useful for treating bone-related disorders that arise as a result of cancer metastasis to bone, or in another embodiment, as a result of estrogen deprivation therapy administered in response to, for example, prostate carcinogenesis in a subject. Menopause can also be induced using GnRH agonists, such as gosalelin (Zoladex), which maintain low levels of endogenous estrogen through inhibition of the hypothalamic-pituitary-gonadal axis.

[0171] In one embodiment, the bone-related disorder is a decrease in bone mineral density (BMD). In another embodiment, the bone-related disorder is osteoporosis. In another embodiment, the bone-related disorder is osteopenia. In another embodiment, the bone-related disorder is increased bone resorption. In another embodiment, the bone-related disorder is bone fracture. In another embodiment, the bone-related disorder is bone fragility. In another embodiment, the bone-related disorder is any combination of osteoporosis, osteopenia, increased bone resorption, bone fracture, bone fragility, and decreased BMD. Each disorder represents a separate embodiment of the present invention.

[0172] "Osteoporosis," in one embodiment, refers to thinning of bones with reduced bone mass due to depletion of calcium and bone protein. In another embodiment, osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture. Patients with osteoporosis have abnormal bone strength, which, in one embodiment, increases the risk of fracture. In another embodiment, osteoporosis depletes both the calcium and protein collagen normally found in bone, resulting, in one embodiment, in either abnormal bone quality or decreased bone density. In another embodiment, bones affected by osteoporosis can fracture with only a minor fall or injury that would not normally result in a fracture. Fractures, in one embodiment, can be in the form of either cracks (as in a hip fracture) or collapses (as in a compression fracture of the spine). Although fractures can occur in other skeletal regions, the spine, hips, and wrists are common areas for osteoporosis-induced fractures. Unchecked osteoporosis can, in another embodiment, lead to changes in posture, physical abnormalities, and decreased mobility.

[0173] In one embodiment, the osteoporosis is due to androgen deprivation. In another embodiment, the osteoporosis occurs following androgen deprivation. In another embodiment, the osteoporosis is due to estrogen deprivation therapy. In another embodiment, the osteoporosis occurs following estrogen deprivation therapy. In another embodiment, the osteoporosis is primary osteoporosis. In another embodiment, the osteoporosis is secondary osteoporosis. In another embodiment, the osteoporosis is postmenopausal osteoporosis. In another embodiment, the osteoporosis is juvenile osteoporosis. In another embodiment, the osteoporosis is idiopathic osteoporosis. In another embodiment, the osteoporosis is senile osteoporosis. In another embodiment, osteoporosis may predispose breast cancer patients to bone metastases and / or predispose patients to the development of skeletal-related events.

[0174] In another embodiment, the primary osteoporosis is primary osteoporosis type I. In another embodiment, the primary osteoporosis is primary osteoporosis type II. Each type of osteoporosis represents a separate embodiment of the present invention.

[0175] According to this aspect of the invention, and in one embodiment, a bone-related disorder is treated with a compound described herein or a combination thereof. In another embodiment, other bone-stimulating compounds may be provided to the subject before, simultaneously with, or after administration of a compound(s) described herein. In one embodiment, such bone-stimulating compounds may include natural or synthetic materials.

[0176] In one embodiment, as will be appreciated by those skilled in the art, bone stimulating compounds can include bone morphogenetic proteins (BMPs), growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF), insulin growth factor (IGF), platelet-derived growth factor (PDGF), hedgehog proteins such as sonic, Indian, and desert hedgehog, hormones such as follicle-stimulating hormone, parathyroid hormone, parathyroid hormone-related peptide, activin, inhibin, follistatin, frizzled, frzb, or frazzled proteins, BMP binding proteins such as chordin and fetuin, cytokines such as IL-3, IL-7, GM-CSF, chemokines such as eotaxin, collagen, osteocalcin, osteonectin, and the like.

[0177] In another embodiment, the composition for use in treating bone disorders of the present invention may comprise a compound(s) described herein, an additional bone-stimulating compound(s), and osteogenic cells. In one embodiment, the bone-forming cells may be stem or progenitor cells that can be induced to differentiate into osteoblasts. In another embodiment, the cells may be osteoblasts. In another embodiment, a nucleic acid encoding a bone-stimulating compound may be administered to a subject, which should be considered part of the present invention.

[0178] In one embodiment, the present invention provides for the treatment, prevention, suppression, or inhibition of, or reduction in the risk of developing, a skeletal-related event (SRE), such as bone fracture, bone surgery, bone radiation, spinal cord compression, new bone metastasis, bone loss, or a combination thereof, in a subject with cancer, comprising administering a compound described herein, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof. The present invention relates, inter alia, to the treatment of an SRE with a compound of Formulas I-XIV of the present invention (a) in a subject with prostate cancer undergoing or who has undergone androgen deprivation therapy (ADT), or (b) in a subject with breast cancer undergoing or who has undergone estrogen deprivation therapy.

[0179] In one embodiment, the skeletal-related event treated using the methods provided herein and / or utilizing the compositions provided herein is a fracture, which in one embodiment is a pathological fracture, a non-traumatic fracture, a vertebral fracture, a non-vertebral fracture, a morphometric fracture, or a combination thereof. In some embodiments, the fracture can be a simple fracture, a compound fracture, a transverse fracture, a greenstick fracture, or a comminuted fracture. In one embodiment, the fracture can be to any bone in the body, and in one embodiment, is a fracture in any one or more bones of the arm, wrist, hand, finger, leg, ankle, foot, toe, hip, clavicle, or a combination thereof. In breast cancer, metastasis most frequently occurs in the hip and vertebrae. In one embodiment, the skeletal-related event is a fracture of the hip and / or vertebrae.

[0180] In another embodiment, the methods and / or compositions provided herein are effective in treating, preventing, suppressing, inhibiting, or reducing the risk of a skeletal-related event, such as pathological fracture, spinal cord compression, hypercalcemia, bone-related pain, or a combination thereof.

[0181] In another embodiment, the skeletal-related events sought to be treated using the methods provided herein and / or utilizing the compositions provided herein include the need for bone surgery and / or bone radiation, which in some embodiments is for the treatment of pain resulting from bone injury or nerve compression. In another embodiment, the skeletal-related events sought to be treated using the methods provided herein and / or utilizing the compositions provided herein include spinal cord compression in a subject or the need for a change in anti-neoplastic therapy, including a change in hormone therapy. In some embodiments, the skeletal-related events sought to be treated using the methods provided herein and / or utilizing the compositions provided herein include treating, inhibiting, preventing, reducing the incidence of, or delaying the progression or severity of bone metastasis or bone loss. In one embodiment, bone loss can include osteoporosis, osteopenia, or a combination thereof. In one embodiment, the skeletal-related events can include any combination of the embodiments enumerated herein.

[0182] In one embodiment, the methods provided herein and / or methods utilizing the compositions provided herein are effective in reducing bone metastasis, e.g., in terms of number of lesions, size of lesions, or a combination thereof. According to this aspect of the invention, and in one embodiment, provided herein is a method of preventing or inhibiting cancer metastasis to bone in a subject, the method comprising administering to the subject a composition comprising toremifene, raloxifene, tamoxifen, or an analog, functional derivative, metabolite, or combination thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, such metabolites may include ospemifene, fispemifene, or a combination thereof. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is breast cancer.

[0183] In one embodiment, the skeletal-related events are a result of cancer therapy, in one embodiment, the skeletal-related events are a result of hormone deprivation therapy, in another embodiment, they are a product of androgen deprivation therapy (ADT), and in another embodiment, they are a product of estrogen deprivation therapy.

[0184] As used herein, the term "sexual desire" may refer to sexual desire or as defined in Example 9.

[0185] As used herein, the term "quality of life" may refer to a focus on the health and well-being of a subject suffering from a condition or disease, e.g., breast cancer, from post-treatment through the end of life. This encompasses the physical, psychosocial, and economic issues a subject faces beyond the diagnosis and treatment phase. The term "quality of life" may also be referred to herein as "survivorship." In one embodiment, survivorship includes issues related to the ability to receive health care and follow-up treatment, late effects of treatment, a second cancer, and quality of life. Family, friends, and caregivers are also considered part of the survivorship experience.

[0186] In one embodiment, the methods of the present invention are useful for human subjects. In one embodiment, the subject is male. In another embodiment, the subject is female. In some embodiments, the methods described herein may be useful for treating either males or females, although females may respond more favorably to the administration of certain compounds for certain methods. In other embodiments, the methods described herein may be useful for treating either males or females, although males may respond more favorably to the administration of certain compounds for certain methods.

[0187] Selective androgen receptor modulator (SARM) compounds In one embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole), or the like. ol, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; and / or p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER mutant-expressing breast cancer; s) treating a subject with Y537S ER mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer; 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Compounds of the present invention that are effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake have the structure of Formula I:

[0188] [ka] X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0189] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0190] [ka] n is an integer from 1 to 4, and m is an integer from 1 to 3), and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof.

[0191] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat a subject with ER-positive breast cancer that has not been treatable with conventional chemotherapy, p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer, q) to prolong survival of a subject with ER-positive breast cancer, r) to slow the progression of ER-positive breast cancer in a subject, s) to prolong progression-free survival of a subject with ER-positive breast cancer, t) to treat a subject with AR-positive, HER2-positive breast cancer, u) to treat a subject with ER-mutant-expressing breast cancer, v) to treat a subject with Y537S ER-mutant-expressing breast cancer, and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to a subject a compound of formula I:

[0192] [ka] X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0193] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0194] [ka] n is an integer from 1 to 4, m is an integer from 1 to 3. and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0195] In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of formula I:

[0196] [ka] X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is H, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R3 is H, F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, Sn(R)3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the following structure:

[0197] [ka] Z is NO, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0198] [ka] n is an integer from 1 to 4, m is an integer from 1 to 3. and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0199] In one embodiment, G in Formula I is O. In another embodiment, X in Formula I is O. In another embodiment, T in Formula I is OH. In another embodiment, R1 in Formula I is CH3. In another embodiment, Z in Formula I is NO2. In another embodiment, Z in Formula I is CN. In another embodiment, Y in Formula I is CF3. In another embodiment, Y in Formula I is Cl. In another embodiment, Q in Formula I is CN. In another embodiment, Q in Formula I is halogen. In another embodiment, Q in Formula I is F. In another embodiment, Q in Formula I is Cl. In another embodiment, Q in Formula I is NHCOCH3. In another embodiment, Q in Formula I is CN and R2 is F. In another embodiment, Q in Formula I is Cl and R2 is F. In another embodiment, Q in Formula I is in the para position. In another embodiment, Z in Formula I is in the para position. In another embodiment, Y in Formula I is in the meta position.

[0200] The substituents Z, Y, and R3 may be located at any position on the ring bearing these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is located at the para position of the A ring. In another embodiment, the substituent Y is located at the meta position of the A ring. In another embodiment, the substituent Z is located at the para position of the A ring and the substituent Y is located at the meta position of the A ring.

[0201] The substituents Q and R2 may be located at any position on the ring bearing these substituents (hereinafter "B ring"). In one embodiment, the substituent Q is located at the para position on the B ring. In another embodiment, the substituent R2 is located at the meta position on the B ring. In another embodiment, the substituent Q is CN and located at the para position on the B ring.

[0202] As contemplated herein, when the integers m and n are greater than 1, the substituents R2 and R3 are not limited to one particular substituent, but may be any combination of the substituents listed above.

[0203] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Compounds of the present invention that are effective in treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake are compounds of formula II:

[0204] [ka] (In the formula, X is a bond, O, CH, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0205] [ka] R is C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C1-C4 haloalkyl, halogen, or haloalkenyl; R1 is CH3, CF3, CH2CH3, or CF2CF3), and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof.

[0206] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat a subject with ER-positive breast cancer that has not been treatable with conventional chemotherapy, p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer, q) to prolong survival of a subject with ER-positive breast cancer, r) to slow the progression of ER-positive breast cancer in a subject, s) to prolong progression-free survival of a subject with ER-positive breast cancer, t) to treat a subject with AR-positive, HER2-positive breast cancer, u) to treat a subject with ER-mutant-expressing breast cancer, v) to treat a subject with Y537S ER-mutant-expressing breast cancer, and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to a subject a compound of formula II:

[0207] [ka] (In the formula, X is a bond, O, CH, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0208] [ka] R is C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C1-C4 haloalkyl, halogen, or haloalkenyl; R1 is CH3, CF3, CH2CH3, or CF2CF3, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0209] In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of formula II

[0210] [ka] (In the formula, X is a bond, O, CH, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0211] [ka] R is C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C1-C4 haloalkyl, halogen, or haloalkenyl; R1 is CH3, CF3, CH2CH3, or CF2CF3, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0212] In one embodiment, G in Formula II is O. In another embodiment, X in Formula II is O. In another embodiment, T in Formula II is OH. In another embodiment, R1 in Formula II is CH3. In another embodiment, Z in Formula II is NO2. In another embodiment, Z in Formula II is CN. In another embodiment, Y in Formula II is CF3. In another embodiment, Y in Formula II is a halogen. In another embodiment, Y in Formula II is Cl. In another embodiment, Q in Formula II is CN. In another embodiment, Q in Formula II is a halogen. In another embodiment, Q in Formula II is Cl. In another embodiment, Q in Formula II is F. In another embodiment, Q in Formula II is NHCOCH3. In another embodiment, Q in Formula II is in the para position. In another embodiment, Z in Formula II is in the para position. In another embodiment, Y in Formula II is in the meta position. In another embodiment, in Formula II, G is O, T is OH, R1 is CH3, X is O, Z is CN, Y is CF3 or a halogen, and Q is CN or F. In another embodiment, in Formula II, G is O, T is OH, R1 is CH3, X is O, Z is NO2, Y is CF3, and Q is NHCOCH3, F, or Cl.

[0213] The substituents Z and Y may be located at any position on the ring carrying these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is located at the para position of the A ring. In another embodiment, the substituent Y is located at the meta position of the A ring. In another embodiment, the substituent Z is located at the para position of the A ring and the substituent Y is located at the meta position of the A ring.

[0214] The substituent Q may be at any position of the ring bearing this substituent (hereinafter "B ring"). In one embodiment, the substituent Q is at the para position of the B ring. In another embodiment, the substituent Q is CN and is at the para position of the B ring. [000209] In another embodiment, the therapeutic methods for treating breast cancer include: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from ER-positive breast cancer; i) treating subjects with AR-positive breast cancer with or without expression of HER2, PR, and / or HER2; i) treating subjects with triple-negative breast cancer; j) treating subjects with advanced breast cancer; k) treating subjects with selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, azathioprine, riboflavin), riboflavin-containing steroids (RIs ... nastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly ADP-ribose polymerase (P ARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or u) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Compounds of the present invention that are effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake have the structure of Formula III:

[0215] [ka] (In the formula, Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0216] [ka] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH), and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof.

[0217] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab p) to treat a subject with ER-positive breast cancer that has not been treatable with Izabuconazole (Avastin); p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer; q) to prolong survival of a subject with ER-positive breast cancer; r) to slow the progression of ER-positive breast cancer in a subject; s) to prolong progression-free survival of a subject with ER-positive breast cancer; t) to treat a subject with AR-positive, HER2-positive breast cancer; and / or u) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to the subject a compound of formula III

[0218] [ka] (In the formula, Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0219] [ka] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0220] In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of formula III

[0221] [ka] During the ceremony, Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0222] [ka] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0223] In one embodiment, Z in Formula III is NO2. In another embodiment, Z in Formula III is CN. In another embodiment, Y in Formula III is CF3. In another embodiment, Y in Formula III is Cl. In another embodiment, Y in Formula III is a halogen. In another embodiment, Q in Formula III is CN. In another embodiment, Q in Formula III is a halogen. In another embodiment, Q in Formula III is F. In another embodiment, Q in Formula III is Cl. In another embodiment, Q in Formula III is NHCOCH3. In another embodiment, Z is CN, Y is CF3 or a halogen, and Q is CN or F. In another embodiment, Z is NO2, Y is CF3, and Q is NHCOCH3, F, or Cl.

[0224] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER mutant-expressing breast cancer; s) treating a subject with Y537S ER mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer; 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Compounds of the present invention that are effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake have the structure of Formula IV:

[0225] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; A is a ring selected from

[0226] [ka] B is a ring selected from

[0227] [ka] In the formula, A and B cannot be benzene rings at the same time. Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q1 and Q2 are independently hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, SR; or

[0228] [ka] Q3 and Q4 are, independently of one another, hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, or SR; W1 is O, NH, NR, NO, or S; and W2 is N or NO), and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof.

[0229] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat a subject with ER-positive breast cancer that has not been treatable with conventional chemotherapy, p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer, q) to prolong survival of a subject with ER-positive breast cancer, r) to slow the progression of ER-positive breast cancer in a subject, s) to prolong progression-free survival of a subject with ER-positive breast cancer, t) to treat a subject with AR-positive, HER2-positive breast cancer, u) to treat a subject with ER-mutant-expressing breast cancer, v) to treat a subject with Y537S ER-mutant-expressing breast cancer, and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to a subject a compound of formula IV:

[0230] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; A is a ring selected from

[0231] [ka] B is a ring selected from

[0232] [ka] In the formula, A and B cannot be benzene rings at the same time. Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q1 and Q2 are independently hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, SR; or

[0233] [ka] Q3 and Q4 are, independently of one another, hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, or SR; W1 is O, NH, NR, NO, or S; W2 is N or NO; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0234] In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of formula IV

[0235] [ka] (In the formula, X is a bond, O, CH, NH, S, Se, PR, NO, or NR; G is O or S; R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; A is a ring selected from

[0236] [ka] B is a ring selected from

[0237] [ka] In the formula, A and B cannot be benzene rings at the same time. Z is NO2, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, C(R)3, or Sn(R)3; Q1 and Q2 are independently hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, SR; or

[0238] [ka] Q3 and Q4 are, independently of one another, hydrogen, alkyl, halogen, CF3, CN, C(R)3, Sn(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OR, COR, OCOR, OSO2R, SO2R, or SR; W1 is O, NH, NR, NO, or S; W2 is N or NO; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0239] In one embodiment, G in Formula IV is O. In another embodiment, X in Formula IV is O. In another embodiment, T in Formula IV is OH. In another embodiment, R1 in Formula IV is CH3. In another embodiment, Z in Formula IV is NO2. In another embodiment, Z in Formula IV is CN. In another embodiment, Y in Formula IV is CF3. In another embodiment, Y in Formula IV is halogen. In another embodiment, Y in Formula IV is Cl. In another embodiment, Q1 in Formula II is CN. In another embodiment, Q1 in Formula IV is F. In another embodiment, Q1 in Formula IV is Cl. In another embodiment, Q1 in Formula II is NHCOCH3. In another embodiment, Q1 in Formula IV is in the para position. In another embodiment, Z in Formula IV is in the para position. In another embodiment, Y in Formula IV is in the meta position. In another embodiment, G in formula IV is O, T is OH, R1 is CH3, X is O, Z is NO2 or CN, Y is CF3 or halogen, and Q1 is CN, F, Cl, or NHCOCH3.

[0240] The substituents Z and Y may be located at any position on the ring carrying these substituents (hereinafter "A ring"). In one embodiment, the substituent Z is located at the para position of the A ring. In another embodiment, the substituent Y is located at the meta position of the A ring. In another embodiment, the substituent Z is located at the para position of the A ring and the substituent Y is located at the meta position of the A ring.

[0241] The substituents Q1 and Q2 may be located at any position on the ring bearing these substituents (hereinafter "B ring"). In one embodiment, the substituent Q1 is located at the para position of the B ring. In another embodiment, the substituent Q2 is H. In another embodiment, the substituent Q1 is located at the para position of the B ring and the substituent Q2 is H. In another embodiment, the substituent Q1 is CN and located at the para position of the B ring and the substituent Q2 is H.

[0242] As contemplated herein, it is within the scope of the present invention to treat a) subjects with breast cancer, b) subjects with metastatic breast cancer, c) subjects with refractory breast cancer, d) subjects with AR-positive breast cancer, e) subjects with AR-positive refractory breast cancer, f) subjects with AR-positive metastatic breast cancer, g) subjects with AR-positive and ER-positive breast cancer. h) treating subjects with AR-positive breast cancer with or without ER, PR, and / or HER2 expression; i) treating subjects with triple-negative breast cancer; j) treating subjects with advanced breast cancer; k) treating subjects with selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (retrozole), and steroids (steroids). ol, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), poly (ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) extending survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) extending progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; t) treating a subject with breast cancer for the first time 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Other specific embodiments of compounds useful for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake are of Formula V or VI.

[0243] [ka] (In the formula, Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0244] [ka] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH), it is understood that analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, polymorphs, crystals, prodrugs, or combinations thereof are included within the scope of the present invention.

[0245] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat a subject with ER-positive breast cancer that has not been treatable with conventional chemotherapy, p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer, q) to prolong survival of a subject with ER-positive breast cancer, r) to slow the progression of ER-positive breast cancer in a subject, s) to prolong progression-free survival of a subject with ER-positive breast cancer, t) to treat a subject with AR-positive, HER2-positive breast cancer, u) to treat a subject with ER-mutant-expressing breast cancer, v) to treat a subject with Y537S ER-mutant-expressing breast cancer, and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to a subject a compound of the following structure of Formula V or VI:

[0246] [ka] (In the formula, Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0247] [ka] A, B, C, R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0248] In another embodiment, the present invention provides a therapeutic agent for treating a) subjects with HER2-positive breast cancer, b) subjects with HER2-positive refractory breast cancer, c) subjects with HER2-positive metastatic breast cancer, d) subjects with HER2-positive and ER-negative breast cancer, e) subjects with HER2-positive and ER-positive breast cancer, f) subjects with HER2-positive and PR-positive breast cancer, g) subjects with HER2-positive and PR-negative breast cancer, h) subjects with HER2-positive and AR-positive breast cancer, i) subjects with HER2-positive and AR-negative breast cancer, j) subjects with HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of Formula V or VI

[0249] [ka] (In the formula, Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOOR, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structure A, B, or C;

[0250] [ka] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, or OH; and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0251] In one embodiment, Q in Formula V or VI is CN. In one embodiment, Q in Formula V or VI is halogen. In one embodiment, Q in Formula V or VI is F. In one embodiment, Q in Formula V or VI is Cl. In one embodiment, Q in Formula V or VI is NHCOCH3.

[0252] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 Compounds of the present invention that are effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake have the structure of Formula VII:

[0253] [ka] wherein Z is Cl or CF3, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof.

[0254] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugate (HER2 ADC) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1-blocking antibody), pembrolizumab (Keytruda) (PD-L1-blocking antibody), sacituzumab govitecan (Trodelvy) (antibody-drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer; q) to prolong survival of a subject with ER-positive breast cancer; r) to slow the progression of ER-positive breast cancer in a subject; s) to prolong progression-free survival of a subject with ER-positive breast cancer; t) to treat a subject with AR-positive, HER2-positive breast cancer; and / or u) to treat a subject with ER-mutant-expressing breast cancer; v) to treat a subject with Y537S ER-mutant-expressing breast cancer; and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering to a subject a compound of the following structure of Formula VII:

[0255] [ka] wherein Z is Cl or CF. and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject. In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer. k) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer; l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a compound of formula VII

[0256] [ka] wherein Z is Cl or CF. and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0257] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula VIII below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0258] [ka]

[0259] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula IX below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0260] [ka]

[0261] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula X below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0262] [ka]

[0263] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula XI below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0264] [ka]

[0265] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula XII below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0266] [ka]

[0267] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the compound of Formula XIII below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0268] [ka]

[0269] In another embodiment, the present invention is directed to the treatment of a subject with breast cancer, b) treating a subject with metastatic breast cancer, c) treating a subject with refractory breast cancer, d) treating a subject with AR-positive breast cancer, e) treating a subject with AR-positive refractory breast cancer, f) treating a subject with AR-positive metastatic breast cancer, g) treating a subject with AR-positive and ER-positive breast cancer, h) treating a subject with AR-positive breast cancer with or without ER, PR, and / or HER2 expression, i) treating a subject with triple-negative breast cancer, j) treating a subject with advanced breast cancer, k) treating a subject with a selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, zole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitor (everolimus), poly (ADP-ribose polymerase (PAR) P) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) l) treating a subject with ER-positive breast cancer; m) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) treating a subject with HER2-positive breast cancer; r) treating a subject with ER-mutant-expressing breast cancer; s) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or t) initially treating a subject with breast cancer. 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A compound that is effective for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake is a compound represented by the structure of Formula XIV below, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof:

[0270] [ka]

[0271] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject, e.g., a female subject. Accordingly, the present invention is directed to a) treating AR-positive breast cancer in a subject, b) treating metastatic AR-positive breast cancer or advanced AR-positive breast cancer, c) treating refractory AR-positive breast cancer, d) treating, preventing, suppressing, or inhibiting metastasis in a subject with breast cancer, e) prolonging progression-free survival in a subject with breast cancer, f) treating a subject with ER-positive breast cancer, g) treating a subject with metastatic ER-positive breast cancer, and h) treating a subject with refractory ER-positive breast cancer. i) to treat subjects with AR-positive, ER-positive breast cancer; j) to treat subjects with AR-positive, ER-positive refractory breast cancer; k) to treat subjects with AR-positive, ER-positive metastatic breast cancer; l) to treat subjects with AR-positive and ER-positive breast cancer; m) to treat subjects with AR-positive, ER-positive breast cancer with or without PR and / or HER2 expression; n) to treat subjects with advanced ER-positive breast cancer; o) to treat subjects with selective estrogen receptor modulators Serum modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib, alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol phosphate), cyclosporine (CDK4 / 6) inhibitors (alcohol-releasing hormone (CVD ... inhibitors of inositol-3-kinase subunit alpha (PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta),margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1-blocking antibody), pembrolizumab (Keytruda) (PD-L1-blocking antibody), sacituzumab govitecan (Trodelvy) (antibody-drug conjugate for TNBC), and / or bevacizumab (Avastin) p) to treat a subject with ER-positive breast cancer that has not been cured in a prior art setting; p) to treat, prevent, suppress or inhibit metastasis in a subject with ER-positive breast cancer; q) to prolong survival of a subject with ER-positive breast cancer; r) to slow the progression of ER-positive breast cancer in a subject; s) to prolong progression-free survival of a subject with ER-positive breast cancer; and / or t) to treat a subject with AR-positive, HER2-positive breast cancer; u) to treat a subject with ER-mutant-expressing breast cancer; v) to treat a subject with Y537S ER-mutant-expressing breast cancer; and / or w) initially, 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 1. A method for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake, comprising administering a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound described herein, represented by the following structure of Formula VIII, IX, X, XI, XII, XIII, or XIV:

[0272] [ka]

[0273] [ka] and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0274] In another embodiment, the present invention provides a therapeutic agent for treating a) a subject suffering from HER2-positive breast cancer, b) a subject suffering from HER2-positive refractory breast cancer, c) a subject suffering from HER2-positive metastatic breast cancer, d) a subject suffering from HER2-positive and ER-negative breast cancer, e) a subject suffering from HER2-positive and ER-positive breast cancer, f) a subject suffering from HER2-positive and PR-positive breast cancer, g) a subject suffering from HER2-positive and PR-negative breast cancer, h) a subject suffering from HER2-positive and AR-positive breast cancer, i) a subject suffering from HER2-positive and AR-negative breast cancer, j) a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-positive breast cancer, k) a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-positive breast cancer. l) treating a subject suffering from HER2-positive, ER-positive, PR-negative, and AR-negative breast cancer; m) treating a subject suffering from HER2-positive, ER-positive, PR-positive, and AR-negative breast cancer; n) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-positive breast cancer; o) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-positive breast cancer; p) treating a subject suffering from HER2-positive, ER-negative, PR-positive, and AR-negative breast cancer; and / or q) treating a subject suffering from HER2-positive, ER-negative, PR-negative, and AR-negative breast cancer, comprising administering to a subject a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound described herein, represented by the following structure of Formula VIII, IX, X, XI, XII, XIII, or XIV:

[0275] [ka]

[0276] [ka] and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, crystals, polymorphs, prodrugs, or any combination thereof, to a subject. In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject.

[0277] In one embodiment, the methods of the present invention utilize a compound of Formula VIII. In one embodiment, the methods of the present invention utilize a compound of Formula IX. In one embodiment, the methods of the present invention utilize a compound of Formula X. In one embodiment, the methods of the present invention utilize a compound of Formula XI. In one embodiment, the methods of the present invention utilize a compound of Formula XII. In one embodiment, the methods of the present invention utilize a compound of Formula XIII. In one embodiment, the methods of the present invention utilize a compound of Formula XIV.

[0278] In one embodiment, the methods of the present invention comprise administering an analog of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a derivative of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering an isomer of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a metabolite of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a pharmaceutically acceptable salt of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a pharmaceutical product of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a hydrate of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering an N-oxide of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a polymorph of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a crystal of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a prodrug of a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering any combination of analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, polymorphs, crystals, or prodrugs of compounds of Formulas I-XIV.

[0279] In one embodiment, the methods of the present invention comprise administering a compound of Formula I-XIV. In another embodiment, the methods of the present invention comprise administering a compound of Formula I. In another embodiment, the methods of the present invention comprise administering a compound of Formula II. In another embodiment, the methods of the present invention comprise administering a compound of Formula III. In another embodiment, the methods of the present invention comprise administering a compound of Formula IV. In another embodiment, the methods of the present invention comprise administering a compound of Formula V. In another embodiment, the methods of the present invention comprise administering a compound of Formula VI. In another embodiment, the methods of the present invention comprise administering a compound of Formula VII. In another embodiment, the methods of the present invention comprise administering a compound of Formula VIII. In another embodiment, the methods of the present invention comprise administering a compound of Formula IX. In another embodiment, the methods of the present invention comprise administering a compound of Formula X. In another embodiment, the methods of the present invention comprise administering a compound of Formula XI. In another embodiment, the methods of the present invention comprise administering a compound of Formula XII. In another embodiment, the methods of the present invention comprise administering a compound of Formula XIII. In another embodiment, the methods of the present invention comprise administering a compound of Formula XIV.

[0280] The compounds of the present invention, either alone or as pharmaceutical compositions, are useful for a) treating subjects with breast cancer, b) treating subjects with metastatic breast cancer, c) treating subjects with refractory breast cancer, d) treating subjects with AR-positive breast cancer, e) treating subjects with AR-positive refractory breast cancer, f) treating subjects with AR-positive metastatic breast cancer, g) treating subjects with AR-positive and ER-positive breast cancer. h) treating subjects with AR-positive breast cancer with or without ER, PR, and / or HER2 expression; i) treating subjects with triple-negative breast cancer; j) treating subjects with advanced breast cancer; k) treating subjects with selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (retinoic acid), and the like. lorzole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), poly (ADP-ribose) polymerase PARP inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin); l) subjects with ER-positive breast cancer m) treating, preventing, suppressing or inhibiting metastasis in a subject with breast cancer; n) prolonging survival of a subject with breast cancer; o) slowing the progression of breast cancer in a subject; p) prolonging progression-free survival of a subject with breast cancer; q) prolonging survival of a subject with ER-positive breast cancer; r) slowing the progression of ER-positive breast cancer in a subject; s) prolonging progression-free survival of a subject with ER-positive breast cancer; t) treating a subject with AR-positive, HER2-positive breast cancer; u) treating a subject with ER-mutant-expressing breast cancer; v) treating a subject with Y537S ER-mutant-expressing breast cancer; and / or w) for the first time 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 The present invention is useful for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake.

[0281] The compounds of the present invention offer a significant advance over steroidal androgen therapy because treatment of breast cancer with these compounds is not associated with severe side effects, inconvenient modes of administration, or high cost, while still possessing the advantages of oral bioavailability, lack of cross-reactivity with other steroid receptors, lack of aromatizability, and long biological half-life.

[0282] In one embodiment, the present invention relates to the treatment of androgen receptor-positive breast cancer in a subject. Accordingly, the present invention provides a therapeutically effective amount of a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, as described herein, to treat a subject suffering from breast cancer, b) treat a subject suffering from metastatic breast cancer, c) treat a subject suffering from refractory breast cancer, d) treat a subject suffering from AR-positive breast cancer, by administering to the subject a therapeutically effective amount of a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, as described herein. e) treating subjects with AR-positive refractory breast cancer; f) treating subjects with AR-positive metastatic breast cancer; g) treating subjects with AR-positive and ER-positive breast cancer; h) treating subjects with AR-positive breast cancer with or without ER, PR, and / or HER2 expression; i) treating subjects with triple-negative breast cancer; j) treating subjects with advanced breast cancer; k) treating subjects with selective estrogen receptor modulators (SERMs) (tamoxifen) , toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol-3-kinase subunit alpha (PI3Kα inhibitors), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)),HER2 antibody drug conjugates (HER2 ADCs) (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avast in) treating a subject with breast cancer that was refractory to prior treatment, l) treating a subject with ER-positive breast cancer, m) treating, preventing, suppressing or inhibiting metastasis in a subject with breast cancer, n) extending the survival of a subject with breast cancer, o) slowing the progression of breast cancer in a subject and / or p) extending the progression-free survival of a subject with breast cancer, q) treating a subject with HER2-positive breast cancer, r) treating a subject with ER-mutant-expressing breast cancer, s) treating a subject with Y537S ER-mutant-expressing breast cancer, and / or t) initially 18 F-16β-fluoro-5α-dihydrotestosterone ( 18 F-DHT) tumor uptake was determined, 18 A method is provided for treating breast cancer in a subject by identifying the subject as having AR-positive breast cancer based on F-DHT tumor uptake.

[0283] As defined herein, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, etc. As used herein, the term "isomer" may also be referred to herein as an "enantiomer," which possesses all of the qualities and properties of an "isomer."

[0284] In one embodiment, the present invention encompasses the use of various optical isomers of the selective androgen receptor modulators. It will be understood by those skilled in the art that the selective androgen receptor modulators of the present invention contain at least one chiral center. Thus, the selective androgen receptor modulators used in the methods of the present invention may exist and be isolated in optically active or racemic forms. Some compounds may also exhibit polymorphism. It is understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or combinations thereof, which have properties useful for treating the androgen-related conditions described herein. In one embodiment, the selective androgen receptor modulator is a pure (R)-isomer. In another embodiment, the selective androgen receptor modulator is a pure (S)-isomer. In another embodiment, the selective androgen receptor modulator is a mixture of the (R) and (S) isomers. In another embodiment, the selective androgen receptor modulator is a racemic mixture containing equal amounts of the (R) and (S) isomers. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0285] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which may be produced by reaction of a compound of the present invention with an acid or a base.

[0286] The present invention includes pharmaceutically acceptable salts of amino-substituted compounds with organic and inorganic acids, such as citric acid and hydrochloric acid. The present invention also includes N-oxides of the amino substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with inorganic bases, such as sodium hydroxide. Esters of phenolic compounds can also be prepared with aliphatic and aromatic carboxylic acids, such as acetic acid and benzoic acid esters.

[0287] Formulas I-XIV Suitable pharmaceutically acceptable salts of the compounds of formula (I) may be prepared from inorganic acids or organic acids. In one embodiment, examples of inorganic salts of the compounds of the present invention are hydrogen sulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-hydroxyethylsulfonate (hydroxyethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfonate, halogen-substituted alkylsulfonate, halogen-substituted arylsulfonate), sulfonate, and thiocyanate.

[0288] In one embodiment, exemplary organic salts of the compounds of the present invention may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include acetate, arginine, aspartate, ascorbate, adipate, anthranilate, algenate, alkanecarboxylate, substituted alkanecarboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphor, camphorsulfonate, cyclohexylsulfamate, cyclopentanepropionate, calcium edetate, camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylate, estolate, esylate, fumarate, formate, fluoride, and galacturonate.Gluconate, glutamate, glycolate, glucolate, glucoheptanoate, glycerophosphate, gluceptate, glycolylarsanilate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinate, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis(beta-oxynaphthoate), malonate, mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methanesulfonate, monopotassium maleate, mucate, monocarboxylate, nitrate, naphthalenesulfonate, 2-naphthoate The salts are talensulfonate, nicotinate, napsylate, N-methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, subacetate, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, teoclate, trihaloacetate, triethiodide, tricarboxylate, undecanoate, and valerate.

[0289] In one embodiment, the salts may be formed by conventional means such as 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, under vacuum, or by lyophilization, or by exchanging the existing salt ion with another ion or a suitable ion exchange resin, which is removed.

[0290] The present invention further includes derivatives of selective androgen receptor modulators. The term "derivatives" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like. In addition, the present invention further includes hydrates of selective androgen receptor modulators. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[0291] The present invention further includes metabolites of the selective androgen receptor modulators. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

[0292] The present invention further includes pharmaceutical products of the selective androgen receptor modulators. The term "pharmaceutical product," as defined herein, means a composition suitable for pharmaceutical use (pharmaceutical composition).

[0293] The present invention further includes prodrugs of selective androgen receptor modulators. The term "prodrug" means a substance that can be converted in vivo into a biologically active agent by reactions such as hydrolysis, esterification, deesterification, activation, salt formation, and the like.

[0294] The present invention further includes crystals of the selective androgen receptor modulators. Additionally, the present invention provides polymorphs of the selective androgen receptor modulators. The term "crystal" refers to a substance in a crystalline state. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectrum, melting point, etc.

[0295] In one embodiment of the present invention, there is provided a method for treating a subject suffering from breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0296] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with metastatic breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0297] In another embodiment of the present invention, there is provided a method for treating a subject suffering from refractory breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0298] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0299] In one embodiment, the AR-positive breast cancer is ER-, PR-, and HER2-positive. In another embodiment, the AR-positive breast cancer is ER-, PR-, and HER2-negative. In one embodiment, the AR-positive breast cancer is ER-positive and PR- and HER2-negative. In another embodiment, the AR-positive breast cancer is ER- and PR-positive and HER2-negative. In yet another embodiment, the AR-positive breast cancer is ER- and HER2-positive and PR-negative. In yet another embodiment, the AR-positive breast cancer is ER-negative and PR- and HER2-positive. In a further embodiment, the AR-positive breast cancer is ER- and PR-negative and HER2-positive. In a still further embodiment, the AR-positive breast cancer is ER- and HER2-negative and PR-positive. In one embodiment, the AR-positive breast cancer is ER-negative. In another embodiment, the AR-positive breast cancer is ER-positive.

[0300] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive refractory breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0301] In another embodiment of the present invention, there is provided a method for treating a subject suffering from AR-positive metastatic breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0302] In another embodiment of the present invention, there is provided a method for treating a subject suffering from ER-positive breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat ER-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0303] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with AR-positive and ER-positive breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0304] In another embodiment of the present invention, there is provided a method for treating a subject suffering from ER-positive refractory breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the ER-positive refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0305] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with ER-positive metastatic breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat ER-positive metastatic breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0306] In one embodiment, the ER-positive breast cancer is AR-positive. In another embodiment, the ER-positive breast cancer is AR-negative.

[0307] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with advanced breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat advanced breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0308] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with AR-positive and ER-positive breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat the AR-positive and ER-positive refractory breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0309] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with AR-positive and ER-negative breast cancer, comprising administering to a subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in The present invention provides a method for treating AR-positive and ER-negative metastatic breast cancer in a subject, comprising administering to the subject an amount effective to treat the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0310] In another embodiment of the present invention, there is provided a method for treating a subject suffering from triple-negative breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat triple-negative breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0311] In another embodiment of the present invention, selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonists (goserelin), aromatase inhibitors (AIs) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (phosphatidylinositol-3-carboxylates), ribosomal acid dehydrogenase inhibitors (RIDM1 ... inhibitors of PI3Kα), mTOR inhibitors (everolimus), poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro) or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin The present invention also provides a method for treating a subject suffering from breast cancer that has been previously treated with a selective androgen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), a gonadotropin-releasing hormone (GnRH) receptor modulator (GnRH-R) or a selective androgen receptor modulator (SERM) of Formulas I-XIV of the present invention, and / or an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in a subject. Nist (goserelin), aromatase inhibitors (AI) (letrozole, anastrozole, exemestane), fulvestrant, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio), trilaciclib, relociclib), alpelisib (Piqray) (inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), mTOR inhibitors (everolimus), Poly ADP-ribose polymerase (PARP) inhibitors (olaparib (Lynparza) or talazoparib (Talzenna)), human epidermal growth factor receptor 2 (HER2) kinase inhibitors (lapatinib, neratinib (Nerlynx), dacomitinib (Vizimpro), or tucatinib (Tukysa)), HER2 antibodies (trastuzumab (Herceptin), pertuzumab (Perjeta), margetuximab-cmkb (Margenza)), HER2 antibody-drug conjugates (HER2ADCs (am-trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)), atezolizumab (Tecentriq) (PD-L1 blocking antibody), pembrolizumab (Keytruda) (PD-L1 blocking antibody), sacituzumab govitecan (Trodelvy) (antibody drug conjugate for TNBC), and / or bevacizumab (Avastin) are administered to a subject in an amount effective to treat breast cancer that has failed to be treated with trastuzumab-deruxtecan-nxki (Enhertu), ado-trastuzumab emtansine (Kadcyla), or pertuzumab / trastuzumab / hyaluronidase-zzxf (Phesgo)). In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0312] In another embodiment of the present invention, there is provided a method for treating, preventing, suppressing, or inhibiting metastasis in a subject afflicted with breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat, prevent, suppress, or inhibit metastasis in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0313] In another embodiment of the present invention, there is provided a method for treating and / or preventing a skeletal-related event in an afflicted subject, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat and / or prevent a skeletal-related event in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0314] In another embodiment of the present invention, there is provided a method for improving libido in a subject, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to improve libido in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0315] In another embodiment of the present invention, there is provided a method for improving quality of life in a subject, comprising administering to the subject a selective androgen receptor modulator of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to improve quality of life in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0316] In another embodiment of the present invention, there is provided a method for treating, preventing, suppressing, or inhibiting metastasis in a subject afflicted with breast cancer, comprising administering to the subject a selective androgen receptor modulator of Formulae I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat, prevent, suppress, or inhibit metastasis in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0317] In another embodiment of the present invention, there is provided a method for treating a subject afflicted with HER2-positive breast cancer, comprising administering to the subject a compound of Formulas I-XIV of the present invention, and / or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug, or any combination thereof, in an amount effective to treat HER2-positive breast cancer in the subject. In one embodiment, the subject is a female subject. In another embodiment, the subject is a male subject.

[0318] In one embodiment, the HER2-positive breast cancer is HER2-positive refractory breast cancer. In another embodiment, the HER2-positive breast cancer is HER2-positive metastatic breast cancer. In one embodiment, the HER2-positive breast cancer is ER-negative. In another embodiment, the HER2-positive breast cancer is ER-positive. In one embodiment, the HER2-positive breast cancer is PR-positive. In another embodiment, the HER2-positive breast cancer is PR-negative. In one embodiment, the HER2-positive breast cancer is AR-positive. In another embodiment, the HER2-positive breast cancer is AR-negative.

[0319] In certain embodiments, the HER2-positive breast cancer is ER-positive, PR-positive, and AR-p...

Claims

1. 1. A method for treating a subject suffering from breast cancer, the method comprising administering to the subject a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor; The SARM compounds have the structure of formula I: 【Chemistry 1】 (In the formula, X is a bond, O, CH2, NH, S, Se, PR, NO, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, 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, F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, N(R)2, or SR; R 3 is H, F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure: 【Chemistry 2】 Z is NO2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or Sn(R)3; Q is CN, alkyl, halogen, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structures A, B, or C; 【Chemistry 3】 n is an integer from 1 to 4, m is an integer from 1 to 3; or an optical isomer, a racemic mixture, a pharma- ceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or a crystal thereof; The breast cancer is AR-positive breast cancer, ER-positive breast cancer, triple-negative breast cancer, HER2-positive breast cancer, advanced breast cancer, refractory breast cancer, metastatic breast cancer, or breast cancer that has failed to be treated with a selective estrogen receptor modulator (SERM), an aromatase inhibitor, fulvestrant, and / or breast cancer that has failed to be treated with a cyclin-dependent kinase 4 / 6 (CDK 4 / 6) inhibitor, and / or the breast cancer is breast cancer that has failed to be treated with an mTOR inhibitor.

2. The method of claim 1, wherein the breast cancer is AR-positive metastatic breast cancer or AR-positive refractory breast cancer.

3. 2. The method of claim 1, wherein the breast cancer has not been treatable with a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor or the subject is resistant or non-responsive to treatment with the CDK4 / 6 inhibitor.

4. 4. The method of claim 3, wherein the CDK4 / 6 inhibitor is palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, relociclib, or abemaciclib (Vorzenio).

5. 4. The method of claim 3, wherein the CDK4 / 6 inhibitor is palbociclib (Ibrance).

6. 4. The method of claim 3, wherein the CDK4 / 6 inhibitor is abemaciclib (Vorzenio).

7. 13. The method of claim 1, wherein the SARM compound resensitizes the breast cancer to a treatment that was not treatable with the CDK4 / 6 inhibitor.

8. 13. The method of claim 1, wherein the SARM compound overcomes estrogen endocrine resistance.

9. 9. The method of claim 8, wherein the estrogen endocrine therapy comprises at least one of tamoxifen, toremifene, raloxifene, exemestane, letrozole, anastrozole, and fulvestrant.

10. The method of claim 1, wherein the SARM compound overcomes resistance to estrogen endocrine and CDK4 / 6 inhibitor combination therapy.

11. 2. The method of claim 1, wherein the ER-positive breast cancer is AR-positive and ER-positive breast cancer, or AR-negative and ER-positive breast cancer.

12. 2. The method of claim 1, wherein the AR-positive breast cancer is ER-negative, ER-negative, PR-negative and HER2-negative, ER-negative, PR-negative and HER2-positive, ER-negative, PR-positive and HER2-negative, ER-negative, PR-positive and HER2-positive, ER-positive, PR-negative and HER2-negative, ER-positive, PR-positive and HER2-negative, ER-positive, PR-negative and HER2-positive, or ER-positive, PR-positive and HER2-positive.

13. 13. The method of claim 1, wherein the SARM compound is administered intravenously, intraarterially, intramuscularly, subcutaneously, orally, or topically.

14. 10. The method of claim 1, wherein the selective androgen receptor modulator is administered at 1 mg to 50 mg per day.

15. 10. The method of claim 1, wherein the selective androgen receptor modulator is administered at 9 mg per day or at 18 mg per day.

16. The SARM compound of claim 1, wherein the SARM compound has the structure of formula II: 【Chemistry 4】 (In the formula, X is a bond, O, CH2, NH, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; Z is NO2, CN, COR, COOH, or CONHR; Y is I, CF3, Br, Cl, or Sn(R)3; Q is CN, alkyl, halogen, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, or SR; or Q, together with the benzene ring to which it is attached, is a fused ring system represented by structures A, B, or C; 【Chemistry 5】 R is C 1 -C 4 alkyl, aryl, phenyl, alkenyl, hydroxyl, C 1 -C 4 haloalkyl, halogen, or haloalkenyl; 2. The method of claim 1, wherein R1 is CH3, CF3, CH2CH3, or CF2CF3.

17. The method of claim 1, wherein the SARM compound is represented by the structure of formula VIII, IX, X, XI, XII, XIII, or XIV: 【Chemistry 6】 【Chemistry 7】 18. The method of claim 1, wherein the SARM compound is represented by the structure of formula IX: 【Chemistry 8】 19. The method of claim 1, wherein the SARM compound is represented by the structure of formula IX below, or an optical isomer, racemic mixture, pharma- ceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and the CDK4 / 6 inhibitor is palbociclib. 【Chemistry 9】 20. The method of claim 1, wherein the SARM compound is represented by the structure of formula IX below, or an optical isomer, racemic mixture, pharma- ceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal thereof, and the CDK4 / 6 inhibitor is abemaciclib. 【Chemistry 10】

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