US 20190040000A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 / 0040000 A1 Narayanan et al. (43 ) Pub . Date : Feb . 7 , 2019 (54 ) SELECTIVE RECEPTOR (60 ) Provisional application No .62 / 220 ,094 , filed on Sep . DEGRADER (SARD ) LIGANDS AND 17 , 2015 , provisional application No . 62 /150 ,768 , METHODS OF USE THEREOF filed on Apr. 21 , 2015 . ( 71 ) Applicants :GTx , Inc ., Memphis , TN (US ) ; University of Tennessee Research Publication Classification Foundation , Knoxville , TN (US ) (51 ) Int. Cl. C07C 237 / 20 ( 2006 .01 ) ( 72 ) Inventors : Ramesh Narayanan , Cordova , TN A61P 25 / 00 ( 2006 .01 ) ( US) ; Duane D . MILLER , Collierville , A61P 5 / 28 TN (US ) ; Thamarai PONNUSAMY , (2006 .01 ) Memphis , TN (US ) ; Dong - Jin A61P 35 / 00 ( 2006 .01 ) HWANG , Arlington , TN (US ) ; Charles (52 ) U . S . CI. B . DUKE , Memphis , TN (US ) ; CPC ...... C07C 237/ 20 ( 2013 .01 ); A61P 25 /00 Christopher C . COSS , Upper ( 2018 .01 ) ; A61P 35 / 00 ( 2018 .01 ) ; A61P 5 /28 Arlington , OH (US ) ; Amanda JONES , ( 2018 .01 ) Silver Spring , MI (US ) ; James T . DALTON , Ann Arbor , MI (US ) (57 ) ABSTRACT (21 ) Appl. No. : 16 /153 , 193 This invention provides novel 3 - amino propanamide selec tive degrader (SARD ) compounds , phar ( 22 ) Filed : Oct . 5 , 2018 maceutical compositions and uses thereof in treating pros tate cancer, advanced prostate cancer, castration resistant Related U . S. Application Data prostate cancer , androgenic alopecia or other 5 hyperandro (63 ) Continuation of application No . 15 / 830 , 688, filed on genic dermal diseases, Kennedy ' s disease , amyotrophic lat Dec . 4 , 2017 , now Pat. No . 10 , 093 ,613 , which is a eral sclerosis ( ALS ) , and uterine fibroids , and to methods for continuation - in - part of application No . 15 /331 , 751 , reducing the levels of androgen receptor- full length (AR filed on Oct. 21 , 2016 , now Pat . No. 9 , 834 ,507 , which FL ) including pathogenic or resistance mutations, AR - splice is a continuation - in -part of application No . 15/ 135 , variants (AR -SV ) , and pathogenic polyglutamine (polyQ ) 151, filed on Apr. 21, 2016 , now Pat. No . 9 ,815 ,776 . polymorphisms of AR in a subject .

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SELECTIVE ANDROGEN RECEPTOR [0006 ] A critical barrier to progress in treating CRPC is DEGRADER (SARD ) LIGANDS AND that AR signaling inhibitors such as enzalutamide, bicalu METHODS OF USE THEREOF tamide , and abiraterone , acting through the LBD , fail to inhibit growth driven by the N -terminal domain (NTD ) CROSS REFERENCE TO RELATED dependent constitutively active AR - SV such as AR - V7, the APPLICATIONS most prominent AR - SV . Recent high - impact clinical trials with enzalutamide and abiraterone in CRPC patients dem [ 0001 ] This Application is a Continuation -in - Part applica onstrated that just 13 . 9 % of AR - V7 - positive patients among tion of U . S . patent application Ser . No . 15 /830 ,688 , filed on 202 patients starting treatment with enzalutamide (Xtandi ) Dec . 4 , 2017 , which is a Continuation - in -Part application of or ( Zytiga ) had PSA responses to either U .S . patent application Ser. No . 15 /331 ,751 , filed on Oct. 21 , of the treatments (Antonarakis E S , Lu C , Luber E , et al. J . 2016 , now U . S . Pat . No. 9 ,834 , 507, which is a Continuation Clin . Oncol . 2017 April 6 . doi: 25 10 . 1200 /X0 . 2016 . 70 . in -Part application of U .S . patent application Ser. No . 1961) , indicating the requirement for next generation AR 15 / 135 , 151 , filed on Apr. 21 , 2016 , now U . S . Pat . No. antagonists that target AR - SVs. In addition , a significant 9 , 815 , 776 , which claims the benefit of U . S . Provisional number of CRPC patients are becoming refractory to abi Application Ser. No . 62 /220 , 094 , filed on Sep . 17 , 2015 , and raterone or enzalutamide , emphasizing the need for next U . S . Provisional Application Ser . No. 62 / 150 , 768 , filed on generation AR antagonists . Apr. 21 , 2015 , which are incorporated in their entirety herein [0007 ] Current evidences demonstrate that CRPC growth by reference . is dependent on constitutively active AR including AR -SV ' s that lack the LBD such as AR - V7 and therefore cannot be FIELD OF THE INVENTION inhibited by conventional antagonists . AR inhibition and [0002 ] This invention is directed to 3 - amino -propanamide degradation through binding to a domain that is distinct from selective androgen receptor degrader (SARD ) compounds, the AR LBD provides alternate strategies to manage CRPC . pharmaceutical compositions and uses thereof in treating [0008 ] Herein the NTD is biophysically characterized to prostate cancer , advanced prostate cancer , castration resis interact with the SARDs of this invention via fluorescence tant prostate cancer, androgenic alopecia or other hyperan polarization ( FP ; Example 11 and FIG . 11 ) and biolayer drogenic dermal diseases, Kennedy 's disease, amyotrophic interferometry (Example 12 and FIG . 12 ). Biochemical lateral sclerosis ( ALS) , and uterine fibroids, and to methods evidence also supports the SARDs of this invention binding for reducing the levels of androgen receptor- full length to a domain other than the LBD . E . g . , SARDs of this ( AR - FL ) including pathogenic or resistance mutations, AR invention degrade AR -SV in 22RV - 1 cells expressing splice variants ( AR -SV ) , and pathogenic polyglutamine AR -V7 ( FIGS . 3 and 10 ) . Eurther , the R - and S - isomers of ( polyQ ) polymorphisms of AR in a subject. the SARDs of this invention possess equipotent SARD activity despite demonstrated differences in the binding and BACKGROUND OF THE INVENTION inhibition of androgen -dependent transactivation via the [0003 ] Prostate cancer (PCA ) is one of the most frequently LBD . The report of SARD activity mediated through the diagnosed noncutaneous cancers among men in the US and NTD of AR is an unprecedented observation that may help is the second most common cause of cancer deaths with explanation the prodigious AR antagonism profiles seen more than 200 , 000 new cases and over 30 ,000 deaths each with the SARDs of this invention . year in the United States. PCa therapeutics market is grow [0009 ] Molecules that degrade the AR prevent any inad ing at an annual rate of 15 - 20 % globally . vertent AR activation through growth factors or signaling [0004 ] Androgen - deprivation therapy ( ADT) is the stan pathways, or promiscuous ligand -dependent activation . In dard of treatment for advanced PCa . Patients with advanced addition ,molecules that inhibit the constitutive activation of prostate cancer undergo ADT, either by luteinizing hormone AR -SVs are extremely important to provide extended ben releasing hormone (LHRH ) agonists , LHRH antagonists or efit to CRPC patients . by bilateral orchiectomy. Despite initial response to ADT, [0010 ] Currently only a few chemotypes are known to disease progression is inevitable and the cancer emerges as degrade AR which include the SARDS ARN -509 , AZD castration -resistant prostate cancer (CRPC ). Up to 30 % of 3514 , and ASC - 19 . However , these molecules degrade AR patients with prostate cancer that undergo primary treatment indirectly at much higher concentrations than their binding by radiation or surgery will develop metastatic disease coefficient and they fail to degrade the AR -SVs that have within 10 years of the primary treatment. Approximately become in recent years the primary reason for resurgence of 50 ,000 patients a year will develop metastatic disease , which treatment- resistant CRPC . is termed metastatic CRPC (mCRPC ) . [0011 ] This invention describes novel AR antagonists with [0005 ] Patients with CRPC have a median survival of unique pharmacology that strongly (high potency and effi 12 - 18 months. Though castration -resistant , CRPC is still cacy ) and selectively bind AR (better than known antago dependent on the androgen receptor ( AR ) signaling axis for nists ; bind to LBD and / or NTD ) , antagonize AR , and continued growth . The primary reason for CRPC re - emer degrade AR full length ( AR -FL ) and AR - SV . Selective gence is re - activation of AR by alternate mechanisms such androgen receptor degrader (SARD ) compounds possess as 1 ) intracrine androgen synthesis, 2 ) AR splice variants dual degradation and AR - SV inhibitory functions and hence ( AR - SV ) that lack ligand binding domain (LBD ) , 3 ) AR are distinct from any available CRPC therapeutics . These LBD mutations with potential to resist AR antagonists (i . e ., novel selective androgen receptor degrader (SARD ) com mutants that are not sensitive to inhibition by AR antago pounds inhibit the growth of PCa cells and tumors that are nists , and in some cases AR antagonists act as agonists of the dependent on AR -FL and AR - SV for proliferation . AR bearing these LBD mutations ) ; and 4 ) amplications of [0012 ] SARDs have the potential to evolve as new thera the AR gene within the tumor. peutics to treat CRPCs that are untreatable with any other US 2019 /0040000 A1 Feb . 7 , 2019 antagonists . This unique property of degrading AR -SV has cancers . Correspondingly , chemotherapy is often the initial extremely important health consequences for prostate can pharmacotherapy for TNBC . Interestingly , AR is often still cer . Till date only one series of synthetic molecules ( EPI expressed in TNBC and may offer a hormone targeted 001 , EPI- 506 , etc . ) and some marine natural products such therapeutic alternative to chemotherapy . In ER - positive as the sinkotamides and glycerol ether Naphetenone B , are breast cancer, AR is a positive prognostic indicator as it is reported to bind to AR -NTD and inhibit AR function and believed that activation of AR limits and /or opposes the PCa cell growth , albeit at lower affinity and inability to effects of the ER in breast tissue and tumors . However , in the degrade the receptor . The SARDs reported herein also bind absence of ER , it is possible that AR actually supports the to AR -NTD and inhibit NTD - driven ( e . g . , ligand indepen growth ofbreast cancer tumors. Though the role of AR is not dent) AR activity . fully understood in TNBC , we have evidence that certain [0013 ] The positive correlation between AR and PCa and TNBC ' s may be supported by androgen independent acti the lack of a fail - safe AR antagonist , emphasize the need for vation of AR - SVs lacking the LBD or androgen -dependent molecules that inhibit AR function through novel or alter activation of AR full length ( see US2017 /0368003A1 ) . As nate mechanisms and / or binding sites , and that can elicit such , enzalutamide and other LBD directed traditional AR antagonistic activities within an altered cellular environ antagonists would not be able to antagonize AR -S Vs in ment. these TNBC ' s . However, SARDs of this invention which are [0014 ] Although traditional such as enzalu capable of destroying AR - SVs ( Example 3 and FIGS . 3 and tamide , , and and andro 10 ) through a binding site in the NTD of AR ( see Examples gen deprivation therapies (ADT ) were approved for use in 11 and 12 ) would be able to antagonize AR including prostate cancer, there is significant evidence that antiandro AR -SV observed in TNBC patient derived xenograpfts and gens could also be used in a variety of other hormonal provide an anti - tumor effect . dependent and hormone independent cancers . For example , [0016 ] Traditional antiandrogens such as bicalutamide and antiandrogens have been tested in breast cancer ( enzaluta flutamide were approved for use in prostate cancer. Subse mide; Breast Cancer Res. ( 2014 ) 16 ( 1 ): R7) , non - small cell quent studies have demonstrated the utility of antiandrogens lung cancer ( shRNAI AR ) (Mol . Cell Endocrinol. 2010 , ( e . g ., flutamide , , acetate , finas 317 ( 1 - 2 ) : 14 - 24 ) , renal cell carcinoma (ASC - J9 ) ( Cancer teride and acetate ) in androgen - dependent Res. 2014 , 74 ( 16 ) :4420 - 30 ) , partial androgen insensitivity dermatological conditions such as androgenic alopecia syndrome ( PAIS ) associated malignancies such as gonadal (male pattern baldness ) , acne vulgaris , and hirsutism ( e . g . , in tumors and seminoma, advanced pancreatic cancer (World J. female facial hair ) . Prepubertal castration prevents sebum Gastroenterology 20 (29 ) : 9229 ) , cancer of the ovary , fallo production and androgenic alopecia but this can be reversed pian tubes (Clinical Trials . gov, Identifier : NCT01974765) , or by use of , suggesting its androgen -dependence . peritoneum , cancer of the salivary gland (Head and Neck [0017 ] The AR gene has a polymorphism of glutamine ( 2016 ) 38 : 724 - 731 ; ADT was tested in AR -expressing repeats (polyQ ) within exon 1 which when shortened may recurrent/ metastatic salivary gland cancers and was con augment AR transactivation ( i . e . , hyperandrogenism ). It has firmed to have benefit on progression free survival and been found that shortened polyQ polymorphisms are more overall survival endpoints ) , esophageal cancer (World J . common in people with alopecia , hirsutism , and acne . Clas Gastroenterol, 2015 , 21 ( 20 ) :6146 -56 ), bladder cancer (On sic antiandrogens are undesirable for these purposes because cotarget 6 (30 ) : 29860 - 29876 ; Int J. Endocrinol ( 2015 ) , they are ineffective through dermal dosing and their long Article ID 384860 ), pancreatic cancer, lymphoma ( including term systemic use raises the risks of untoward sexual effects mantle cell) ( Exp . Hematol. 2017 , 49 :34 - 38 .e2 ) , melanoma such as gynecomastia and impotence. Further, similar to (Melanoma Res. 2002 , 12 (6 ) : 529 - 38 ), gastric cancer ( J . CPRC discussed above , inhibition of ligand -dependent AR Cancer Res. Clin . Oncol. 2004 , 130 ( 5 ) : 253 - 8 ) , colon cancer activity alone may not be sufficient as AR can be activated ( Virchows Arch B Cell Pathol. Incl. Mol. Pathol. 1982 , by various cellular factors other than the endogeneous 38 ( 3 ) :351 - 5 ) , and hepatocellular carcinoma (World J . Gas testosterone ( T ) and (DHT ) , troenterol. 2014 , 20 ( 28 ) :9229 - 36 ) . Use of a more potent such as growth factors , kinases , co - activator overexpression such as a SARD in these cancers may treat the and /or promiscuous activation by other hormones ( e. g ., progression of these and other cancers. Many hormonal and or glucocorticoids ). Consequently , blocking the non - hormonal cancers may benefit from SARD treatment binding of T and DHT to AR with a classical antiandrogen such as breast cancer , testicular cancer , cancers associated may not be sufficient to have the desired efficacy . with partial androgen insensitivity syndromes (PAIS ) such [0018 ] An emerging concept is the topical application of a as gonadal tumors and seminoma, uterine cancer, ovarian SARD to destroy the AR locally to the affected areas of the cancer, cancer of the fallopian tubes or peritoneum , salivary skin or other tissue without exerting any systemic antian gland cancer, bladder cancer, urogenital cancer , brain cancer, drogenism . For this use, a SARD that does not penetrate the skin cancer, lymphoma, melanoma, mantle cell lymphoma, skin or is rapidly metabolized would be preferrable . liver cancer, hepatocellular carcinoma , renal cancer , renal [0019 ] Supporting this approach is the observation that cell carcinoma , osteosarcoma, pancreatic cancer, esophageal cutaneous wound healing has been demonstrated to be cancer, endometrial cancer, lung cancer, non -small cell lung suppressed by androgens . Castration of mice accelerates cancer (NSCLC ) , gastric cancer , colon cancer , perianal cutaneous wound healing while attenuating the inflamma adenoma, or central nervous system cancer . tion in the wounds . The negative correlation between andro [0015 ] Triple negative breast cancer ( TNBC ) is a type of gen levels and cutaneous healing and inflammation , in part , breast cancer lacking the expression of the receptor explains another mechanism by which high levels of endog (ER ), (PR ) , and HER2 receptor enous androgens exacerbate hyperandrogenic dermatologi kinase . As such , TNBC lacks the hormone and kinase cal conditions. Further , it provides a rationale for the treat therapeutic targets used to treat other types of primary breast ment of wounds such as diabetic ulcers or even trauma, or US 2019 /0040000 A1 Feb . 7 , 2019 skin disorders with an inflammatory component such as acne Overall, these results shed light on the role of androgens as or psoriasis , with a topical SARD . modifiers of ALS pathogenesis via dysregulation of andro [0020 ] Androgenic alopecia occurs in ~ 50 % of Caucasian gen receptor homeostasis . Antiandrogens should block the males by midlife and up to 90 % by 80 years old . Minoxidil effects of undecanoate or endogeneous andro ( a topical vasodilator ) and ( a systemic 5alpha gens and reverse the toxicities due to AR aggegregation . reductase type II inhibitor ) are FDA approved for alopecia Eurther, an antiandrogen that can block action of LBD but require 4 - 12 months of treatment to produce a therapeu dependent AR agonists and concomitantly lower AR protein tic effect and only arrest hair loss in most with mild to levels , such as the SARDs of this invention , would be moderate hair regrowth in 30 -60 % . Since currently available therapeutic in ALS . Riluzole is an available drug for ALS treatments have slow and limited efficacy that varies widely treatment, however, it only provides short - term effects . between individuals , and produce unwanted sexual side There is an urgent need for drugs that extend the survival of effects, it is important to find a novel approach to treat ALS patients . Uterine fibroids are also known as leiomyoma. androgenic alopecia and other hyperandrogenic dermato Androgens promote uterine proliferation and the formation logic diseases . of leiomyoma . Leiomyoma has been associated with [0021 ] Anti -androgens are effective in hyperandrogenic increased mutations in polyQ AR ( J . Assist . Reprod . Genet. hormonal conditions in females such as precocious puberty, 2004 , 21 ( 12 ), 453 -457 ; Clin . Chem . Lab . Med . 2008 , 46 (6 ), early puberty , dysmenorrhea , amenorrhea , multilocular 814 -823 ) . Degradation of the pathogenic polyQ AR may be uterus syndrome, endometriosis , hysteromyoma, abnormal preventative of and therapeutic in leiomyomas. For example , uterine bleeding , early menarche, fibrocystic breast disease , the SWAN study ( J . Clin . Endocrinol. Metab . 2016 , 101 ( 1 ) , fibroids of the uterus , ovarian cysts , polycystic ovary syn 123 - 130 ) established that middle aged women with high drome, pre- eclampsia , eclampsia of pregnancy, preterm testosterone had a 33 % increased incidence of new uterine labor, premenstrual syndrome, and / or vaginal dryness . fibroids and the risk was further elevated to 52 % in those These hormonal conditions are hyperandrogenic . For with high testosterone and . example, hyperandrogenic central precocious puberty ( CPP ) [0024 ] Androgen receptor action promotes uterine prolif is discussed in Pediatric Research ( 1993 ) 33 , S14 -S14 or in eration . Hyperandrogenicity of the short polyQ AR has been the Pediatric Research supplement ( abstract 64 ) and others associated with increased leiomyoma or uterine fibroids . are known in the art . (Hsieh Y Y , Chang C C , Tsai E J , Lin CC , Yeh L S , Peng [0022 ] Amyotrophic lateral sclerosis (ALS ) is a fatal neu CT. J . Assist. Reprod . Genet. 2004 , 21 ( 12 ) , 453 -457 ) . A rodegenerative disease . Patients with ALS are characterized separate study of Brazilian women found that shorter and by extended AR polyglutamine repeats . Riluzole is an avail longer [CAG ] ( n ) repeat alleles of AR were exclusive to the able drug for ALS treatment, however, only provides short leiomyoma group in their study (Rosa E E , Canevari Rde A , term effects . There is an urgent need for drugs that extend the Ambrosio E P , Ramos Cirilo P D , Pontes A , Rainho CA , survival of ALS patients . Transgenic animals of ALS were Rogatto S R . Clin . Chem . Lab . Med . 2008 , 46 ( 6 ) , 814 -823 ) . shown to survive longer upon castration and reduction in AR Similarly , in Asian Indian women long polyQ AR was levels compared to castration + nandrolone (agonist ) supple associated with endometriosis and leiomyoma and can be mentation . Castration reduces the AR level, which may be regarded as high - risk markers . SARDs could be used in the reason for extended survival. women with uterine fibroids, especially those expressing [ 0023 ] Amyotrophic lateral sclerosis (ALS ) is a fatal neu shorter and longer (CAG ) ( n ) repeat alleles, to treat existing rodegenerative disease characterized by selective loss of uterine fibroids , prevent worsening of fibroids and /or ame upper and lower motor neurons and skeletal muscle atrophy. liorate carcinogenicity associated with fibroids . An abdomi Epidemiologic and experimental evidence suggest the nal aortic aneurysm (AAA ) is an enlarged area in the lower involvement of androgens in ALS pathogenesis (“ Anabolic / part of the aorta , the major blood vessel that supplies blood androgenic nandrolone exacerbates gene expression to the body. The aorta , about the thickness of a garden hose , modifications induced by mutant SOD1 in muscles of mice runs from your heart through the center of your chest and models of amyotrophic lateral sclerosis . ” Galbiati M , Onesto abdomen . Because the aorta is the body ' s main supplier of E , Zito A , Crippa V , Rusmini P , Mariotti R , Bentivoglio M , blood , a ruptured abdominal aortic aneurysm can cause Bendotti C , Poletti A . Pharmacol . Res . 2012 , 65 ( 2 ) , 221 life - threatening bleeding . Depending on the size and the rate 230 ) , but the mechanism through which androgens modify at which your abdominal aortic aneurysm is growing , treat the ALS phenotype is unknown . A transgenic animal model mentmay vary from watchful waiting to emergency surgery . of ALS demonstrated improved survival upon surgical cas Once an abdominal aortic aneurysm is found , doctors will tration {i . e ., androgen ablation ). Treatment of these castrated closely monitor it so that surgery can be planned if it 's animals with the androgen agonist necessary . Emergency surgery for a ruptured abdominal worsened disease manifestations. Castration reduces the AR aortic aneurysm can be risky. AR blockade ( pharmacologic level, which may be the reason for extended survival . The or genetic ) reduces AAA . Davis et al. (Davis J P, Salmon M , survival benefit is reversed by androgen agonist (“ Andro Pope N H , Lu G , Su G , Meher A , Ailawadi G , Upchurch G gens affect muscle , motor neuron , and survival in a mouse R Jr . J Vasc Surg (2016 ) 63 (6 ) : 1602 - 1612 ) showed that model of SOD1- related amyotrophic lateral sclerosis . ” flutamide (50 mg /kg ) or ( 150 mg/ kg ) attenu Aggarwal T, Polanco M J , Scaramuzzino C , Rocchi A , ated porcine pancreatic elastase ( 0 .35 U mL/ ) induced AAA Milioto C , Emionite L , Ognio E , Sambataro E , Galbiati M , by 84 . 2 % and 91. 5 % compared to vehicle ( 121 % ) . Further Poletti A , Pennuto M . Neurobiol. Aging. 2014 35 ( 8 ) , 1929 AR - / - mice showed attenuated AAA growth (64 . 4 % ) com 1938 ) . Notably , stimulation with nandrolone decanoate pro - pared to wildtype (both treated with elastase ) . Correspond moted the recruitment of endogenous androgen receptor into ingly , administration of a SARD to a patient suffering from biochemical complexes that were insoluble in sodium dode - an AAA may help reverse, treat or delay progression of AAA cyl sulfate , a finding consistent with protein aggregation . to the point where surgery is needed . US 2019 /0040000 A1 Feb . 7 , 2019

10025 ] X - linked spinal- bulbar muscular atrophy tate cancer, castration - resistant prostate cancer, castration (SBMA — also known as Kennedy ' s disease ) is a muscular sensitive prostate cancer , AR - V7 expressing prostate cancer , atrophy that arises from a defect in the androgen receptor or d567ES expressing prostate cancer, comprising adminis gene on the X chromosome . Proximal limb and bulbar tering to the subject a therapeutically effective amount of a muscle weakness results in physical limitations including selective androgen receptor degrader (SARD ) compound of dependence on a wheelchair in some cases. The mutation this invention results in a protracted polyglutamine tract added to the [0030 ] In other embodiments , the castration -resistant N - terminal domain of the androgen receptor (polyQ AR ) . prostate cancer is AR overexpressing castration -resistant Binding and activation of this lengthened polyQ AR by prostate cancer, F876L mutation expressing castration -resis endogeneous androgens ( testosterone and DHT) results in tant prostate cancer, F876L _ T877A double mutation unfolding and nuclear translocation of the mutant androgen expressing castration - resistant prostate cancer, AR -V7 receptor . The androgen - induced toxicity and androgen e xpressing castration -resistant prostate cancer, d567ES dependent nuclear accumulation of polyQ AR protein seems expressing castration -resistant prostate cancer, and / or cas to be central to the pathogenesis . Therefore, the inhibition of tration -resistant prostate cancer characterized by intratu the androgen - activated polyQ AR might be a therapeutic moral androgen synthesis . option ( A . Baniahmad . Inhibition of the androgen receptor 0031 ] In other embodiments , the castration - sensitive by antiandrogens in spinobulbar muscle atrophy . J . Mol. prostate cancer is F876L mutation expressing castration Neurosci. 2016 58 ( 3 ) , 343 - 347 ) . These steps are required for sensitive prostate cancer, F876L _ T877A double mutation pathogenesis and result in partial loss of transactivation castration - sensitive prostate cancer , and /or castration - sensi function ( i . e . , an androgen insensitivity ) and a poorly under tive prostate cancer characterized by intratumoral androgen stood neuromuscular degeneration . Support of use antian synthesis . drogen comes in a report in which the antiandrogen fluta 10032 ]. In other embodiments , the treating of castration mide protects male mice from androgen - dependent toxicity sensitive prostate cancer is conducted in a non - castrate in three models of spinal bulbar muscular atrophy (Renier K setting , or as monotherapy , or when castration - sensitive J , Troxell -Smith S M , Johansen JA , Katsuno M , Adachi H , prostate cancer tumor is resistant to enzalutamide , apaluta Sobue G , Chua J P , Sun Kim H , Lieberman A P , Breedlove mide , and / or abiraterone . S M , Jordan CL . Endocrinology 2014 , 155 ( 7 ) , 2624 - 2634 ) . [0033 ] In other embodiments , the compound is repre Currently there are no disease -modifying treatments but sented by the structure of formula IA : rather only symptom directed treatments. Efforts to target the polyQ AR of Kennedy 's disease as the proximalmedia tor of toxicity by harnessing cellular machinery to promote IA its degradation , i . e . , through the use of a SARD , hold Q5 promise for therapeutic intervention . Selective androgen receptor degraders such as those reported herein bind to and degrade all androgen receptors tested ( full length , splice variant, antiandrogen resistance mutants , etc . ) so degrada tion of polyQ AR polymorphism is also expected , indicating NH I Q2 that they are promising leads for treatment of SBMA . RU T R2 03 10026 ] Here we describe 3 - amino -propanamide SARDs that bind to LBD and an alternate binding and degradation domain (BDD ; located in the NTD ), antagonize AR , and 10034 ] wherein degrade AR thereby blocking ligand -dependent and ligand [ 0035 ] Tis OH , OR , - NHCOCH3, or NHCOR ; [0036 ] Z is NO2, CN , COOH , COR , NHCOR or independent AR activities. This novel mechanism produces CONHR ; improved efficacy when dosed systemically (e .g . , for pros [0037 ] Y is CF3, F , I , Br, C1, CN , C (R ), or Sn ( R )3 ; tate cancer ) or topically ( e . g ., dermatological diseases ) . [0038 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , CHZF , CHF2, CF3, CF2CF3, aryl, phenyl, F , Cl, Br, I , SUMMARY OF THE INVENTION alkenyl or OH ; [ 0027 ] In some embodiment, this invention provides a [ 0039 ] R , is CH3, CHYF , CHF2, CF3, CH2CH3, or method of treating, suppressing , reducing the incidence , CF , CFz ; reducing the severity , or inhibiting the progression of a [0040 ] R2 is hydrogen , C . -C12 - alkyl, SO2- aryl , hormonal condition in a male in need thereof, comprising SO2- phenyl , CO - aryl, arylalkyl , benzyl, aryl, or administering to the subject a therapeutically effective Cz- Cz - cycloalkyl; amount of a selective androgen receptor degrader (SARD ) [0041 ] Q1, Q4, and Qs are each independently selected compound of this invention . from hydrogen , substituted or unsubstituted linear or [0028 ] In other embodiment, the hormonal condition is branched alkyl, substituted aryl, F , C1, Br, I , CF3, CN , hypergonadism , hypersexuality , sexual dysfunction , gyne NO , , substituted or unsubstituted cycloalkyl, substi comastia , precocious puberty in a male , alterations in cog tuted or unsubstituted heterocycloalkyl, substituted or nition and mood , depression , hair loss, hyperandrogenic unsubstituted arylalkyl, C (R ) 3, N (R ) 2 , NHCOCHZ, dermatological disorders , pre -cancerous lesions of the pros NHCOCF4, NHCOR , NHCONHR, NHCOOR , tate , benign prostate hyperplasia , prostate cancer and /or OCONHR , CONHR , NHCSCHZ , NHCSCF3, NHCSR , other androgen -dependent cancers . NHSO , CH3, NHSO R , OR , COR , OCOR , OSO , R , [0029 ] In some embodiments , this invention provides a SO , R , SR , NCS , SCN , NCO , or OCN ; method of treating prostate cancer in a subject in need [ 0042 ] Q2 and Q3 are each independently selected from thereof, wherein said subject has AR overexpressing pros hydrogen , substituted or unsubstituted linear or US 2019 /0040000 A1 Feb . 7 , 2019

branched alkyl, substituted aryl , F , C1, Br, I , CF3, CN , [0058 ] wherein said formed carbocyclic or heterocyclic NO2, substituted or unsubstituted cycloalkyl, substi ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) tuted or unsubstituted heterocycloalkyl, substituted or one or 1H -pyrrole ; unsubstituted arylalkyl, C (R ) 3, N (R ) 2, NHCOCHZ, [0059 ] or its optical isomer, its racemic mixture , phar NHCOCF , NHCOR , NHCONHR , NHCOOR , maceutically acceptable salt , pharmaceutical product , OCONHR, CONHR , NHCSCH , NHCSCFX, NHCSR , polymorph , hydrate , or any combination thereof . NHSO , CH , , NHSO , R , OR , COR , OCOR , OSO , R , [0060 ] In other embodiments , Qi is CN . SOR, SR , NCS , SCN , NCO , or OCN ; [0061 ] In other embodiments , Qz and Q3 are joined [0043 ] wherein at least two of Q1, Q2, Q3, Q4, and Q5 together to form a substituted or unsubstituted C5- Cg non are not hydrogens; or aromatic carbocyclic or a substituted or unsubstituted C . - C . [ 0044 ] Qi and Q2 are joined together to form a substi heterocyclic ring . tuted or unsubstituted C . - C , carbocyclic or heterocy 10062 ] In other embodiments, the compound is repre clic ring, and Q3 , Q4, and Qs are as defined above ; or sented by the structure of any one of the following com [ 0045 ] Q2 and Q3 are joined together to form a substi pounds : tuted or unsubstituted C5- C , carbocyclic or heterocy clic ring , and Q1, Q4, and Qs are as defined above; and [0046 ] wherein said formed carbocyclic or heterocyclic 13 ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) one or 1H -pyrrole ; [ 0047 ] or its optical isomer, its racemic mixture , phar maceutically acceptable salt , pharmaceutical product , NC polymorph , hydrate , or any combination thereof. [0048 ] In other embodiments , the compound is repre NH sented by the structure of formula III: F3C NH 14 III

NC . MOH z- - NH wherein N [0049 ] Z is NO , or CN ; 15 [0050 ] Y is CF3, F , I, Br, Cl, or CN ; ON [0051 ] R2 is hydrogen , C .- C12 - alkyl, SO2- aryl , SO2- phenyl , CO - aryl, arylalkyl, benzyl, aryl , or Cz- Cz -cycloalkyl ; NC [0052 ] Qi is substituted or unsubstituted aryl, substi tuted or unsubstituted phenyl, substituted or unsubsti - NH tuted arylalkyl, F , C1, Br, I, CF3, CN , NO2, or substi F3C tuted or unsubstituted heterocycloalkyl ; ZI antul [0053 ] Q2 is hydrogen , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F , C1, Br, I, CF3, 16 CN , NO2, substituted or unsubstituted cycloalkyl, sub NO stituted or unsubstituted heterocycloalkyl, or substi tuted or unsubstituted arylalkyl; [0054 ] Qz is hydrogen , substituted or unsubstituted aryl, F3C substituted or unsubstituted phenyl, F , C1, Br, I, CF3, CN , NO2, substituted or unsubstituted cycloalkyl, sub stituted or unsubstituted heterocycloalkyl, or substi Automa tuted or unsubstituted arylalkyl; [0055 ] wherein at least one of Q?, Q2 and Qz is a substituted aryl, substituted phenyl, or substituted or unsubstituted arylalkyl; or [ 0056 ] Qi and Q2 are joined together to form a substi NO tuted or unsubstituted C5- C , carbocyclic or heterocy clic ring and Q3 is as defined above ; or [ 0057 ] Q2 and Q3 are joined together to form a substi F C NH tuted or unsubstituted C5- C , non -aromatic carbocyclic " NOH or a heterocyclic ring and Q , is as defined above; and US 2019 /0040000 A1 Feb . 7 , 2019

-continued cells were fixed and stained with sulphorhodamine blue stain 19 to measure cell growth . Enzalutamide and ARN - 509 are NC . CN other AR antagonists reported to degrade AR . [ 0066 ] FIG . 3 depicts the effect of SARDs on AR -FL and AR -SV protein levels . (A ) and ( B ) SARD 17 degrades AR F3C full length and splice variant in 22RV - 1 cells . 22RV - 1 cells •110110 were plated in serum free medium and treated with the indicated concentrations of compound 17 , ARN -509 or ASC - J9 in the presence or absence of R1881 . Cells were harvested , protein extracted and Western blotted for AR and actin . Blots were quantified using Image - J ( panel B ) . ( C ) Same experiment repeated with compound 14 . AR -FL NC androgen receptor- full length ; AR - V7 — androgen receptor splice variant 7 ( lacks ligand binding domain ); ARN -509 and ASC - J9 are other AR antagonists reported to degrade F3C AR . 10067] FIG . 4 depicts degradation of AR by SARDs under varying conditions ( A - D ), without degradation of other receptors ( E - F ) . ( A ) and ( B ) LNCP cells were serum starved and treated with compound 17 ( 10 uM in panel A and bas 21 a dose response in panel B ) in the presence or absence of R1881. Bicalutamide was used as a negative control. Cells were harvested , protein extracted , and Western blotted for NC AR and actin . ( C ) LNCAP cells were plated in full serum and treated with compound 17 (dose response ). Cells were harvested , protein extracted , and Western blotted for AR and actin . ( D ) HeLa cells were infected with adenovirus con taining AR and were treated with compound 17 in the presence or absence of R1881 . Cells were harvested , protein extracted , and Western blotted for AR and actin . ( E ) and ( F ) SARDs do not degrade other nuclear receptors . T47D ( left panel ) and MCF - 7 (right panel ) cells were plated in full BRIEF DESCRIPTION OF THE DRAWINGS serum and treated with compound 17 ( dose response ) . Cells 10063 ] The subject matter regarded as the invention is were harvested , protein extracted , and Western blotted for particularly pointed out and distinctly claimed in the con PR (progesterone receptor ) or ER - a ( estrogen receptor cluding portion of the specification . The invention , however , alpha ) and actin . both as to organization and method of operation , together [0068 ] FIG . 5 depicts the effect of SARDs 17 and 14 on with objects , features , and advantages thereof, may best be AR - target tissues (SV or S . V . - seminal vesicles and pros understood by reference to the following detailed descrip tate ) in the Hershberger assay . The numbers at the bottom of tion when read with the accompanying drawings in which : the graphs are the area under the curve (AUC ) for drug 10064 ) FIG . 1 depicts the effect of novel AR antagonists on AR protein levels (i . e . the SARD effect ). ( A ) Serum - starved concentration . LNCAP cells treated with R1881 and SARD compound (17 ) . 100691. FIG . 6 depicts that SARDs do not inhibit transac ( B ) Dose response of 17 in the presence of 0 . 1 nM R1881 tivation of other receptors until 10 UM . HEK -293 cells were in LNCAP cells . ( C ) LNCAP cells were plated in full serum transfected with the indicated receptors and GRE - LUC and and treated with compound 17 (dose response ) . Cells were CMV - renilla luc . Cells were treated with 17 for 24 hrs after harvested , protein extracted , and Western blotted for AR and transfection and luciferase assay performed 48 hrs after actin . ( D ) Effect of 17 on wild -type AR transfected into transfection . GR — glucocorticoid receptor ; Dex - dexam HeLa cells . ( E ) Effect of 14 on AR expression in VCaP . ( F ) ethasone ; MR - mineralocorticoid receptor ; Ald — aldoster Time- course response of AR to SARD ( 14 ) in LNCaP cells . one ; PR — progesterone receptor ; and Progprogesterone . 17 -AAG - 17 - allylamino - 17 - demethoxygeldanamycin , a [0070 ] FIG . 7 depicts that SARD treatment inhibited AR Hsp90 inhibitor. MDV -3100 , an AR antagonist (antiandro recruitment to the promoter of androgen responsive genes gen ) also known as enzalutamide . AR — androgen receptor; (PSA , FKBP , & TMPRSS2 ) and lowered AR levels in the R1881 — an AR agonist . nucleus in R1881 treated animals . ( A ) LNCaP cells were [0065 ] FIG . 2A and FIG . 2B depict the AR degradation by serum starved for 3 days and treated as indicated above with SARD compound 17 in LNCAP cells . ( A ) LNCaP cells were SARD ( 17 ) or bicalutamide at 10 uM in the presence or plated in serum free medium and treated with the indicated absence of 0 . 1 nM R1881 . Proteins were cross - linked to concentrations of compound 17 and ARN -509 in the pres DNA and chromatin immunoprecipitation studies were con ence or absence of R1881 . Cells were harvested , protein ducted with AR and RNA - Pol II antibodies . ( B ) SARDs extracted and Western blotted for AR and actin . ( B ) LNCAP degrade AR . LNCAP cells were serum starved for 3 days and cells were plated in 96 well plates at 10 , 000 cells /well in treated as indicated above with SARD ( 17 ) at 10 uM in the RPMI+ 1 % csFBS without phenol red . Cells were treated as presence or absence of 0 . 1 nM R1881. Cells were fixed and indicated above in combination with 0 . 1 nM R1881 for 6 immunofluorescence for AR performed . Nucleus was days with medium change on day 3 . At the end of 6 days, the stained with DAPI. US 2019 /0040000 A1 Feb . 7 , 2019

[0071 ] FIG . 8 depicts that SARDs inhibit LNCAP cell The emission spectra were all corrected for buffer alone or growth by non - competitive binding of AR . LNCAP cells buffer with TMAO /urea / compounds as necessary . There was were plated in serum free medium and were treated with no dramatic effect of enobosarm ( left panel ) on the mor for increasing concentrations of enzalutamide or compound 17 tryptophan , while 17 (right panel) reduces the wavelength in the presence of a dose range of R1881. Seven days after (i . e . , a 'blue shift ) , indicating that 17 binds to the AF - 1 and treatment, cells were fixed and growth measured by WST- 1 enobosarm does not bind to AF - 1 . Also , the shoulder is assay . missing on the AF1 + TMAO + 17 trace . FIG . 11B : Left Panel: [0072 ] FIG . 9 depicts that 49 in the presence of R1881 A dose -dependent shift in the fluorescence intensity ( i . e . , degrades AR in LNCAP cells . LNCAP cells were plated in 6 quenching ) by 17 was observed when incubated with AR well plates at 1 million cells /well . The cells were maintained AF - 1 . The fluorescence shoulder observed at 307 nm , which in serum free conditions for 3 days . The cells were treated corresponds to tyrosine residues in the AF - 1 , is shifted by as indicated in the figure , harvested , protein extracted , and 17 . The overall fluorescence is also markedly altered by 17 . Western blotted for AR . 49 (and other SARDs disclosed This indicates that 17 interacts with the AR AF - 1 in addition herein ) demonstrated selective degradation of AR i . e . , to the LBD binding demonstrated in other experiments ) . SARD activity) in the nM range , i. e. , at concentrations Right Panel. Data shown in the left panel was plotted as a comparable to their antagonist IC50 values . LNCAP cells are difference in fluorescence plot between control and 17 known to express the AR mutant T877A , demonstrating the treated samples ( fluorescence in the absence of compound ability of SARDs of this invention to degrade antiandrogen fluorescence in the presence of compound ) , a dose depen resistance conferring mutant androgen receptors . dent increase was observed in the presence of 17 , again [0073 ] FIG . 10 depicts that 49 degrades AR in RV22 - 1 supporting that 17 interacts with the AR AF - 1 . AF1 — cells . 22RV - 1 cells were plated in a 6 well plate at 1 - 1 . 5 activation function - 1 which is a domain in the NTD of AR ; million cells /well in growth medium (RPMI + 10 % FBS) . TMAO - trimethylamine - N -oxide ; E — enobosarm which is Next day , medium was changed and treated with vehicle or a selective androgen receptormodulator which does not bind a dose response of 49 . After overnight treatment ( 12 - 16 hrs ) , NTD ; 17 — a selective androgen receptor degrader (SARD ) cells were washed in ice cold PBS and harvested by scrap of this invention . ping in 1 mL PBS . Cells were pelleted , protein extracted , [0075 ] FIG . 12 depicts biolayer - interferometry (BLI ) quantified using BCA assay , and equal quantity of protein raw data measurements of AF1 binding to compound 17 at was fractionated on a SDS - PAGE. The proteins were trans the concentration of 50 nM . The first 60 seconds are baseline ferred to nylon membrane and Western blotted with AR ( does not start at 0 ) , followed by 300 seconds of an asso antibody (N20 from SCBT) and actin antibody. 49 ( and ciation and dissociation phase ( ~ 1650 - 1950 on y - axis ) . AF1 other SARDs disclosed herein ) was capable of degrading loaded bio sensors are the top two traces . Addition of 17 to full- length androgen receptor (AR - FL ) and truncated AR AF - 1 loaded sheets causes a stronger shift as compared to ( AR -SV ) in 22RV - 1 cells , suggesting that SARDs of this controls loaded with ERD14 and biocytin (bottom two invention may be able to overcome AR - V7 dependent traces) as reference sensors suggesting that 17 has a direct prostate cancers . interaction with AF - 1 at concentrations as low as 50 nM . [0074 ] FIGS . 11A - 11B depict that SARDs bind to the [0076 ] FIGS. 13A - 13C depict inhibitory AR function of N - terminal activation function 1 of AR ( AR - AF1) in addi 17 . 17 potently inhibited AR transactivation . AR transacti tion to the C - terminal ligand binding domain ( LBD ) which vation was performed by transfecting human AR cDNA , contains the AR - AF2 . FIG . 11A : There are two tryptophan GRE -LUC , and CMV- renilla LUC into HEK - 293 cells . residues and up to 12 tyrosine residues. This has allowed us Cells were treated 24 hrs after transfection with a dose to study the folding properties of this domain using intrinsic response of 17 and 0 . 1 nM R1881 and luciferase assay was steady state fluorescence emission spectra . Excitation at 287 performed 48 hrs after transfection . Values provided are nm excites both tyrosine and tryptophan residues. The IC . ( FIG . 13A ) . 17 comparably inhibited transactivation of emission maximum amor ) for the tryptophan is sensitive to wildtype and LBD -mutant AR . Transactivation assay with the exposure to solvent . In the presence of the natural 17 was performed with wildtype AR or AR carrying com osmolyte TMAO (AF1 + TMAO ) there is a characteristic monly known LBD mutants . ( FIG . 13B ) . 17 does not “ blue shift ' consistent with the tryptophan residues being cross - react with mineralocorticoid receptor (MR ) or gluco less solvent exposed and a loss of the shoulder ( - 307 nm ; corticoid receptor (GR ) . Transactivation was performed by see solid black trace as compared to AF1 ( alone ) which is the transfecting human AR , GR , or MR cDNA , GRE - LUC , and 2nd to top trace at 300 nm in the left panel and top trace at CMV - renilla LUC into HEK - 293 cells . Cells were treated 24 300 nm in the right panel) for tyrosine as there is increased hrs after transfection with indicated doses of 17 in combi energy transfer to tryptophan as the polypeptide folds. In nation with 0 . 1 nM R1881 (AR ) , dexamethasone (GR ) and contrast in the presence of urea ( causes unfolding ) there is (MR ) and luciferase assay was performed 48 hrs a ‘ red shift' as the tryptophan residues becomemore solvent after transfection . (FIG . 13C ) . 17 potently inhibited the exposed and a defined peak for tyrosine emission appears . expression of AR -target genes in LNCAP cells . LNCAP cells To test if the compounds (enobosarm ( E ) and 17 ) interact were maintained in charcoal stripped serum containing with AF - 1 and /or alter the folding of this domain we medium for two days and treated with vehicle or indicated measured the steady state fluorescence for each compound compounds ( 17 or enzalutamide with concentration range with AR - AF1 alone or the presence of TMAO ( 3 M ) or urea between 1 and 10 ,000 nM ) in the presence of 0 . 1 nMR1881 . ( 4 or 6 M ) . Enobosarm was used as a negative control RNA was isolated and expression of PSA (not shown ) or ( should not interact) while TMAO serves as a positive FKBP5 was quantified and normalized to GAPDH by real control ( should promote folding ) . We used 1 uM of AR - AF1 time PCR ( FIG . 13D ) . and 5 uM of the individual compounds and preincubated for [0077 ] FIGS. 14A - 14B depict degradation of AR using 17 at least 30 minutes prior to measuring the emission spectra . under multiple conditions . LNCAP cells were maintained in US 2019 /0040000 A1 Feb . 7 , 2019 charcoal stripped serum containing medium for 2 days and F8767T877 { i. e ., MR49 cells ) , and H87471877 {Genome treated as indicated in the figure for 24 hrs . Western blot for Biol. (2016 ) 17 : 10 (doi : 10 . 1186 /s13059 -015 - 0864 - 1 ) ) . Abi the AR with N20 antibody and actin was performed ( FIG . raterone resistance mutations include L702H mutations 14A ) . LNCAP cells were maintained in charcoal stripped which results in activation of the AR by glucocorticoids such serum containing medium for 2 days and treated with as prednisone, causing resistance to abiraterone because vehicle or 17 in the presence of 0 . 1 nMR1881. Western blot abiraterone is usually prescribed in combination with pred for the AR with AR C19 antibody and actin was performed nisone . If resistance develops to enzalutamide then often the ( FIG . 14B ) . patient is refractory to abiraterone also and vice versa ; or the [0078 ] FIG . 15 shows that 17 does not inhibit AR mRNA . duration of response is very short. This situation highlights LNCAP cells were maintained in charcoal stripped serum the need for a definitive androgen ablation therapy to containing medium for two days and treated for 24 hours prevent AR reactivation in advanced prostate cancers . with vehicle or 17 ( 0 . 001 - 10 ,000 nM ) in the presence of 0 . 1 [0083 ] Despite initial response to androgen deprivation nM R1881 . RNA was isolated and expression of AR or therapy ( ADT) , PCa disease progression is inevitable and FKBP5 was quantified and normalized to GAPDH by real the cancer emerges as castration - resistant prostate cancer time PCR . (CRPC ) . The primary reason for castration resistant prostate [0079 ] FIGS. 16A - 16B depict inhibition of DNA binding cancer (CRPC ) re -emergence is re -activation of androgen of the AR and RNA Pol II using 17 . LNCaP cells were serum receptor ( AR ) by alternate mechanisms such as: starved for 2 days and were treated with 0 . 1 nM R1881 in 10084 ] ( a ) intracrine androgen synthesis ; the presence or absence of 10 um 17 or bicalutamide (Bical ) [ 0085 ] (b ) expression of AR splice variants ( AR - SV ) for 2 hrs . DNA -protein complex was cross - linked and AR that lack ligand binding domain (LBD ) ; (FIG . 16A ) and RNA Pol II (FIG . 16B ) were immunopre 10086 ) ( c ) AR -LBD mutations with potential to resist cipitated and their recruitment to PSA regulatory regions antagonists ; was measured by realtime PCR . N = 3 . Values are expressed [0087 ] (d ) hyper- sensitization of AR to low androgen as average : S . E . levels , e . g ., due to AR gene amplification or AR muta [0080 ] It will be appreciated that for simplicity and clarity tion ; of illustration , elements shown in the figures have not [0088 ] (e ) amplication of the AR gene within the tumor ; necessarily been drawn to scale . For example , the dimen and sions of some of the elements may be exaggerated relative [ 0089 ] ( f) over expression of coactivators . to other elements for clarity . Further, where considered 0090 ] In one embodiment , this invention is directed to appropriate , reference numerals may be repeated among the novel selective androgen receptor degrader (SARD ) com figures to indicate corresponding or analogous elements . pounds , which inhibit the growth of prostate cancer (PCa ) cells and tumors that are dependent on AR full length DETAILED DESCRIPTION OF THE PRESENT (AR - FL ) including pathogenic and resistance mutations and INVENTION wildtype , and AR splice variants (AR - SV ) for proliferation . [0081 ] In the following detailed description , numerous [0091 ] According to this invention , a “ selective androgen specific details are set forth in order to provide a thorough receptor degrader ” (SARD ) compound is an androgen recep understanding of the invention . However , it will be under tor antagonist that is capable of inhibiting the growth of PCa stood by those skilled in the art that the present invention cells and tumors that are dependent on AR - full length may be practiced without these specific details . In other ( AR - FL ) and/ or AR splice variants (AR - SV ) for prolifera instances, well -known methods, procedures , and compo tion . In another embodiment, the SARD compound does not nents have not been described in detail so as not to obscure bind to ligand binding domain (LBD ) . In another embodi the present invention . ment, the SARD compound binds to the N - terminal domain [0082 ] Androgens act in cells by binding to the AR , a (NTD ) of the AR . In another embodiment, the SARD member of the steroid receptor superfamily of transcription compound binds to an alternate binding and degradation factors . As the growth and maintenance of prostate cancer domain (BDD ) of the AR . In another embodiment, the ( PCa ) is largely controlled by circulating androgens , treat SARD compound binds both to the AR ligand binding ment of PCa heavily relies on therapies that target AR . domain (LBD ) and to an alternate binding and degradation Treatment with AR antagonists such as enzalutamide , domain (BDD ) . In another embodiment , the SARD com bicalutamide , apalutamide or to disrupt pound binds both to the N - terminal domain (NTD ) and to the receptor activation has been successfully used in the past to ligand binding domain (LBD ) of the AR . In another embodi reduce PCa growth . All currently available AR antagonists ment, the SARD compound is capable of inhibiting growth competitively bind AR and recruit corepressors such as driven by the N - terminal domain (NTD ) - dependent consti NCOR and SMRT to repress transcription of target genes . tutively active AR - SV . In another embodiment, the SARD However, altered intracellular signaling , AR mutations, and compound inhibits the AR through binding to a domain that increased expression of coactivators lead to functional is distinct from the AR LBD . In another embodiment, the impairment of antagonists or even transformation of antago SARD compound is a strong ( i. e ., highly potent and highly nists into agonists . Studies have demonstrated thatmutation efficacious ) selective androgen , which of W741 and 1877 within AR converts bicalutamide and antagonizes the AR stronger than other known AR antago hydroxyflutamide , respectively , to agonists . Similarly , nists ( e . g . , enzalutamide , apalutamide, bicalutamide and increased intracellular cytokines recruit coactivators instead abiraterone ). In another embodiment , the SARD compound of corepressors to AR -responsive promoters subsequently is a selective androgen receptor antagonist , which targets converting bicalutamide to an agonist . Similarly , mutations AR - SVs, which cannot be inhibited by conventional antago that have been linked to enzalutamide resistance include nists . In another embodiment, the SARD compound exhibits F876 , H874 , 1877 , and di- mutants T877 / 5888, T877/ D890 , AR -splice variant (AR - SV ) degradation activity . In another US 2019 /0040000 A1 Feb . 7 , 2019 embodiment, the SARD compound further exhibits AR - full further possess dual AR -FL degradation and AR -FL inhibi length (AR - FL ) degradation activity . In another embodi tory functions . In another embodiment, this invention is ment, the SARD compound exhibits AR -splice variant ( AR directed to novel selective androgen receptor degrader SV ) inhibitory activity ( i. e ., is an AR -SV antagonist) . In (SARD ) compounds , which possess dual AR - SV and AR - FL another embodiment, the SARD compound further exhibits degradation , and AR - SV and AR - FL inhibitory functions . AR - full length ( AR - FL ) inhibitory activity ( i . e . , is an AR - FL [ 0097 ] In one embodiment, this invention is directed to antagonist ) . In another embodiment, the SARD compound novel selective androgen receptor degrader (SARD ) com possesses dual AR -SV degradation and AR -SV inhibitory pounds , for use in treating CRPC that cannot be treated with functions. In another embodiment, the SARD compound any other antagonist . further possesses dual AR - FL degradation and AR - FL [0098 ] In one embodiment , this invention is directed to inhibitory functions including pathogenic point mutations selective androgen receptor degrader (SARD ) compounds , associated with the emergence of antiandrogen resistance . In for use in treating CRPC , by degrading AR -SVs . another embodiment, the SARD compound is a selective [0099 ] In one embodiment, the novel SARD compounds androgen receptor antagonist , which targets AR - SVs. In according to this invention maintain their antagonistic activ another embodiment, the SARD compound further targets ity in AR mutants that normally convert AR antagonists to AR - FLs. In another embodiment, the SARD compound agonists . In another embodiment , the SARD compounds inhibits the constitutive activation of AR -SVs . In another maintain their antagonistic activity to AR mutants W741 and embodiment, the SARD compound further inhibits the con T877 . In another embodiment, the SARD compounds elicit stitutive activation of AR - FLs. In another embodiment, the antagonistic activity within an altered cellular environment SARD compound is a selective androgen receptor antago in which LBD - targeted agents are not effective . In another nist , which degrades AR - full length ( AR - FL ) and AR splice embodiment, the SARD compounds elicit antagonistic variants (AR - SV ) . In another embodiment, the SARD com - activity within an altered cellular environment in which pound degrades the AR through binding to a domain that is NTD -dependent AR activity is constitutively active . distinct from the AR LBD . In another embodiment, the SARD compound possesses dual degradation and AR -SV Selective Androgen Receptor Degrader (SARD ) inhibitory functions that are distinct from any available Compounds CRPC therapeutics . In another embodiment, the SARD compound inhibits the re -activation of the AR by alternate [0100 ] In one embodiment, this invention is directed to a mechanisms such as : intracrine androgen synthesis , expres selective androgen receptor degrader (SARD ) compound sion of AR splice variants (AR - SV ) that lack ligand binding represented by the structure of formula I: domain (LBD ) and AR -LBD mutations with potential to resist antagonists . In another embodiment, the SARD com pound inhibits re -activated androgen receptors present in pathogenic altered cellular environments . [0092 ] Nonlimiting examples of AR - splice variants (AR SVs) are : AR - V7 and ARv567es ( a . k . a . AR -V12 ) . Nonlim iting examples of AR mutations conferring antiandrogen resistance are : W741L mutation and T877A mutation . AR - V7 is a splice variant of AR that lacks the LBD . It is constitutively active and has been demonstrated to be R2 Q3 responsible for aggressive PCa and resistance to endocrine therapy. [0101 ] wherein [0093 ] In one embodiment, this invention is directed to [0102 ] T is OH , OR , - NHCOCHz, or NHCOR ; novel selective androgen receptor degrader (SARD ) com [0103 ] Z is NO2, CN , COOH , COR , NHCOR or pounds , which bind to the AR through an alternate binding CONHR ; and degradation domain (BDD ) . In another embodiment, the [0104 ] Y is CF3, F , I , Br, C1, CN , C ( R ) 3 or Sn ( R ) 3 ; SARDs further binds the AR ligand binding domain (LBD ). [0105 ] R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl , [ 0094 ] In one embodiment, this invention is directed to CH F , CHF2, CF3, CF CF3, aryl, phenyl, F , Cl , Br, I , novel selective androgen receptor degrader (SARD ) com alkenyl or OH ; pounds, which exhibit AR - splice variant ( AR - SV ) inhibitory [0106 ] R , is CH3, CHF, CHF2, CF3, CH ,CHz , or activity ( i. e . , is an AR -SV antagonist ) . In another embodi CF CFz; ment, the novel selective androgen receptor degrader [0107 ] R2 is hydrogen , C .- C12 - alkyl , SO2- aryl , ( SARD ) compounds, further exhibit AR - full length ( AR - FL ) SO2- phenyl, — CO - aryl , arylalkyl, benzyl , aryl, or inhibitory activity (i . e ., is an AR - FL antagonist ) . C3 - C7 -cycloalkyl ; [0095 ] In one embodiment, this invention is directed to [0108 ] Q .1 , Q2, Q3, Q4, and Qs are each independently novel selective androgen receptor degrader (SARD ) com selected from hydrogen , substituted or unsubstituted pounds, which exhibit AR - splice variant (AR - SV ) degrada linear or branched alkyl, substituted or unsubstituted tion activity . In another embodiment, the novel selective aryl, substituted or unsubstituted phenyl, F , C1, Br, I, androgen receptor degrader ( SARD ) compounds, further CF , CN , NO , , substituted or unsubstituted cycloalkyl, exhibit AR - full length ( AR - FL ) degradation activity . substituted or unsubstituted heterocycloalkyl, substi [0096 ] In one embodiment, this invention is directed to tuted or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , novel selective androgen receptor degrader (SARD ) com NHCOCHA, NHCOCF4 , NHCOR , NHCONHR , pounds, which possess dual AR - SV degradation and AR - SV NHCOOR , OCONHR , CONHR , NHCSCH?, NHC inhibitory functions. In another embodiment , the SARDS SCF3, NHCSR , NHSO2CH3, NHSO _ R , OR , COR , US 2019 /0040000 A1 Feb . 7 , 2019 10

OCOR , OSO , R , SO , R , SR , NCS , SCN , NCO , or OCN ; [0125 ] wherein said formed carbocyclic or heterocyclic or its isomer, pharmaceutically acceptable salt , phar ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) maceutical product , polymorph , hydrate or any com one or 1H - pyrrole . bination thereof; [ 0109 ] wherein at least two of Q?, Q2, Q3, Q4, and Qs [0126 ] In one embodiment , this invention is directed to a are not hydrogens; or selective androgen receptor degrader ( SARD ) compound [0110 ] Qi and Q2 are joined together to form a substi represented by the structure of formula IB : tuted or unsubstituted C5 - C , carbocyclic or heterocy clic ring , and Q3 , Q4, and Qs are as defined above; or [0111 ] Q2 and Q3 are joined together to form a substi tuted or unsubstituted C3 - C , carbocyclic or heterocy clic ring, and Q1, Q4, and Qs are as defined above ; and [0112 ] wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin - 2 ( 1H ) - one, pyridin - 2 ( 1H ) one or 1H -pyrrole . N [0113 ] In one embodiment, this invention is directed to a RT RS Q3 selective androgen receptor degrader (SARD ) compound represented by the structure of formula IA : [0127 ] wherein IA [0128 ] T is OH , OR , - NHCOCHz, or NHCOR ; [ 0129 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; (0130 ] Y is CF3, F , I, Br, C1, CN , C (R ) z or Sn (R )3 ; [0131 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, NH z CH F , CHF2, CF3, CF2CF3, aryl, phenyl, F , Cl, Br, I, alkenyl or OH ; [ 0132] R , is CH3, CHZF, CHF2, CF3, CH2CH3, or [0114 ] wherein CF ,CF3 ; [0115 ] Tis OH , OR , — NHCOCHz, or NHCOR ; [0133 ] R2 is hydrogen , C . -C12 -alkyl , SO2- aryl , [0116 ] Z is NO2, CN , COOH , COR , NHCOR or - SO2- phenyl , — CO -aryl , arylalkyl, benzyl, aryl, or CONHR ; [0117 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; Cz- Cz - cycloalkyl; [0118 ] R is alkyl, haloalkyl , dihaloalkyl, trihaloalkyl, [0134 ] Q .1 , Q2, Q3, Q4, and Qs are each independently CH _ F , CHF2, CF3 , CF2CF3, aryl, phenyl, F , Cl, Br, I , selected from hydrogen , substituted or unsubstituted alkenyl or OH ; linear or branched alkyl, substituted or unsubstituted [0119 ] Ri is CH3, CHF, CHF2, CF3, CH2CH3, or aryl, substituted or unsubstituted phenyl, F , C1, Br, I , CF CFz ; CF3, CN , NO2, substituted or unsubstituted cycloalkyl, [0120 ] R2 is hydrogen , C7 -C12 - alkyl, SO2- aryl, substituted or unsubstituted heterocycloalkyl, substi SO2- phenyl, CO - aryl, arylalkyl, benzyl, aryl , or tuted or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , C3- C4- cycloalkyl ; NHCOCHA, NHCOCF4 , NHCOR , NHCONHR , [0121 ] Q1, Q2, Q3, Q4 , and Qs are each independently NHCOOR , OCONHR , CONHR , NHCSCH , NHC selected from hydrogen , substituted or unsubstituted SCF3, NHCSR , NHSO , CH3, NHSOZR , OR , COR , linear or branched alkyl , substituted or unsubstituted OCOR , OSO , R , SO , R , SR , NCS , SCN , NCO , or OCN ; aryl, substituted or unsubstituted phenyl, F , C1, Br, I , or its isomer , pharmaceutically acceptable salt, phar CF3 , CN , NO2, substituted or unsubstituted cycloalkyl, maceutical product , polymorph , hydrate or any com substituted or unsubstituted heterocycloalkyl, substi bination thereof; tuted or unsubstituted arylalkyl, C (R ) 3 , N ( R ) 2 , [0135 ] wherein at least two of Q1 , Q2, Q3, Q4 , and Qs NHCOCHA, NHCOCF , NHCOR , NHCONHR , are not hydrogens ; or NHCOOR, OCONHR , CONHR , NHCSCH?, NHC SCF3, NHCSR , NHSO2CH3, NHSO , R , OR , COR , [0136 ] Qi and Q2 are joined together to form a substi OCOR , OSO , R , SO , R , SR , NCS, SCN , NCO , or OCN ; tuted or unsubstituted C5 - C , carbocyclic or heterocy or its isomer, pharmaceutically acceptable salt , phar clic ring, and Q3, Q4, and Qs are as defined above; or maceutical product, polymorph , hydrate or any com [0137 ] Q2 and Q3 are joined together to form a substi bination thereof; tuted or unsubstituted C5- C , carbocyclic or heterocy [0122 ] wherein at least two of Q1, Q2, Q3, Q4, and Q5 clic ring , and Q1, Q4, and Qs are as defined above ; and are not hydrogens ; or [0123 ] Qi and Q2 are joined together to form a substi [0138 ] wherein said formed carbocyclic or heterocyclic tuted or unsubstituted C5- C , carbocyclic or heterocy ring is not dihydropyridin - 2 ( 1H ) - one , pyridin - 2 ( 1H ) clic ring , and Q2 , Q4, and Q are as defined above ; or one or 1H -pyrrole . [0124 ] Q2 and Q3 are joined together to form a substi [0139 ] In one embodiment, this invention provides a tuted or unsubstituted C5- C , carbocyclic or heterocy selective androgen receptor degrader (SARD ) compound clic ring , and Q?, Q4, and Qs are as defined above; and represented by the structure of formula II : US 2019 /0040000 A1 Feb . 7 , 2019

[0151 ] wherein II T is OH , OR , - NHCOCH3, or NHCOR ; [0152 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; Rí T R2 [0153 ] Y is CF3, F, I, Br, C1, CN , C (R ) 3 or Sn (R ) 3; [0154 ] R is alkyl , haloalkyl, dihaloalkyl , trihaloalkyl, CHZF , CHF2 , CF3, CF2CF3, aryl, phenyl, F , Cl, Br, I , wherein alkenyl or OH ; [0140 ] T is OH , OR , NHCOCHz, or NHCOR ; [0155 ] R , is CH3, CH , F , CHF2, CF3 , CH2CH3, or [0141 ] Z is NO2, CN , COOH , COR , NHCOR or CF CF3 ; CONHR; [0156 ] R2 is hydrogen , C . -C12 -alkyl , SO2- aryl, [0142 ] Y is CF3, F , I , Br, C1, CN , C (R ) z or Sn ( R ) 3 ; - SO2 -phenyl , — CO - aryl, arylalkyl, benzyl, aryl, or [0143 ] R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, C3- C4- cycloalkyl ; CHZF , CHF2, CF3, CF CF3, aryl, phenyl, F , Cl, Br, I, [0157 ] Qi is hydrogen , substituted or unsubstituted lin alkenyl or OH ; ear or branched alkyl, substituted or unsubstituted aryl, [0144 ] R , is CH3, CHF, CHF2, CF3, CH2CH3, or substituted or unsubstituted phenyl, F , C1, Br, I, CF3, CF CF3; CN , NO2, substituted or unsubstituted cycloalkyl, sub [0145 ] R2 is hydrogen , C . -C12 - alkyl, SO2- aryl , stituted or unsubstituted heterocycloalkyl, substituted - SO2- phenyl , CO - aryl , arylalkyl, substituted or or unsubstituted arylalkyl, C ( R ) , N ( R ) , , NHCOCHZ, unsubstituted benzyl, substituted or unsubstituted aryl, NHCOCF , NHCOR , NHCONHR, NHCOOR , or C3- C7- cycloalkyl; OCONHR , CONHR, NHCSCH , NHCSCF , NHCSR , [0146 ] Q1, Q2, Q3, Q4, and Qs are each independently NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , selected from hydrogen , substituted or unsubstituted SO _ R , SR , NCS, SCN , NCO , or OCN ; linear or branched alkyl, substituted or unsubstituted [0158 ] Q2 is hydrogen , substituted or unsubstituted lin aryl, substituted or unsubstituted phenyl , F , C1, Br, I , ear or branched alkyl, substituted or unsubstituted aryl, CF3 , CN , NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl, F , C1, Br, I , CF3, substituted or unsubstituted heterocycloalkyl, substi CN , NO , , substituted or unsubstituted cycloalkyl, sub tuted or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , stituted or unsubstituted heterocycloalkyl, substituted NHCOCHE , NHCOCF , NHCOR , NHCONHR , or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, NHCOOR , OCONHR , CONHR , NHCSCH , NHC NHCOCF4, NHCOR , NHCONHR, NHCOOR , SCF2 , NHCSR , NHSO , CH , NHSO , R , OR , COR , OCONHR , CONHR, NHCSCH , NHCSCF , , NHCSR , OCOR , OSO , R , SO R , SR , NCS, SCN , NCO , or OCN ; NHSO , CH3, NHSO R , OR , COR , OCOR , OSO , R , or its isomer , pharmaceutically acceptable salt, phar SO _ R , SR , NCS , SCN , NCO , or OCN ; maceutical product, polymorph , hydrate or any com [0159 ] Q3 is hydrogen , substituted or unsubstituted lin bination thereof; ear or branched alkyl, substituted or unsubstituted aryl, [0147 ] wherein at least two of Q1, Q2, Q3, Q4, and Q5 substituted or unsubstituted phenyl, F , C1, Br, I, CF3, are not hydrogens; or CN , NO , , substituted or unsubstituted cycloalkyl, sub stituted or unsubstituted heterocycloalkyl, substituted [0148 ] Qi and Q2 are joined together to form a substi or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCHZ, tuted or unsubstituted C3 -C , carbocyclic or heterocy NHCOCFX, NHCOR , NHCONHR, NHCOOR , clic ring , and Q3 , Q4, and Qs are as defined above; or OCONHR , CONHR , NHCSCHZ, NHCSCF3, NHCSR , [0149 ] Q , and Q3 are joined together to form a substi NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , tuted or unsubstituted C5- C , carbocyclic or heterocy SO R , SR , NCS , SCN , NCO , or OCN ; or its isomer , clic ring , and Q1, Q4, and Qs are as defined above; and pharmaceutically acceptable salt , pharmaceutical prod wherein said formed carbocyclic or heterocyclic ring is uct , polymorph , hydrate or any combination thereof; not dihydropyridin - 2 ( 1H ) - one , pyridin - 2 ( 1H ) - one or [0160 ] wherein at least two of Q1, Q2 and Q3 are not 1H -pyrrole . hydrogens; or [0150 ] In one embodiment, this invention is directed to a [0161 ] Qi and Q2 are joined together to form a substi selective androgen receptor degrader (SARD ) compound tuted or unsubstituted C . - C , carbocyclic or heterocy represented by the structure of formula IIA : clic ring and Q3 is as defined above; or [0162 ] Q2 and Q3 are joined together to form a substi IIA tuted or unsubstituted C5- C , carbocyclic or heterocy clic ring and Q , is as defined above ; and wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin - 2 (1H ) -one , pyridin -2 ( 1H )- one or 1H -pyr role . RI Ó [0163 ] In one embodiment, this invention is directed to a R2 selective androgen receptor degrader ( SARD ) compound represented by the structure of formula IIA : US 2019 /0040000 A1 Feb . 7 , 2019

[0176 ] wherein said formed carbocyclic or heterocyclic IIA ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) one or 1H -pyrrole . [0177 ] In one embodiment, this invention is directed to a selective androgen receptor degrader (SARD ) compound represented by the structure of formula IIB : # T Q3 II? wherein o, [0164 ] T is OH , OR , — NHCOCH3, or NHCOR ; [0165 ] Z is NO2, CN , COOH , COR , NHCOR or | CONHR ; 11 [0166 ] Y is CF3 , F , I, Br, C1, CN , C (R ), or Sn ( R ) 3; [0167 ] R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, CH F , CHF2, CF3, CF2CF3, aryl, phenyl, F , Cl, Br, I, wherein alkenyl or OH ; [0178 ] T is OH , OR , - NHCOCHz, or NHCOR ; [0168 ] R , is CH3, CH , F , CHF2, CF3, CH2CH3, or [ 0179 ] Z is NO2, CN , COOH , COR , NHCOR or CF2CF3; CONHR ; [0169 ] R2 is hydrogen , C1- C12 - alkyl , SO2- aryl , [0180 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; - SO2- phenyl , CO - aryl, arylalkyl , benzyl, aryl, or [0181 ] R is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl, C3- C4- cycloalkyl ; CH _ F , CHF2, CF3, CF CF3, aryl, phenyl, F , Cl, Br, I, [0170 ] Qi is hydrogen , substituted or unsubstituted lin alkenyl or OH ; ear or branched alkyl, substituted or unsubstituted aryl, [0182 ] R , is CH3, CHF, CHF2, CF3, CH2CH3, or substituted or unsubstituted phenyl, F , C1, Br, I, CF3 , CF CFz; CN , NO , , substituted or unsubstituted cycloalkyl, sub [0183 ] R2 is hydrogen , C7 -C12 - alkyl, SO2 - aryl, stituted or unsubstituted heterocycloalkyl, substituted - SO2- phenyl , — CO - aryl, arylalkyl, benzyl, aryl, or or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCHZ, C3- C4 - cycloalkyl; NHCOCF , NHCOR , NHCONHR, NHCOOR , [0184 ] Q , is hydrogen , substituted or unsubstituted lin OCONHR , CONHR , NHCSCH4, NHCSCF , NHCSR , ear or branched alkyl, substituted or unsubstituted aryl, NHSO ,CH , , NHSO , R , OR , COR , OCOR , OSO , R , substituted or unsubstituted phenyl, F , Cl, Br, I , CF3, SOR, SR , NCS , SCN , NCO , or OCN ; CN , NO2, substituted or unsubstituted cycloalkyl, sub [0171 ] Q2 is hydrogen , substituted or unsubstituted lin stituted or unsubstituted heterocycloalkyl, substituted ear or branched alkyl, substituted or unsubstituted aryl, or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, substituted or unsubstituted phenyl, F , C1, Br, I , CF3, NHCOCF , , NHCOR, NHCONHR , NHCOOR , CN , NO2, substituted or unsubstituted cycloalkyl, sub OCONHR , CONHR , NHCSCH , , NHCSCFz, NHCSR , stituted or unsubstituted heterocycloalkyl, substituted NHSO , CH3, NHSO R , OR , COR , OCOR , OSO _ R , or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCH3, SO _ R , SR , NCS , SCN , NCO , or OCN ; NHCOCF , NHCOR , NHCONHR, NHCOOR , [0185 ] Q2 is hydrogen , substituted or unsubstituted lin OCONHR , CONHR , NHCSCH , NHCSCF4, NHCSR , ear or branched alkyl, substituted or unsubstituted aryl, NHSO , CH , , NHSO , R , OR , COR , OCOR , OSO , R , substituted or unsubstituted phenyl, F , C1, Br, I, CF3 , SO R , SR , NCS, SCN , NCO , or OCN ; CN , NO , , substituted or unsubstituted cycloalkyl, sub [0172 ] Q3 is hydrogen , substituted or unsubstituted lin stituted or unsubstituted heterocycloalkyl, substituted ear or branched alkyl , substituted or unsubstituted aryl, or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2, NHCOCHZ, substituted or unsubstituted phenyl, F , C1, Br, I, CF3, NHCOCF , NHCOR , NHCONHR, NHCOOR , CN , NO2, substituted or unsubstituted cycloalkyl, sub OCONHR , CONHR, NHCSCH , NHCSCF , NHCSR , stituted or unsubstituted heterocycloalkyl, substituted NHSO ,CHz , NHSO , R , OR , COR , OCOR , OSO , R , or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCH , SO R , SR , NCS , SCN , NCO , or OCN ; NHCOCF , NHCOR , NHCONHR, NHCOOR , [0186 ] Q3 is hydrogen , substituted or unsubstituted lin OCONHR , CONHR , NHCSCHZ, NHCSCF2, NHCSR , ear or branched alkyl, substituted or unsubstituted aryl, NHSO , CH , , NHSO , R , OR , COR , OCOR , OSO , R , substituted or unsubstituted phenyl, F , C1, Br, I, CF3, SO R , SR , NCS , SCN , NCO , or OCN ; or its isomer, CN , NO2, substituted or unsubstituted cycloalkyl, sub pharmaceutically acceptable salt, pharmaceutical prod stituted or unsubstituted heterocycloalkyl, substituted uct, polymorph , hydrate or any combination thereof; or unsubstituted arylalkyl, C ( R )3 , N (R ) 2, NHCOCH3, [0173 ] wherein at least two of Q1, Q2 and Q3 are not NHCOCF , NHCOR, NHCONHR , NHCOOR, hydrogens ; or OCONHR , CONHR , NHCSCH?, NHCSCF , NHCSR , [0174 ] Qi and Q2 are joined together to form a substi NHSO ,CH3 , NHSO R , OR , COR , OCOR , OSO , R , tuted or unsubstituted Cs -Cg carbocyclic or heterocy SO , R , SR , NCS, SCN , NCO , or OCN ; or its isomer , clic ring and Q3 is as defined above ; or pharmaceutically acceptable salt, pharmaceutical prod [0175 ] Q2 and Q3 are joined together to form a substi uct , polymorph , hydrate or any combination thereof; tuted or unsubstituted C5- C , carbocyclic or heterocy [0187 ] wherein at least two of Q1, Q2 and Q3 are not clic ring and Q , is as defined above ; and hydrogens; or US 2019 /0040000 A1 Feb . 7 , 2019 13

[0188 ] Qi and Q2 are joined together to form a substi SO _ R , SR , NCS , SCN , NCO , or OCN ; or its isomer, tuted or unsubstituted C . - C , carbocyclic or heterocy pharmaceutically acceptable salt , pharmaceutical prod clic ring and Qz is as defined above ; or uct, polymorph , hydrate or any combination thereof; 10189 ] Q , and Q? are joined together to form a substi tuted or unsubstituted C5 -Cg carbocyclic or heterocy [0200 ] wherein at least two of Q1, Q2 and Q3 are not clic ring and Q , is as defined above; and hydrogens ; or wherein said formed carbocyclic or heterocyclic ring is not [0201 ] Qi and Q2 are joined together to form a substi dihydropyridin - 2 (1H )- one , pyridin - 2 ( 1H )- one or 1H -pyr tuted or unsubstituted C5 - C , carbocyclic or heterocy role . clic ring and Q3 is as defined above ; or [0190 ] In one embodiment, this invention is directed to a [0202 ] Q2 and Q3 are joined together to form a substi selective androgen receptor degrader (SARD ) compound tuted or unsubstituted C3 - C , carbocyclic or heterocy represented by the structure of formula IIB : clic ring and Q , is as defined above ; and [ 0203 ] wherein said formed carbocyclic or heterocyclic IIB ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) ce one or 1H - pyrrole . [0204 ] In one embodiment, this invention is directed to a selective androgen receptor degrader ( SARD ) compound RT represented by the structure of formula III : wherein III [0191 ] T is OH , OR , — NHCOCHz, or NHCOR ; [0192 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; [0193 ] Yis CF3, F , I , Br, C1, CN , C (R ) 3 or Sn ( R ) 3 ; N [0194 ] R is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl, H?COH k CH , F , CHF , CF3, CF CF3, aryl, phenyl , F , C1, Br, I, alkenyl or OH ; [0195 ] R , is CH3, CH , F , CHF2, CF3, CH , CHz, or [0205 ] wherein CF CF3; [0196 ] R2 is hydrogen , C7 -C12 - alkyl , SO2- aryl, [0206 ] Z is NO , or CN ; - SO2- phenyl , — CO - aryl, arylalkyl, benzyl, aryl, or [0207 ] Y is CF3, F , I , Br, Cl, or CN ; Cz- Cz - cycloalkyl ; [0208 ] R , is hydrogen , C . -C12 - alkyl, SO2- aryl, [0197 ] Q , is hydrogen , substituted or unsubstituted lin SO2- phenyl , CO - aryl, arylalkyl , benzyl, aryl, or ear or branched alkyl, substituted or unsubstituted aryl, C3- C4- cycloalkyl substituted or unsubstituted phenyl, F , C1, Br, I , CF2. CN , NO , , substituted or unsubstituted cycloalkyl, sub [0209 ] Qi is substituted or unsubstituted aryl , substi stituted or unsubstituted heterocycloalkyl, substituted tuted or unsubstituted phenyl, substituted or unsubsti or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCHZ, tuted arylalkyl, CN , or NO2; NHCOCF , NHCOR , NHCONHR , NHCOOR , [0210 ] Q2 is hydrogen , substituted or unsubstituted aryl , OCONHR , CONHR , NHCSCHZ, NHCSCF3, NHCSR , substituted or unsubstituted phenyl, F , C1, Br, I , CF3, NHSO2CH3, NHSO R , OR , COR , OCOR , OSO , R , CN , NO2, substituted or unsubstituted cycloalkyl, sub SO _ R , SR , NCS, SCN , NCO , or OCN ; stituted or unsubstituted heterocycloalkyl , or substi [0198 ] Q2 is hydrogen , substituted or unsubstituted lin tuted or unsubstituted arylalkyl; ear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F , C1, Br, I , CF2 , [0211 ] Q3 is hydrogen , substituted or unsubstituted aryl, CN , NO2, substituted or unsubstituted cycloalkyl, sub substituted or unsubstituted phenyl, F , C1, Br, I, CF2 , stituted or unsubstituted heterocycloalkyl, substituted CN , NO2, substituted or unsubstituted cycloalkyl, sub or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCH , stituted or unsubstituted heterocycloalkyl , or substi NHCOCF , NHCOR , NHCONHR, NHCOOR , tuted or unsubstituted arylalkyl; OCONHR , CONHR , NHCSCHz, NHCSCF2 , NHCSR , [ 0212 ] wherein at least one of Q , and Q3 is a substituted NHSO , CH3, NHSOR , OR , COR , OCOR , OSO , R , or unsubstituted aryl , substituted or unsubstituted phe SO R , SR , NCS , SCN , NCO , or OCN ; nyl or substituted or unsubstituted arylalkyl; or [0199 ] Q3 is hydrogen , substituted or unsubstituted lin ear or branched alkyl, substituted or unsubstituted aryl, [ 0213 ] Q2 and Q3 are joined together to form a substi substituted or unsubstituted phenyl, F , C1, Br, I, CF3, tuted or unsubstituted C . - C , carbocyclic or heterocy CN , NO2, substituted or unsubstituted cycloalkyl, sub clic ring and Qi is as defined above ; or its isomer, stituted or unsubstituted heterocycloalkyl, substituted pharmaceutically acceptable salt, pharmaceutical prod or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCH3, uct , polymorph , hydrate or any combination thereof. NHCOCF4, NHCOR , NHCONHR, NHCOOR , [0214 ] In another embodiment, this invention is directed OCONHR , CONHR , NHCSCH , NHCSCF4, NHCSR , to a selective androgen receptor degrader (SARD ) com NHSO ,CH3 , NHSOZR , OR , COR , OCOR , OSOR, pound represented by the structure of formula III: US 2019 /0040000 A1 Feb . 7 , 2019 14

[ 0232 ] R , is CH3, CHF, CHF2, CF3, CH ,CHz , or III CF2CF3 ; [0233 ] Qi is hydrogen , substituted or unsubstituted lin ear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F , C1, Br, I, CF3 , CN , NO , , substituted or unsubstituted cycloalkyl, sub N stituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C ( R ) z , N ( R ) , , NHCOCHz, NHCOCF , , NHCOR, NHCONHR , NHCOOR, [ 0215 ] wherein OCONHR , CONHR , NHCSCH?, NHCSCF , NHCSR , [0216 ] Z is NO , or CN ; NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , [0217 ] Y is CF3, F , I, Br, Cl, or CN ; SO _ R , SR , NCS , SCN , NCO , or OCN ; [0218 ] R2 is hydrogen , C1- C12 - alkyl, SO2- aryl , [0234 ] Q2 is hydrogen , substituted or unsubstituted lin _ SO , - phenyl, - CO - aryl, substituted or unsubstituted ear or branched alkyl, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted benzyl, substi substituted or unsubstituted phenyl, F , C1, Br, I , CF3, tuted or unsubstituted aryl, or substituted or unsubsti CN , NO2, substituted or unsubstituted cycloalkyl , sub tuted C3 -C4 - cycloalkyl ; stituted or unsubstituted heterocycloalkyl, substituted [0219 ] Q1, Q2 and Q3 are each independently selected or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, from hydrogen , substituted or unsubstituted aryl, sub NHCOCF4, NHCOR , NHCONHR, NHCOOR , stituted or unsubstituted phenyl, substituted or unsub OCONHR , CONHR , NHCSCHZ, NHCSCF , NHCSR , stituted arylalkyl , F , C1, Br, I , CF3, CN , NO2, substi NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , tuted or unsubstituted cycloalkyl , or substituted or SO R , SR , NCS , SCN , NCO , or OCN ; unsubstituted heterocycloalkyl; [0235 ] or [0220 ] wherein least one of Q1, Q2 and Q2 is a substi [0236 ] Qi and Q2 are joined together to form a substi tuted or unsubstituted aryl, substituted or unsubstituted tuted or unsubstituted C3 -C , carbocyclic or heterocy arylalkyl, or substituted or unsubstituted phenyl; clic ring ; or its isomer , pharmaceutically acceptable [0221 ] or salt, pharmaceutical product, polymorph , hydrate or 10222 ] Q , and Q , are joined together to form a substi any combination thereof. tuted or unsubstituted C5 - C , carbocyclic or heterocy [0237 ] In one embodiment, this invention is directed to a clic ring and Q3 is as defined above ; selective androgen receptor degrader (SARD ) compound [ 0223 ] or represented by the structure of formula V : [0224 ] Q2 and Q3 are joined together to form a substi tuted or unsubstituted C3 -C , carbocyclic or heterocy clic ring and Q , is as defined above ; and [0225 ] wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin - 2 ( 1H ) - one , pyridin - 2 ( 1H ) one or 1H - pyrrole ; or its isomer, pharmaceutically acceptable salt , pharmaceutical product, polymorph , N hydrate or any combination thereof. RI [ 0226 ] In one embodiment, this invention is directed to a selective androgen receptor degrader (SARD ) compound represented by the structure of formula IV : [0238 ] wherein IV [0239 ] T is OH , OR , — NHCOCHz, or NHCOR ; [0240 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; [0241 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; 10242 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, NH CHZF , CHF2, CF3, CF2CF3 , aryl, phenyl, F , C1, Br, I, alkenyl or OH ; [ 0243 ] R , is CH3, CHF, CHF2, CF3, CH , CHz, or CF2CF3 ; and [0244 ] Qi is hydrogen , substituted or unsubstituted lin ear or branched alkyl, substituted or unsubstituted aryl, [0227 ] wherein substituted or unsubstituted phenyl, F , C1, Br, I, CF2 , [0228 ] T is OH , OR , - NHCOCHz, or NHCOR ; CN , NO2, substituted or unsubstituted cycloalkyl , sub [0229 ] Z is NO2, CN , COOH , COR , NHCOR or stituted or unsubstituted heterocycloalkyl, substituted CONHR ; or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCH3, [0230 ] Y is CF3, F , I, Br, C1, CN , C ( R ) , or Sn ( R ) 3; NHCOCF , NHCOR , NHCONHR, NHCOOR , 10231 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, OCONHR , CONHR, NHCSCH , NHCSCF , NHCSR , CHZF , CHF2, CF3, CF2CF3, aryl, phenyl , F , Cl, Br, I , NHSO , CH3, NHSO R , OR , COR , OCOR , OSO R , alkenyl or OH ; SOR , SR , NCS , SCN , NCO , or OCN ; or its isomer , US 2019 /0040000 A1 Feb . 7 , 2019 15

pharmaceutically acceptable salt , pharmaceutical prod uct , polymorph , hydrate or any combination thereof. VII [0245 ] In one embodiment, this invention is directed to a selective androgen receptor degrader (SARD ) compound represented by the structure of formula VI: RI

V

N RY 3 [0257 ] wherein [0258 ] T is OH , OR , — NHCOCHz, or NHCOR ; [ 0259 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; [0260 ] Y is CF3 , F, I, Br, C1, CN , C ( R ) , or Sn ( R ) z; [0261 ] R is alkyl , haloalkyl , dihaloalkyl, trihaloalkyl, [ 0246 ] wherein CH _ F , CHF2, CF3, CF CF3, aryl, phenyl, F, CI, Br, I, alkenyl or OH ; [0247 ] Tis OH , OR , NHCOCHz, or NHCOR ; [ 0262] R , is CH3, CH , F , CHF2, CF3, CH2CH3, or [0248 ] Z is NO2, CN , COOH , COR , NHCOR or CF2CFz; and CONHR; [ 0263 ] Qi is hydrogen , substituted or unsubstituted lin ear or branched alkyl, substituted or unsubstituted aryl, [0249 ] Y is CF3 , F , I, Br, C1, CN , C ( R ) z or Sn( R ) 3 ; substituted or unsubstituted phenyl, F , C1, Br, I, CF3, [0250 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CN , NO , , substituted or unsubstituted cycloalkyl, sub CHZF , CHF2, CF3, CF CF3, aryl, phenyl , F , CI, Br, I , stituted or unsubstituted heterocycloalkyl, substituted alkenyl or OH ; or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCHZ, NHCOCF , , NHCOR , NHCONHR, NHCOOR , [0251 ] R , is CH3, CH ,F , CHF2, CF3, CH ,CHz , or OCONHR , CONHR, NHCSCH , NHCSCF , , NHCSR , CF CF3; NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , [ 0252 ] Q , is hydrogen , substituted or unsubstituted lin SO _ R , SR , NCS, SCN , NCO , or OCN ; or its isomer, ear or branched alkyl, substituted or unsubstituted aryl, pharmaceutically acceptable salt , pharmaceutical prod substituted or unsubstituted phenyl, F , C1, Br, I , CF3 , uct , polymorph , hydrate or any combination thereof. CN , NO , , substituted or unsubstituted cycloalkyl, sub [0264 ] In one embodiment, Q . of compound of formulas stituted or unsubstituted heterocycloalkyl, substituted I -VII , IA - IB , and IIA - IIB is CN . In another embodiment, Qi or unsubstituted arylalkyl, C ( R ) , N ( R ) , , NHCOCH , , is F . In another embodiment, Qi is Cl. In another embodi NHCOCF4, NHCOR , NHCONHR, NHCOOR , ment, Qi is Br. In another embodiment, Qi is I . In another OCONHR , CONHR , NHCSCH4, NHCSCF , NHCSR , embodiment, Q . is NO2. In another embodiment, Q . is H . In NHSO ,CH , , NHSO , R , OR , COR , OCOR , OSO , R , another embodiment, Q . is phenyl. In another embodiment, Q , is aryl. In another embodiment, Q . is arylalkyl. In another SO R , SR , NCS, SCN , NCO , or OCN ; embodiment, the arylalkyl is benzyl. In another embodi [0253 ] Q2 is hydrogen , substituted or unsubstituted lin ment, Q , is 4 - fluorophenyl. ear or branched alkyl, substituted or unsubstituted aryl, [ 0265 ] In one embodiment, Q . of compound of formula III substituted or unsubstituted phenyl, F , C1, Br, I , CF3, is CN . In another embodiment, Q , is phenyl . In another CN , NO2, substituted or unsubstituted cycloalkyl, sub embodiment, Qi is aryl. In another embodiment, Q . is stituted or unsubstituted heterocycloalkyl, substituted arylalkyl. In another embodiment, the arylalkyl is benzyl. In or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCH3, another embodiment, Q , is 4 - fluorophenyl . NHCOCF , NHCOR , NHCONHR, NHCOOR , [0266 ] In one embodiment, Q , of compound of formulas OCONHR, CONHR , NHCSCH?, NHCSCF , NHCSR , VI or VII is F . In another embodiment, Qi is Cl. In another NHSO2CH3, NHSO , R , OR , COR , OCOR , OSO R , embodiment, Q , is Br. In another embodiment, Q , is I. In SO _ R , SR , NCS, SCN , NCO , or OCN ; another embodiment , Q . is NO2. In another embodiment , Qi [0254 ] or is CN . [0267 ] In one embodiment, Q , of compound of formulas [0255 ] Qi and Q2 are joined together to form a substi I - IV , IA - IB , IIA - IIB , and VI is CN . In another embodiment, tuted or unsubstituted C5 - Cg carbocyclic or heterocy Q2 is H . In another embodiment, Q2 is phenyl. In another clic ring ; or its isomer, pharmaceutically acceptable embodiment, Q2 is aryl. In another embodiment, Q2 is salt , pharmaceutical product, polymorph , hydrate or arylalkyl. In another embodiment, the arylalkyl is benzyl. In any combination thereof. another embodiment, Q , is 4 - fluorophenyl. [0256 ] In one embodiment, this invention is directed to a [0268 ] In one embodiment, Q3 of compound of formula selective androgen receptor degrader (SARD ) compound I- III , IA - IB , and IIA -IIB is CN . In another embodiment, Q3 represented by the structure of formula VII : is H . In another embodiment, Qz is phenyl. In another US 2019 /0040000 A1 Feb . 7 , 2019 16

embodiment, ez is aryl . In another embodiment, Qz is [0276 ] In one embodiment, R , of compound of formulas arylalkyl. In another embodiment, the arylalkyl is benzyl. In I - II , IA -IB , IIA - IIB and IV - VII is CHz. In another embodi another embodiment , Q3 is 4 - fluorophenyl. ment, R , is CF3. [ 0269] In one embodiment, Qi and Q2 of compound of formulas I- IV , IA - IB , IIA - IIB and VI are joined together to [0277 ] In one embodiment, T of compound of formulas form a substituted or unsubstituted C5- Cg carbocyclic or I - II , IA - IB , IIA - IIB and IV -VII is OH . In another embodi heterocyclic ring . In another embodiment, the C . - C , carbo ment, T is OCHz. cyclic ring is benzene . In another embodiment, the C3- C , [0278 ] In one embodiment, R of compound of formulas carbocyclic ring is substituted benzene , wherein the substi I - II , IA - IB , IIA -IIB and IV - VII is alkyl. In another embodi tution is one or more groups selected from halogen , ment, R is haloalkyl. In another embodiment, R is diha haloalkyl, hydroxy, alkoxy carbonyl, amido , alkylamido , loalkyl . In another embodiment, R is trihaloalkyl. In another dialkylamido , nitro , amino , alkylamino , dialkylamino , car embodiment, Ris CH , F . In another embodiment, R is CHF , . boxy , thio or thioalkyl. In another embodiment, Q , and Q2 In another embodiment, R is CFz. In another embodiment, are — ( CH ) 4 – . In another embodiment, the C3 - C , hetero R is CF CF3 . In another embodiment, R is aryl. In another cyclic ring is piperidine, pyridine , furan , thiophene , pyrrole , embodiment, R is phenyl. In another embodiment, R is F . In pyrrolidine, pyrazine , piperazine or pyrimidine . another embodiment, R is Cl. In another embodiment, R is [ 0270 ] In one embodiment, Q2 and Q3 of compound of Br. In another embodiment, R is I . In another embodiment, formulas I - III , IA - IB , and IIA - IIB are joined together to R is alkenyl. In another embodiment , R is hydroxyl (OH ) . form a substituted or unsubstituted C3 - C , carbocyclic or heterocyclic ring . In another embodiment, the C3 - Cg carbo [0279 ] In one embodiment , this invention is directed to a cyclic ring is benzene . In another embodiment, the C3- C , selective androgen receptor degrader (SARD ) compound carbocyclic ring is substituted benzene, wherein the substi selected from any one of the following structures: tution is one or more groups selected from halogen , haloalkyl, hydroxy, alkoxy carbonyl, amido , alkylamido , dialkylamido , nitro , amino , alkylamino , dialkylamino , car 13 boxy , thio or thioalkyl. In another embodiment, Q , and Q3 are — ( CH ) . — In another embodiment, the Cz- C , hetero cyclic ring is piperidine, pyridine , furan , thiophene, pyrrole , pyrrolidine, pyrazine, piperazine or pyrimidine . NC . [0271 ] In one embodiment, Q , of compound of formulas I - III , IA - IB , and IIA - IIB is CN , Q2 is phenyl and Qz is - NH hydrogen . In another embodiment, Q , is CN , Q2 is hydrogen F3C and Q3 is phenyl. In another embodiment, Q , is CN , and Q2 N and Q3 are joined to form benzene ring (i . e . are — (CH )4 – ). 14 [0272 ] In one embodiment, R , of compound of formulas I - III, IA - IB , and IIA - IIB is alkyl. In another embodiment, R2 is methyl. In another embodiment, R , is ethyl. In another embodiment, R2 is propyl. In another embodiment, R2 is isopropyl. In another embodiment, R , is pentyl. In another NO embodiment, R , is hexyl. In another embodiment, R , is C3 - C , cycloalkyl. In another embodiment, R2 is cyclobutyl. NH In another embodiment, R , is benzyl. In another embodi F C * * ment , R2 is methyl - cyclohexyl. In another embodiment, R2 NH is CO -phenyl . In another embodiment, R , is SO2- phenyl . In another embodiment, R2 is SO2- phenyl- OCHz . In another CN embodiment, R2 is SO2- phenyl- F . [0273 ] In one embodiment, Z of compound of formulas I- VII , IA -IB , and IIA - IIB is CN . In another embodiment, Z NO is NO2. In another embodiment, Z is COOH . In another embodiment, Z is COR . In another embodiment, Z is NH NHCOR . In another embodiment, Z is CONHR . F C [0274 ] In one embodiment, Y of compound of formulas I - VII , IA - IB , and IIA - IIB is CF3. In another embodiment, Y is F . In another embodiment, Y is I . In another embodiment, 16 Y is Br. In another embodiment, Y is C1. In another embodi NC CN ment, Y is CN . In another embodiment , Y is C ( R ) 3 . In another embodiment , Y is Sn ( R ) 3 . 10275 ] In one embodiment, Z of compound of formulas F30 I - VII , IA - IB , and IIA - IIB is CN and Y is CF3. In another POH embodiment, Z is NO , and Y is CF3 . In another embodi ment, Z is NO , and Y is halogen . In another embodiment, Z is CN and Y is halogen . US 2019 /0040000 A1 Feb . 7 , 2019

- continued -continued 49

OH

F3C F , or SayboX * OH NC grella CF3 17a

OH

??O

NC en NO2 osegaCF : NC 18 CF3 NC . LCN [0280 ] The term " carbocyclic ring” refers to either satu rated , unsaturated or aromatic ring composed exclusively of F3CH carbon atoms. NH OHL [ 0281 ] The term " heterocycle ” group refers , in one Ph embodiment, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen , nitrogen or any combination ho thereof, as part of the ring. In another embodiment , the 19 heterocycle is a 3 - 12 membered ring. In another embodi NC . C ment, the heterocycle is a 6 membered ring . In another embodiment, the heterocycle is a 5 - 7 membered ring . In another embodiment, the heterocycle is a 4 - 8 membered ring . In another embodiment, the heterocycle group may be unsubstituted or substituted by a halogen , haloalkyl, hydroxyl, alkoxy , carbonyl, amido , alkylamido , dialky lamido , cyano , nitro , CO , H , amino , alkylamino , dialky lamino , carboxyl, thio and / or thioalkyl. In another embodi ??? ment, the heterocycle ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3 - 8 membered ring. In another embodiment , the heterocyclic ring is a saturated ring . In another embodiment, the heterocyclic ring is an unsaturated ring . In another embodiment , the hetero NC cycle is piperidine . In another embodiment, the heterocycle is pyridine . In another embodiment, the heterocycle is piperidine, pyridine, furan , thiophene, pyrrole , pyrrolidine , F C Vpyrazine , piperazine or pyrimidine . [0282 ] The term “ cycloalkyl” refers to a non -aromatic , monocyclic or polycyclic ring comprising carbon and hydro gen atoms. A cycloalkyl group can have one or more carbon - carbon double bonds in the ring so long as the ring sasa is not rendered aromatic by their presence . Examples of cycloalkyl groups include , but are not limited to , (C3 - C7) cycloalkyl groups , such as cyclopropyl, cyclobutyl , cyclo NC . pentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and ( C3 - C ,) cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohex enyl, and cycloheptenyl, and unsaturated cyclic and bicyclic F3C terpenes . A cycloalkyl group can be unsubstituted or sub stituted by one or two substituents . Preferably, the DON cycloalkyl group is a monocyclic ring or bicyclic ring . US 2019 /0040000 A1 Feb . 7 , 2019

[0283 ] Non limiting examples for “ C3 - C , carbocyclic or substituted by a formyl group , wherein the aryl is as defined heterocyclic rings ” are carbocyclic rings such as cyclopen hereinabove . Examples of aldehydes are : formyl, acetal , tane , cyclopentene , cyclohexane , benzene, and cyclohexene propanal , butanal, pentanal , benzaldehyde . In another rings, and heterocyclic rings such as pyran , dihydropyran , embodiment, the aldehyde group is a formyl group . tetrahydropyran , dihydropyrrole , tetrahydropyrrole , pyra [0289 ] A " haloalkyl” group refers , in another embodi zine , dihydropyrazine , tetrahydropyrazine , pyrimidine , ment, to an alkyl group as defined above, which is substi dihydropyrimidine , tetrahydropyrimidone , pyrazole , dihy tuted by one or more halogen atoms, e . g . by F , C1, Br or I . dropyrazole , tetrahydropyrazole , piperidine , piperazine , [0290 ] A “ hydroxyl” group refers , in another embodiment, pyridine , dihydropyridine, tetrahydropyridine, morpholine , to an OH group . It is understood by a person skilled in the thiomorpholine , furan , dihydrofuran , tetrahydrofuran , thio art that when R1, R2 or Rz in the compounds of the present phene , dihydrothiophene , tetrahydrothiophene , thiazole , invention is OR , then R is not OH . imidazole , isoxazole , and the like . [0291 ] In one embodiment , the term “ halogen ” or “ halo ” [0284 ] The term “ alkyl” refers , in one embodiment, to a refers to a halogen , such as F , C1, Br or I . saturated aliphatic hydrocarbon , including straight -chain , [ 0292 ] In another embodiment, the phrase “ phenol” refers branched -chain and cyclic alkyl groups. In one embodiment, to an alcohol (OH ) derivative of benzene . the alkyl group has 1 - 12 carbons. In another embodiment, [0293 ] In one embodiment, this invention provides for the the alkyl group has 1 - 7 carbons . In another embodiment, the use of a compound as herein described and /or , its derivative , alkyl group has 1 - 6 carbons . In another embodiment , the isomer , metabolite , pharmaceutically acceptable salt , phar alkyl group has 1 - 4 carbons . In another embodiment, the maceutical product , hydrate , N -oxide , prodrug, polymorph , cyclic alkyl group has 3 - 8 carbons . In another embodiment, crystal or combinations thereof. the cyclic alkyl group has 3 - 12 carbons . In another embodi [0294 ] In one embodiment, the methods of this invention ment, the branched alkyl is an alkyl substituted by alkyl side make use of " pharmaceutically acceptable salts ” of the chains of 1 to 5 carbons . In another embodiment , the compounds, which may be produced , by reaction of a branched alkyl is an alkyl substituted by haloalkyl side compound of this invention with an acid or base . chains of 1 to 5 carbons. The alkyl group may be unsubsti [0295 ] Suitable pharmaceutically acceptable salts of tuted or substituted by a halogen , haloalkyl, hydroxyl, amines of the compounds of the methods of this invention alkoxy carbonyl, amido , alkylamido , dialkylamido , nitro , may be prepared from an inorganic acid or from an organic amino , alkylamino , dialkylamino , carboxyl, thio and /or thio acid . In one embodiment, examples of inorganic salts of alkyl. amines are bisulfates, borates, bromides , chlorides , hemisul [ 0285 ] An “ arylalkyl” group refers to an alkyl bound to an fates, hydrobromates, hydrochlorates, 2 -hydroxyethylsul aryl, wherein alkyl and aryl are as defined above . An fonates (hydroxyethanesulfonates ), iodates, iodides , isothi example of an arylalkyl group is a benzyl group . onates , nitrates , persulfates , phosphate , sulfates , sulfamates , [0286 ] An “ alkenyl” group refers , in another embodiment, sulfanilates, sulfonic acids ( alkylsulfonates, arylsulfonates , to an unsaturated hydrocarbon, including straight chain , halogen substituted alkylsulfonates , halogen substituted branched chain and cyclic groups having one or more double arylsulfonates ), sulfonates and thiocyanates . bonds. The alkenyl group may have one double bond , two [0296 ] In one embodiment, examples of organic salts of double bonds , three double bonds, etc . In another embodi amines may be selected from aliphatic , cycloaliphatic , aro ment, the alkenyl group has 2 - 12 carbons . In another matic , araliphatic , heterocyclic , carboxylic and sulfonic embodiment, the alkenyl group has 2 - 6 carbons . In another classes of organic acids , examples of which are acetates , embodiment, the alkenyl group has 2 - 4 carbons . Examples arginines , aspartates , ascorbates , adipates, anthranilates , of alkenyl groups are ethenyl , propenyl, butenyl, cyclohex algenates, alkane carboxylates , substituted alkane carboxy enyl, etc . The alkenyl group may be unsubstituted or sub lates , alginates, benzenesulfonates , benzoates, bisulfates , stituted by a halogen , hydroxy, alkoxy carbonyl, amido , butyrates, bicarbonates , bitartrates , carboxylates , citrates , alkylamido , dialkylamido , nitro , amino , alkylamino , dialky camphorates, camphorsulfonates, cyclohexylsulfamates , lamino , carboxyl , thio and /or thioalkyl. cyclopentanepropionates , edetates, camsylates, car [ 0287] An “ aryl ” group refers to an aromatic group having bonates , clavulanates , cinnamates , dicarboxylates , diglucon at least one carbocyclic aromatic group or heterocyclic ates, dodecylsulfonates, dihydrochlorides , decanoates , aromatic group , which may be unsubstituted or substituted enanthuates, ethanesulfonates , edetates, edisylates , esto by one or more groups selected from halogen , haloalkyl, lates, esylates , fumarates , formates, fluorides , galacturo hydroxy, alkoxy carbonyl, amido , alkylamido , dialky nates , gluconates , glutamates , glycolates , glucorates, gluco lamido, nitro , amino , alkylamino , dialkylamino , carboxy or heptanoates , glycerophosphates, gluceptates, thio or thioalkyl. Nonlimiting examples of aryl rings are glycollylarsanilates, glutarates, glutamates , heptanoates , phenyl, naphthyl , pyranyl, pyrrolyl , pyrazinyl, pyrimidinyl, hexanoates , hydroxymaleates, hydroxycarboxlic acids, hex pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imida ylresorcinates , hydroxybenzoates, hydroxynaphthoates , zolyl , isoxazolyl, and the like . In one embodiment, the aryl hydrofluorates, lactates , lactobionates, laurates, malates, group is a 4 - 8 membered ring . In another embodiment, the maleates , methylenebis ( beta - oxynaphthoate ) , malonates , aryl group is a 4 - 12 membered ring ( s ) . In another embodi mandelates, mesylates , methane sulfonates , methylbro ment, the aryl group is a 6 membered ring. In another mides , methylnitrates , methylsulfonates, monopotassium embodiment, the aryl group is a 5 membered ring . In another maleates , mucates , monocarboxylates , nitrates , naphthale embodiment, the aryl group is 2 - 4 fused ring system . nesulfonates, 2 - naphthalenesulfonates, nicotinates , napsy [0288 ] A “ aldehyde” group refers, in one embodiment, to lates, N -methylglucamines , oxalates , octanoates , oleates , an alkyl , or alkenyl substituted by a formyl group , wherein pamoates , phenylacetates , picrates , phenylbenzoates, piva the alkyl or alkenyl are as defined hereinabove. In another lates, propionates, phthalates, pectinates, phenylpropionates, embodiment, the aldehyde group is an aryl, or phenyl group palmitates , pantothenates, polygalacturates, pyruvates, qui US 2019 /0040000 A1 Feb . 7 , 2019

nates , salicylates , succinates, stearates , sulfanilates , subac - of isomer, metabolite , pharmaceutical product, hydrate , etates, tartarates , theophyllineacetates, p - toluenesulfonates polymorph of a compound of formulas I - VII, IA - IB , and ( tosylates ) , trifluoroacetates , terephthalates, tannates , teo IIA - IIB . clates , trihaloacetates , triethiodide, tricarboxylates , unde [0303 ] In one embodiment, the term “ isomer " includes, canoates and valerates . but is not limited to , optical isomers and analogs, structural [0297 ] In one embodiment, examples of inorganic salts of isomers and analogs , conformational isomers and analogs , carboxylic acids or phenols may be selected from ammo and the like . nium , alkali metals to include lithium , sodium , potassium , [0304 ] In one embodiment , the term “ isomer " is meant to cesium ; alkaline earth metals to include calcium , magne encompass optical isomers of the SARD compound . It will sium , ; , barium , cholines, quaternary ammo be appreciated by those skilled in the art that the SARDs of niums. the present invention contain at least one chiral center. [0298 ] In another embodiment , examples of organic salts Accordingly , the SARDs used in the methods of the present of carboxylic acids or phenols may be selected from argi invention may exist in , and be isolated in , optically -active or nine, organic amines to include aliphatic organic amines , racemic forms. Some compounds may also exhibit polymor alicyclic organic amines, aromatic organic amines , benza phism . It is to be understood that the present invention thines , t -butylamines , benethamines ( N - benzylphenethyl encompasses any racemic , optically - active , polymorphic , or amine ), dicyclohexylamines , dimethylamines, diethano stereroisomeric form , or mixtures thereof, which form pos lamines , ethanolamines , ethylenediamines, hydrabamines , sesses properties useful in the treatment of androgen - related imidazoles, lysines , methylamines , meglamines , N -methyl conditions described herein . In one embodiment, the SARDs D - glucamines , N , N - dibenzylethylenediamines , nicotina are the pure (R )- isomers . In another embodiment, the mides , organic amines, ornithines, pyridines, picolies, pip SARDs are the pure ( S ) - isomers. In another embodiment, erazines , procaine, tris (hydroxymethyl )methylamines , the SARDs are a mixture of the ( R ) and the ( S ) isomers . In triethylamines , triethanolamines, trimethylamines , trometh another embodiment, the SARDs are a racemic mixture amines and ureas. comprising an equal amount of the ( R ) and the ( S ) isomers. [0299 ] In one embodiment, the salts may be formed by It is well known in the art how to prepare optically - active conventional means, such as by reacting the free base or free forms ( for example , by resolution of the racemic form by acid form of the product with one or more equivalents of the recrystallization techniques , by synthesis from optically appropriate acid or base in a solvent or medium in which the active starting materials , by chiral synthesis , or by chro salt is insoluble or in a solvent such as water, which is matographic separation using a chiral stationary phase ) . removed in vacuo or by freeze drying or by exchanging the [ 0305 ] In another embodiment, this invention further of an existing salt for another or suitable ion includes hydrates of the compounds . The invention also exchange resin . includes use of N -oxides of the amino substituents of the 10300 ] In one embodiment, the methods of this invention compounds described herein . make use of a pharmaceutically acceptable salt of the [0306 ] In one embodiment, the term “ hydrate ” refers to compounds of this invention . In one embodiment, the meth hemihydrate , monohydrate , dihydrate , trihydrate or others , ods of this invention make use of a pharmaceutically accept as known in the art. able salt of compounds of formulas I - VII, IA - IB , and IIA - IIB . In one embodiment, the methods of this invention [0307 ] This invention provides, in other embodiments , use make use of a salt of an amine of the compounds of formulas ofmetabolites of the compounds as herein described . In one I - VII , IA - IB , and IIA - IIB of this invention . In one embodi embodiment, “ metabolite ” means any substance produced ment, the methods of this invention make use of a salt of a from another substance by metabolism or a metabolic pro phenol of the compounds of formulas I - VII, IA - IB , and cess . IIA - IIB of this invention . [0308 ] In one embodiment, the compounds of the inven tion can also include all isotopes of atoms occurring in the [0301 ] In one embodiment, the methods of this invention intermediates or fmal compounds. Isotopes include those make use of a free base , free acid , non - charged or non atoms having the same atomic number but different mass complexed compounds of formulas I - VII , IA - IB , and IIA numbers. In one embodiment, the compound is isotopically IIB and / or its isomer, pharmaceutical product, hydrate , labelled with an isotope selected from the group consisting polymorph , or combinations thereof. of 2H , PH , 13C , 14C , and 18F . In one embodiment, the [0302 ] In one embodiment, the methods of this invention compound is isotopically labelled with an isotope of 2H or make use of an isomer of a compound of formulas I - VII , PH . In one embodiment, the compound is isotopically IA - IB , and IIA - IIB . In one embodiment, the methods of this labelled with an isotope of 13C or 14C . In another embodi invention make use of a pharmaceutical product of a com ment, the compound is isotopically labelled with an isotope pound of formulas I - VII, IA - IB , and IIA - IIB . In one embodi of 18F . ment, the methods of this invention make use of a hydrate of a compound of formulas I - VII, IA - IB , and IIA - IIB . In one [0309 ] Compounds as herein described may be prepared embodiment, the methods of this invention make use of a by any means known in the art , including inter alia , those polymorph of a compound of formulas I- VII , IA - IB , and described in U . S . patent application Ser . No. 11/ 505 , 363, IIA - IIB . In one embodiment, the methods of this invention U . S . patent application Ser. No . 11/ 505 ,499 and U . S . patent make use of a metabolite of a compound of formulas I - VII , application Ser. No . 11 / 394 , 181; and U . S . patent application IA - IB , and IIA - IIB . In another embodiment, the methods of Ser. No. 10 /462 ,837 fully incorporated by reference herein this invention make use of a composition comprising a in their entirety . compound of formulas I - VII , IA - IB , and IIA - IIB , as [0310 ] In another example , Compounds 13 -21 , 17a , 49 or described herein , or, in another embodiment, a combination 50 are prepared according to Example 1A and Example 1B . US 2019 /0040000 A1 Feb . 7 , 2019 20

Biological Activity of Selective Androgen Receptor tate cancer (PCa ) and its symptoms, or increasing the Degraders survival of a male subject suffering from prostate cancer [0311 ] In one embodiment, this invention provides a comprising administering to said subject a therapeutically method of treating, suppressing , reducing the incidence , effective amount of a compound or its isomer, pharmaceu reducing the severity , or inhibiting the progression of pros tically acceptable salt , pharmaceutical product, polymorph , tate cancer (PCa ) and its symptoms, or increasing the hydrate or any combination thereof , represented by a com survival of a male subject suffering from prostate cancer pound of formula IA : comprising administering to said subject a therapeutically effective amount of a compound or its isomer, pharmaceu tically acceptable salt , pharmaceutical product , polymorph , IA hydrate or any combination thereof, represented by a com pound of formula I : 04 0

NH R2 03 [0324 ] wherein [0325 ] Tis OH , OR , - NHCOCHz, or NHCOR ; [0326 ] Z is NO , , CN , COOH , COR , NHCOR or ko 03 CONHR ; [0327 ] Yis CF3, F , I, Br, C1, CN , C ( R ) , or Sn ( R ) z ; [0312 ] wherein [0328 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , [ 0313 ] T is OH , OR , — NHCOCH3, or NHCOR ; CH F , CHF2, CF3, CF2CF3, aryl, phenyl, F , C1, Br, I , [0314 ] Z is NO2, CN , COOH , COR , NHCOR or alkenyl or OH ; CONHR ; [0329 ] Ri is CH3, CH F , CHF2, CF3, CH2CH3, or [0315 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; CF CF3; [0316 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, [0330 ] R2 is hydrogen , C .- C12 - alkyl , SO2- aryl , CH _ F , CHF2, CF3, CF CF3, aryl, phenyl, F , C1, Br, I , - SO2- phenyl , - CO - aryl, arylalkyl , benzyl, aryl, or alkenyl or OH ; Cz -C7 - cycloalkyl; [0317 ] R , is CH3, CH , F, CHF2, CF3, CH , CHz, or [ 0331 ] Q?, Q2, Q3, Q4, and Qs are each independently CF CFz ; selected from hydrogen , substituted or unsubstituted [0318 ] R2 is hydrogen , C .- C12 - alkyl , SO2- aryl , linear or branched alkyl, substituted or unsubstituted - SO2- phenyl , — CO - aryl, arylalkyl, benzyl, aryl, or aryl, substituted or unsubstituted phenyl, F , C1, Br, I, C3 -C7 - cycloalkyl; CF3, CN , NO2, substituted or unsubstituted cycloalkyl, [0319 ] Q1, Q2 , Q3, Q4 , and Qs are each independently substituted or unsubstituted heterocycloalkyl, substi selected from hydrogen , substituted or unsubstituted tuted or unsubstituted arylalkyl, C ( R ) 3 , N ( R )2 , linear or branched alkyl, substituted or unsubstituted NHCOCHA, NHCOCF , NHCOR , NHCONHR, aryl, substituted or unsubstituted phenyl , F , C1, Br, I , NHCOOR , OCONHR , CONHR , NHCSCH?, NHC CF3 , CN , NO2, substituted or unsubstituted cycloalkyl, SCF3, NHCSR , NHSO , CHZ , NHSO , R , OR , COR , substituted or unsubstituted heterocycloalkyl, substi OCOR , OSOR , SO R , SR , NCS , SCN , NCO , or OCN ; tuted or unsubstituted arylalkyl, C ( R ) , N ( R ) , or its isomer, pharmaceutically acceptable salt , phar NHCOCHE, NHCOCF4, NHCOR , NHCONHR , maceutical product , polymorph , hydrate or any com NHCOOR , OCONHR , CONHR , NHCSCH, NHC bination thereof; SCF3, NHCSR , NHSO ,CH3 , NHSO R , OR , COR , (0332 ] wherein at least two of Q?, Q2, Q3, Q4, and Qs OCOR , OSO , R , SO , R , SR , NCS, SCN , NCO , or OCN ; are not hydrogens; or or its isomer , pharmaceutically acceptable salt, phar [0333 ] Qi and Q2 are joined together to form a substi maceutical product, polymorph , hydrate or any com tuted or unsubstituted Co - C , carbocyclic or heterocy bination thereof wherein at least two of Q?, Q2, Q3, Q4, clic ring , and Q3, Q4, and Qs are as defined above ; or and Qs are not hydrogens ; or [ 0334 ] Q2 and Q3 are joined together to form a substi [0320 ] Q , and Q are joined together to form a substi tuted or unsubstituted C . - C , carbocyclic or heterocy tuted or unsubstituted C5- C , carbocyclic or heterocy clic ring, and Q1, Q4, and Qs are as defined above ; and clic ring , and Q3, Q4, and Qs are as defined above ; or [0335 ] wherein said formed carbocyclic or heterocyclic [0321 ] Q , and Q? are joined together to form a substi ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) tuted or unsubstituted Cs- Cg carbocyclic or heterocy one or 1H -pyrrole . clic ring , and Q1, Q4 , and Qs are as defined above; and [0336 ] In one embodiment, this invention provides a [ 0322 ] wherein said formed carbocyclic or heterocyclic method of treating , suppressing , reducing the incidence , ring is not dihydropyridin - 2 (1H )- one , pyridin -2 ( 1H ) reducing the severity , or inhibiting the progression of pros one or 1H -pyrrole . tate cancer (PCa ) and its symptoms, or increasing the [0323 ] In one embodiment, this invention provides a survival of a male subject suffering from prostate cancer method of treating , suppressing, reducing the incidence , comprising administering to said subject a therapeutically reducing the severity , or inhibiting the progression of pros effective amount of a compound or its isomer, pharmaceu US 2019 /0040000 A1 Feb . 7 , 2019 21

tically acceptable salt , pharmaceutical product, polymorph , mide, apalutamide , abiraterone, ARN -509 , AZD -3514 , hydrate or any combination thereof, represented by a com , ASC - J9 , flutamide , hydroxyflutamide , niluta pound of formula IB : mide, , ketoconazole , spironolactone , or any combination thereof. In another embodiment, adminis tering the compound to a subject reduces the levels of AR , IB AR - full length (AR - FL ) , AR - FL with antiandrogen resis tance - conferring AR - LBD mutations , AR - splice variant ( AR -SV ) , gene - amplified AR , or any combination thereof, in said subject . [0350 ] In one embodiment, this invention provides a method of treating, suppressing , reducing the incidence , NH reducing the severity , or inhibiting the progression of pros tate cancer (PCa ) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically [ 0337] wherein effective amount of a compound or its isomer, pharmaceu [0338 ] T is OH , OR , - NHCOCHz, or NHCOR ; tically acceptable salt , pharmaceutical product, polymorph , 103391. Z is NO , , CN , COOH , COR , NHCOR or CONHR ; hydrate or any combination thereof, represented by a com 10340 ) Y is CF2, F , I, Br, C1, CN , C (R ) , or Sn ( R )3 ; pound of formula II : [0341 ] R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, CH _ F , CHF2, CF3, CF2CF3, aryl, phenyl , F , C1, Br, I, alkenyl or OH ; II [ 0342] R , is CH3, CH , F, CHF2, CF3, CH2CH3, or CF CFz ; [ 0343 ] R2 is hydrogen , C7 -C12 - alkyl, SO2- aryl, - SO2- phenyl, — CO - aryl, arylalkyl, benzyl, aryl, or NH Rí Cz- Cz- cycloalkyl ; T R . [ 0344 ] Q?, Q2, Q3, Q4, and Qs are each independently selected from hydrogen , substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted 0351] wherein aryl, substituted or unsubstituted phenyl, F , Cl, Br, I , [0352 ] T is OH , OR , - NHCOCHz, or NHCOR ; CF3 , CN , NO , , substituted or unsubstituted cycloalkyl, [0353 ] Z is NO , , CN , COOH , COR , NHCOR or substituted or unsubstituted heterocycloalkyl, substi CONHR ; tuted or unsubstituted arylalkyl, C ( R ) , N ( R ) , [0354 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; NHCOCHE, NHCOCF , NHCOR , NHCONHR, [ 0355 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , NHCOOR , OCONHR , CONHR , NHCSCH , NHC CHZF , CHF2, CF3, CF2CF3 , aryl, phenyl, F , C1, Br, I, SCF , , NHCSR , NHSO , CH , NHSO , R , OR , COR , alkenyl or OH ; OCOR , OSO R , SO , R , SR , NCS , SCN , NCO , or OCN ; [0356 ] R is CH3, CH F , CHF2, CF3, CH , CH3, or or its isomer, pharmaceutically acceptable salt, phar CF CF3 ; maceutical product , polymorph , hydrate or any com [ 0357 ] R2 is hydrogen , C . -C12 - alkyl, SO2- aryl , bination thereof; - SO2- phenyl , - CO - aryl, arylalkyl , benzyl, aryl, or [ 0345 ] wherein at least two of Q1, Q2, Q3, Q4, and Qs C3 -C7 - cycloalkyl; are not hydrogens; or [0358 ] Q , is hydrogen , substituted or unsubstituted lin [0346 ] Qi and Q2 are joined together to form a substi ear or branched alkyl, substituted or unsubstituted aryl, tuted or unsubstituted C - C , carbocyclic or heterocy substituted or unsubstituted phenyl, F , C1, Br, I , CF3, clic ring , and Q3, Qa, and Qs are as defined above ; or CN , NO , , substituted or unsubstituted cycloalkyl , sub [0347 ] Q2 and Q3 are joined together to form a substi stituted or unsubstituted heterocycloalkyl , substituted tuted or unsubstituted C5 - C , carbocyclic or heterocy or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCH , , clic ring , and Q?, Q4, and Qs are as defined above; and NHCOCF4 , NHCOR , NHCONHR , NHCOOR , 10348 ] wherein said formed carbocyclic or heterocyclic OCONHR , CONHR , NHCSCHZ , NHCSCF3, NHCSR , ring is not dihydropyridin - 2 ( 1H ) - one, pyridin - 2 ( 1H ) NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , one or 1H -pyrrole . SO R , SR , NCS, SCN , NCO , or OCN ; [ 0349 ] In another embodiment, the prostate cancer is [0359 ] Q2 is hydrogen , substituted or unsubstituted lin advanced prostate cancer , castration resistant prostate cancer ear or branched alkyl, substituted or unsubstituted aryl, ( CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC substituted or unsubstituted phenyl, F , C1, Br, I, CF3, (nmCRPC ) , high - risk nmCRPC or any combination thereof . CN , NO2, substituted or unsubstituted cycloalkyl, sub In another embodiment , the prostate cancer depends on stituted or unsubstituted heterocycloalkyl, substituted AR - FL and /or AR - SV for proliferation . In another embodi or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCHZ, ment, the subject further receives androgen deprivation NHCOCF4, NHCOR, NHCONHR, NHCOOR , therapy (ADT ) . In another embodiment, the subject has OCONHR , CONHR , NHCSCHZ, NHCSCF2 , NHCSR , failed androgen deprivation therapy ( ADT ) . In another NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , embodiment, the cancer is resistant to treatment with an SO _ R , SR , NCS , SCN , NCO , or OCN ; androgen receptor antagonist . In another embodiment, the [0360 ) Q3 is hydrogen , substituted or unsubstituted lin cancer is resistant to treatment with enzalutamide , bicaluta ear or branched alkyl, substituted or unsubstituted aryl, US 2019 /0040000 A1 Feb . 7 , 2019

substituted or unsubstituted phenyl, F , C1, Br, I, CF3, [0374 ] Q2 is hydrogen , substituted or unsubstituted lin CN , NO , , substituted or unsubstituted cycloalkyl, sub ear or branched alkyl, substituted or unsubstituted aryl, stituted or unsubstituted heterocycloalkyl, substituted substituted or unsubstituted phenyl, F , Cl, Br, I , CF3, or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, CN , NO , , substituted or unsubstituted cycloalkyl, sub NHCOCF , NHCOR , NHCONHR , NHCOOR , stituted or unsubstituted heterocycloalkyl, substituted OCONHR, CONHR , NHCSCH , NHCSCF4, NHCSR , or unsubstituted arylalkyl, C (R )3 , N (R ) , NHCOCHZ, NHSO , CH3, NHSO R , OR , COR , OCOR , OSOR , NHCOCF4, NHCOR , NHCONHR, NHCOOR , SO _ R , SR , NCS , SCN , NCO , or OCN ; or its isomer , OCONHR , CONHR , NHCSCH , , NHCSCF2, NHCSR , pharmaceutically acceptable salt , pharmaceutical prod NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , uct, polymorph , hydrate or any combination thereof; SO R , SR , NCS , SCN , NCO , or OCN ; [0361 ] wherein least two of Q1, Q2 and Q3 are not [0375 ) Q3 is hydrogen , substituted or unsubstituted lin hydrogens; or ear or branched alkyl, substituted or unsubstituted aryl, [0362 ] Qi and Q2 are joined together to form a substi substituted or unsubstituted phenyl, F , Cl, Br, I , CF3, tuted or unsubstituted Cs -Cg carbocyclic or heterocy CN , NO , , substituted or unsubstituted cycloalkyl, sub clic ring and Q2 is as defined above ; or stituted or unsubstituted heterocycloalkyl, substituted [ 0363 ] Q2 and Q3 are joined together to form a substi or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, tuted or unsubstituted C5 - Cg carbocyclic or heterocy NHCOCF4 , NHCOR , NHCONHR , NHCOOR , clic ring and Q , is as defined above ; and OCONHR , CONHR, NHCSCH , NHCSCF , NHCSR , [ 0364 ] wherein said formed carbocyclic or heterocyclic NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , ring is not dihydropyridin - 2 (1H )- one , pyridin -2 (1H ) SO R , SR , NCS, SCN , NCO , or OCN ; or its isomer , one or 1H -pyrrole . pharmaceutically acceptable salt , pharmaceutical prod [0365 ] In one embodiment, this invention provides a uct, polymorph , hydrate or any combination thereof; method of treating, suppressing , reducing the incidence , [0376 ] wherein least two of Q1, Q2 and Q3 are not reducing the severity , or inhibiting the progression of pros hydrogens ; or tate cancer (PCa ) and its symptoms, or increasing the [ 0377 ] Qi and Q2 are joined together to form a substi survival of a male subject suffering from prostate cancer tuted or unsubstituted C . - C , carbocyclic or heterocy comprising administering to said subject a therapeutically clic ring and Q3 is as defined above ; or effective amount of a compound or its isomer , pharmaceu [ 0378 ] Q2 and Q3 are joined together to form a substi tically acceptable salt, pharmaceutical product, polymorph , tuted or unsubstituted C5 - Cg carbocyclic or heterocy hydrate or any combination thereof, represented by a com clic ring and Q , is as defined above ; and pound of formula IIA : wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin - 2 ( 1H ) - one , pyridin - 2 ( 1H ) - one or 1H -pyr role . IIA [0379 ] In one embodiment, this invention provides a e method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of pros tate cancer (PCa ) and its symptoms, or increasing the Q2 survival of a male subject suffering from prostate cancer R2 03 comprising administering to said subject a therapeutically effective amount of a compound or its isomer , pharmaceu tically acceptable salt, pharmaceutical product , polymorph , [ 0366 ] wherein hydrate or any combination thereof , represented by a com [0367 ] T is OH , OR , - NHCOCHz, or NHCOR ; pound of formula IIB : [0368 ] Z is NO2, CN , COOH , COR , NHCOR or CONHR ; [ 0369 ] Y is CF3, F , I , Br, C1, CN , C ( R ) ; or Sn ( R ) 3 ; IIB [0370 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHZF , CHF2, CF3, CF CF3, aryl, phenyl, F , Cl, Br, I , alkenyl or OH ; [ 0371] R , is CH3, CH , F, CHF2, CF3, CH2CH3, or CZ CF2CF3; [ 0372 ] R2 is hydrogen, C . -C12 - alkyl, SO2- aryl, R2 03 SO2- phenyl, CO - aryl, arylalkyl, benzyl, aryl , or C3 - C7 -cycloalkyl ; [ 0373 ] Q , is hydrogen , substituted or unsubstituted lin wherein ear or branched alkyl, substituted or unsubstituted aryl, [0380 ] T is OH , OR , — NHCOCHz, or NHCOR ; substituted or unsubstituted phenyl, F , C1, Br, I , CF3, [0381 ] Z is NO2, CN , COOH , COR , NHCOR or CN , NO , , substituted or unsubstituted cycloalkyl, sub CONHR ; stituted or unsubstituted heterocycloalkyl, substituted [0382 ] Yis CF3, F, I, Br, C1 , CN , C ( R ), or Sn (R ) 3; or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCH , [0383 ] R is alkyl , haloalkyl , dihaloalkyl, trihaloalkyl, NHCOCF , NHCOR , NHCONHR, NHCOOR , CH _ F , CHF2, CF3, CF CF3 , aryl, phenyl, F , C1, Br, I, OCONHR , CONHR , NHCSCH , NHCSCF4, NHCSR , alkenyl or OH ; NHSO ,CH3 , NHSO R , OR , COR , OCOR , OSO , R , [0384 ] R , is CH3, CH , F, CHF2, CF3, CH , CHz, or SOR, SR , NCS , SCN , NCO , or OCN ; CF CF3; US 2019 /0040000 A1 Feb . 7 , 2019 23

[0385 ] R2 is hydrogen , C .- C12 - alkyl, SO2- aryl , tance - conferring AR -LBD mutations, AR - splice variant - SO2- phenyl , — CO - aryl, arylalkyl, benzyl, aryl , or ( AR - SV ), gene -amplified AR , or any combination thereof, C3 -C4 - cycloalkyl; in said subject. [ 0386 ] Q , is hydrogen , substituted or unsubstituted lin [0394 ] In one embodiment , this invention provides a ear or branched alkyl, substituted or unsubstituted aryl, method of treating , suppressing , reducing the incidence , substituted or unsubstituted phenyl, F , C1, Br, I, CF3, reducing the severity, or inhibiting the progression of pros CN , NO2, substituted or unsubstituted cycloalkyl, sub tate cancer (PCa ) and its symptoms, or increasing the stituted or unsubstituted heterocycloalkyl, substituted survival of a male subject suffering from prostate cancer or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, comprising administering to said subject a therapeutically NHCOCF , NHCOR , NHCONHR, NHCOOR , effective amount of a compound or its isomer, pharmaceu OCONHR , CONHR , NHCSCHZ, NHCSCF , NHCSR , tical product , pharmaceutically acceptable salt, polymorph , NHSO , CH3, NHSO R , OR , COR , OCOR , OSOR , hydrate or any combination thereof, represented by a com SO _ R , SR , NCS, SCN , NCO , or OCN ; pound of formula III : [0387 ] Q2 is hydrogen , substituted or unsubstituted lin ear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F , C1, Br, I, CF3, III CN , NO2, substituted or unsubstituted cycloalkyl, sub Le stituted or unsubstituted heterocycloalkyl , substituted or unsubstituted arylalkyl, C ( R ) 2 , N ( R ) , NHCOCHZ, NHCOCF , , NHCOR , NHCONHR , NHCOOR , Y la OCONHR , CONHR , NHCSCHz, NHCSCF2 , NHCSR , MOH R2 NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , 13COH* R 03 SO , R , SR , NCS, SCN , NCO , or OCN ; [0388 ] Q3 is hydrogen , substituted or unsubstituted lin [0395 ] wherein ear or branched alkyl, substituted or unsubstituted aryl, [0396 ] Z is NO , or CN ; substituted or unsubstituted phenyl, F , C1, Br, I , CF , [0397 ] Y is CF3, F , I , Br, Cl, or CN ; CN , NO2, substituted or unsubstituted cycloalkyl, sub [0398 ] R2 is hydrogen , C1- C12 - alkyl, SO2- aryl , stituted or unsubstituted heterocycloalkyl, substituted - SO2- phenyl, - CO - aryl , arylalkyl, benzyl , aryl, or or unsubstituted arylalkyl, C ( R ) , N ( R ) , NHCOCHZ, C3 -C7 - cycloalkyl NHCOCF4, NHCOR , NHCONHR, NHCOOR , [0399 ] Qi is substituted or unsubstituted aryl, substi OCONHR , CONHR , NHCSCH , NHCSCF2 , NHCSR , tuted or unsubstituted phenyl, substituted or unsubsti NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , tuted arylalkyl, CN , or NO2; SO , R , SR , NCS , SCN , NCO , or OCN ; or its isomer, [0400 ] Q2 is hydrogen , substituted or unsubstituted aryl , pharmaceutically acceptable salt, pharmaceutical prod substituted or unsubstituted phenyl, F , Cl, Br, I , CF3, uct , polymorph , hydrate or any combination thereof; CN , NO2, substituted or unsubstituted cycloalkyl, sub [0389 ] wherein at least two of Q1, Q2 and Q3 are not stituted or unsubstituted heterocycloalkyl , or substi hydrogens; or tuted or unsubstituted arylalkyl; [0390 ] Qi and Q2 are joined together to form a substi [ 0401 ] Q2 is hydrogen , substituted or unsubstituted aryl, tuted or unsubstituted C3- C , carbocyclic or heterocy substituted or unsubstituted phenyl, F, C1, Br, I, CF3, clic ring and R , is as defined above ; or CN , NO2, substituted or unsubstituted cycloalkyl, sub [0391 ] Q2 and Q3 are joined together to form a substi stituted or unsubstituted heterocycloalkyl, or substi tuted or unsubstituted C5- Cg carbocyclic or heterocy tuted or unsubstituted arylalkyl; clic ring and Q , is as defined above ; and [0402 ] wherein at least one of Q , and Q , is a substituted [0392 ] wherein said formed carbocyclic or heterocyclic or unsubstituted aryl, substituted or unsubstituted phe ring is not dihydropyridin -2 (1H )- one , pyridin - 2( 1H ) nyl, or substituted or unsubstituted arylalkyl; or one or 1H -pyrrole . 104031 , and Q , are joined together to form a substi [ 0393 ] In another embodiment, the prostate cancer is tuted or unsubstituted C5- Cg carbocyclic or heterocy advanced prostate cancer , castration resistant prostate cancer clic ring and Q , is as defined above . (CRPC ), metastatic CRPC (mCRPC ) , non -metastatic CRPC [0404 In another embodiment, the prostate cancer is ( nmCRPC ) , high - risk nmCRPC or any combination thereof. advanced prostate cancer, castration resistant prostate cancer In another embodiment, the prostate cancer depends on (CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC AR - FL and / or AR -SV for proliferation . In another embodi ( nmCRPC ) , high - risk nmCRPC or any combination thereof. ment, the subject further receives androgen deprivation In another embodiment, the prostate cancer depends on therapy (ADT ) . In another embodiment, the subject has AR - FL and /or AR -SV for proliferation . In another embodi failed androgen deprivation therapy (ADT ) . In another ment, the subject further receives androgen deprivation embodiment, the cancer is resistant to treatment with an therapy ( ADT) . In another embodiment, the subject has androgen receptor antagonist . In another embodiment, the failed androgen deprivation therapy ( ADT) . In another cancer is resistant to treatment with enzalutamide , bicaluta embodiment, the cancer is resistant to treatment with an mide , apalutamide , abiraterone , ARN - 509 , AZD - 3514 , androgen receptor antagonist . In another embodiment, the galeterone , ASC - J9, flutamide, hydroxyflutamide, niluta cancer is resistant to treatment with enzalutamide, bicaluta mide , cyproterone acetate , ketoconazole , spironolactone , or mide , apalutamide , abiraterone , ARN - 509 , AZD - 3514 , any combination thereof. In another embodiment, adminis galeterone , ASC -J9 , flutamide , hydroxyflutamide, niluta tering the compound to a subject reduces the levels of AR , mide , cyproterone acetate , ketoconazole, spironolactone , or AR - full length (AR -FL ), AR -FL with antiandrogen resis any combination thereof. In another embodiment, adminis US 2019 /0040000 A1 Feb . 7 , 2019 24.

tering the compound to a subject reduces the levels of AR , androgen receptor antagonist . In another embodiment, the AR - full length ( AR - FL ) , AR - FL with antiandrogen resis cancer is resistant to treatment with enzalutamide, bicaluta tance - conferring AR -LBD mutations, AR -splice variant mide , apalutamide, abiraterone , ARN -509 , AZD - 3514 , ( AR -SV ) , gene -amplified AR , or any combination thereof, galeterone , ASC - J9 , flutamide , hydroxyflutamide , niluta in said subject . mide, cyproterone acetate , ketoconazole , spironolactone , or [0405 ] In another embodiment, this invention provides a any combination thereof. In another embodiment, adminis method of treating, suppressing , reducing the incidence , tering the compound to a subject reduces the levels of AR , reducing the severity , or inhibiting the progression of pros AR - full length ( AR - FL ) , AR - FL with antiandrogen resis tate cancer (PCa ) and its symptoms, or increasing the tance - conferring AR - LBD mutations , AR - splice variant survival of a male subject suffering from prostate cancer ( AR -SV ) , gene - amplified AR , or any combination thereof, comprising administering to said subject a therapeutically in said subject. effective amount of a compound or its isomer, pharmaceu [0418 ] In one embodiment, this invention provides a tically acceptable salt, pharmaceutical product, polymorph , method of treating , suppressing , reducing the incidence , hydrate or any combination thereof, represented by a com reducing the severity , or inhibiting the progression of pros pound of formula III: tate cancer (PCa ) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically III effective amount of a compound or its isomer, pharmaceu tically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof , represented by a com pound of formula IV :

-Z

[ 0406 ] wherein [0407 ] Z is NO , or CN ; [ 0408 ] Y is CF3, F , I, Br, Cl, or CN ; [0409 ] R2 is hydrogen , C1- C12 - alkyl, SO2-aryl , 11 — SO2- phenyl , CO - aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted benzyl, substi tuted or unsubstituted aryl, or substituted or unsubsti tuted C3 -C7 - cycloalkyl; [0410 ] Q .1 , Q2 and Q3 are each independently selected from hydrogen , substituted or unsubstituted aryl, sub [0419 ] wherein stituted or unsubstituted phenyl, substituted or unsub [0420 ] Tis OH , OR , - NHCOCHz, or NHCOR ; stituted arylalkyl , F , C1, Br, I , CF3, CN , NO2, substi [ 0421 ] Z is NO2, CN , COOH , COR , NHCOR or tuted or unsubstituted cycloalkyl , or substituted or CONHR; unsubstituted heterocycloalkyl ; [0422 ] Y is CF3 , F, I , Br, C1, CN , C ( R ) z or Sn ( R ) 3; [0411 ] wherein at least one of Q?, Q2 and Q3 is a [ 0423 ] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , substituted or unsubstituted aryl, substituted or unsub CH , F , CHF , CF3 , CF CFz, aryl, phenyl, F , C1, Br, I , stituted arylalkyl, or substituted or unsubstituted phe alkenyl or OH ; nyl; [0424 ] R , is CH3, CH ,F , CHF2, CF3, CH2CH3, or [0412 ] or CF , CFz; [0413 ] Qi and Q2 are joined together to form a substi [0425 ] Q , is hydrogen , substituted or unsubstituted lin tuted or unsubstituted C . - C , carbocyclic or heterocy ear or branched alkyl, substituted or unsubstituted aryl, clic ring and Q3 is as defined above ; substituted or unsubstituted phenyl, F , C1, Br, I , CF3, [0414 ] or CN , NO2, substituted or unsubstituted cycloalkyl, sub [ 0415 ] Q2 and Q3 are joined together to form a substi stituted or unsubstituted heterocycloalkyl, substituted tuted or unsubstituted C5- C , carbocyclic or heterocy or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCHZ, clic ring and Q , is as defined above; and NHCOCF , , NHCOR, NHCONHR , NHCOOR, [0416 ] wherein said formed carbocyclic or heterocyclic OCONHR , CONHR, NHCSCH , NHCSCF , , NHCSR , ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , one or 1H -pyrrole . SO _ R , SR , NCS , SCN , NCO , or OCN ; [0417 ] In another embodiment, the prostate cancer is [ 0426 ] Q2 is hydrogen , substituted or unsubstituted lin advanced prostate cancer, castration resistant prostate cancer ear or branched alkyl, substituted or unsubstituted aryl, (CRPC ), metastatic CRPC (mCRPC ) , non -metastatic CRPC substituted or unsubstituted phenyl, F , C1, Br, I, CF2 , (nmCRPC ) , high - risk nmCRPC or any combination thereof . CN , NO2, substituted or unsubstituted cycloalkyl , sub In another embodiment, the prostate cancer depends on stituted or unsubstituted heterocycloalkyl, substituted AR - FL and /or AR - SV for proliferation . In another embodi or unsubstituted arylalkyl, C (R )3 , N (R )2 , NHCOCH3, ment, the subject further receives androgen deprivation NHCOCF , NHCOR , NHCONHR, NHCOOR , therapy ( ADT ) . In another embodiment, the subject has OCONHR , CONHR , NHCSCH , NHCSCF , , NHCSR , failed androgen deprivation therapy ( ADT ) . In another NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , embodiment, the cancer is resistant to treatment with an SO _ R , SR , NCS , SCN , NCO , or OCN ; US 2019 /0040000 A1 Feb . 7 , 2019 25

[0427 ] or NHCOCF , , NHCOR , NHCONHR, NHCOOR, [0428 ] Qi and Q2 are joined together to form a substi OCONHR , CONHR, NHCSCH?, NHCSCF , NHCSR , tuted or unsubstituted C5 - C , carbocyclic or heterocy NHSO , CH3 , NHSO , R , OR , COR , OCOR , OSO , R , clic ring . SO _ R , SR , NCS , SCN , NCO , or OCN . [0429 ] In another embodiment, the prostate cancer is [0438 ] In another embodiment, the prostate cancer is advanced prostate cancer , castration resistant prostate cancer advanced prostate cancer, castration resistant prostate cancer ( CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC ( CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC (nmCRPC ) , high - risk nmCRPC or any combination thereof. (nmCRPC ) , high - risk nmCRPC or any combination thereof. In another embodiment, the prostate cancer depends on In another embodiment, the prostate cancer depends on AR -FL and /or AR -SV for proliferation . In another embodi AR - FL and / or AR - SV for proliferation . In another embodi ment, the subject further receives androgen deprivation ment , the subject further receives androgen deprivation therapy (ADT ) . In another embodiment, the subject has therapy ( ADT ) . In another embodiment, the subject has failed androgen deprivation therapy (ADT ) . In another failed androgen deprivation therapy ( ADT ) . In another embodiment, the cancer is resistant to treatment with an embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the androgen receptor antagonist . In another embodiment, the cancer is resistant to treatment with enzalutamide , bicaluta cancer is resistant to treatment with enzalutamide, bicaluta mide, apalutamide, abiraterone, ARN -509 , AZD -3514 , mide, apalutamide , abiraterone , ARN -509 , AZD -3514 , galeterone , ASC - J9 , flutamide, hydroxyflutamide, niluta galeterone , ASC - J9 , flutamide , hydroxyflutamide, niluta mide , cyproterone acetate , ketoconazole , spironolactone , or mide, cyproterone acetate , ketoconazole, spironolactone , or any combination thereof. In another embodiment, adminis any combination thereof. In another embodiment, adminis tering the compound to a subject reduces the levels of AR , tering the compound to a subject reduces the levels of AR , AR - full length ( AR - FL ), AR -FL with antiandrogen resis AR - full length ( AR - FL ) , AR -FL with antiandrogen resis tance - conferring AR -LBD mutations , AR -splice variant tance - conferring AR - LBD mutations , AR - splice variant ( AR - SV ) , gene -amplified AR , or any combination thereof, ( AR - SV ), gene - amplified AR , or any combination thereof, in said subject. in said subject. [ 0430 ] In one embodiment, this invention provides a [0439 ] In one embodiment, this invention provides a method of treating , suppressing, reducing the incidence , method of treating, suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of pros reducing the severity , or inhibiting the progression of pros tate cancer (PCa ) and its symptoms, or increasing the tate cancer (PCa ) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically comprising administering to said subject a therapeutically effective amount of a compound or its isomer, pharmaceu effective amount of a compound or its isomer, pharmaceu tically acceptable salt , pharmaceutical product, polymorph , tically acceptable salt, pharmaceutical product , polymorph , hydrate or any combination thereof, represented by a com hydrate or any combination thereof, represented by a com pound of formula V : pound of formula VI:

N ZZ Rit.

[0431 ] wherein [0432 ] T is OH , OR , - NHCOCHz, or NHCOR ; [ 0440 ] wherein [0433 ] Z is NO2, CN , COOH , COR , NHCOR or [0441 ] T is OH , OR , — NHCOCHz, or NHCOR ; CONHR ; [0442 ] Z is NO , , CN , COOH , COR , NHCOR or [ 0434 ] Yis CF3, F , I , Br, C1, CN , C (R ) 3 or Sn (R ) 3 ; CONHR ; [ 0435 ] R is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl, [ 0443 ] Yis CF3, F , I , Br, C1, CN , C ( R ) 3 or Sn ( R ) 3 ; CHZF , CHF2, CF3, CF CF3, aryl, phenyl, F , C1, Br, I, 04441 R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, alkenyl or OH ; CHZF , CHF2, CF3, CF2CF3, aryl, phenyl, F , C1, Br, I , [0436 ] Ri is CH3, CHF, CHF2, CF3, CH2CH3, or alkenyl or OH ; CF , CFz ; and [0445 ] R , is CH3, CH ,F , CHF2, CF3, CH2CH3, or [0437 ] Qi is hydrogen , substituted or unsubstituted lin CF CF3; ear or branched alkyl, substituted or unsubstituted aryl, [0446 ] Q , is hydrogen , substituted or unsubstituted lin substituted or unsubstituted phenyl, F , C1, Br, I , CF3 , ear or branched alkyl, substituted or unsubstituted aryl, CN , NO , , substituted or unsubstituted cycloalkyl, sub substituted or unsubstituted phenyl, F , C1, Br, I , CF3, stituted or unsubstituted heterocycloalkyl, substituted CN , NO , , substituted or unsubstituted cycloalkyl, sub or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2, NHCOCHZ, stituted or unsubstituted heterocycloalkyl, substituted US 2019 /0040000 A1 Feb . 7 , 2019

or unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHZ, [0452 ] wherein NHCOCF , NHCOR , NHCONHR, NHCOOR , [0453 ] T is OH , OR , — NHCOCHz, or NHCOR ; OCONHR, CONHR , NHCSCH?, NHCSCF , NHCSR , NHSO , CH , , NHSO , R , OR , COR , OCOR , OSO , R , [0454 ] Z is NO2, CN , COOH , COR , NHCOR or SO , R , SR , NCS, SCN , NCO , or OCN ; CONHR ; [0447 ] Q2 is hydrogen , substituted or unsubstituted lin [0455 ] Yis CF3, F , I, Br, C1, CN , C ( R ) z or Sn ( R ) 3 ; ear or branched alkyl, substituted or unsubstituted aryl, [0456 ] R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl , substituted or unsubstituted phenyl, F , C1, Br , I , CF2 , CHZF , CHF2, CF3, CF CF3, aryl, phenyl , F , CI, Br, I , CN , NO , , substituted or unsubstituted cycloalkyl, sub alkenyl or OH ; stituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R )3 , N (R ) 2, NHCOCHZ, [0457 ] R , is CH , CH F, CHF2, CF3, CH ,CHz , or NHCOCF , NHCOR , NHCONHR , NHCOOR , CF CFz; and OCONHR , CONHR , NHCSCH , NHCSCF2 , NHCSR , [0458 ] Qi is hydrogen , substituted or unsubstituted lin NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , ear or branched alkyl, substituted or unsubstituted aryl, SO _ R , SR , NCS, SCN , NCO , or OCN ; substituted or unsubstituted phenyl, F , C1, Br, I, CF3 , [0448 ] or CN , NO , , substituted or unsubstituted cycloalkyl, sub 0449 ] Q , and Q , are joined together to form a substi stituted or unsubstituted heterocycloalkyl, substituted tuted or unsubstituted C3- C , carbocyclic or heterocy or unsubstituted arylalkyl, C ( R ) 2 , N ( R ) , NHCOCHz, clic ring . NHCOCF4, NHCOR , NHCONHR, NHCOOR , [0450 ] In another embodiment, the prostate cancer is OCONHR, CONHR , NHCSCH , NHCSCF4 , NHCSR , advanced prostate cancer, castration resistant prostate cancer NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , ( CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC SO _ R , SR , NCS , SCN , NCO , or OCN . ( nmCRPC ) , high - risk nmCRPC or any combination thereof. [0459 ] In another embodiment, the prostate cancer is In another embodiment, the prostate cancer depends on advanced prostate cancer, castration resistant prostate cancer AR -FL and / or AR -SV for proliferation . In another embodi (CRPC ), metastatic CRPC (mCRPC ) , non -metastatic CRPC ment, the subject further receives androgen deprivation (nmCRPC ) , high - risk nmCRPC or any combination thereof. therapy (ADT ) . In another embodiment, the subject has In another embodiment, the prostate cancer depends on failed androgen deprivation therapy ( ADT) . In another AR - FL and / or AR - SV for proliferation . In another embodi embodiment, the cancer is resistant to treatment with an ment , the subject further receives androgen deprivation androgen receptor antagonist . In another embodiment, the therapy (ADT ) . In another embodiment, the subject has cancer is resistant to treatment with enzalutamide , bicaluta failed androgen deprivation therapy (ADT ) . In another mide , apalutamide , abiraterone , ARN - 509 , AZD - 3514 , embodiment, the cancer is resistant to treatment with an galeterone , ASC - J9 , flutamide , hydroxyflutamide, niluta androgen receptor antagonist . In another embodiment, the mide, cyproterone acetate , ketoconazole , spironolactone, or cancer is resistant to treatment with enzalutamide, bicaluta any combination thereof. In another embodiment, adminis mide, apalutamide, abiraterone, ARN - 509 , AZD - 3514 , tering the compound to a subject reduces the levels of AR , galeterone, ASC - J9 , flutamide, hydroxyflutamide, niluta AR - full length (AR -FL ), AR -FL with antiandrogen resis mide, cyproterone acetate , ketoconazole , spironolactone , or tance - conferring AR - LBD mutations, AR -splice variant any combination thereof. In another embodiment, adminis ( AR -SV ) , gene -amplified AR , or any combination thereof, tering the compound to a subject reduces the levels of AR , in said subject . AR -full length (AR - FL ) , AR - FL with antiandrogen resis [0451 ] In one embodiment , this invention provides a tance - conferring AR -LBD mutations, AR - splice variant method of treating, suppressing , reducing the incidence , (AR -SV ) , gene - amplified AR , or any combination thereof, reducing the severity , or inhibiting the progression of pros in said subject . tate cancer (PCa ) and its symptoms, or increasing the [ 0460 ] In one embodiment , this invention provides a survival of a male subject suffering from prostate cancer method of treating , suppressing , reducing the incidence , comprising administering to said subject a therapeutically reducing the severity , or inhibiting the progression of pros effective amount of a compound or its isomer, pharmaceu tate cancer (PCa ) and its symptoms, or increasing the tically acceptable salt, pharmaceutical product, polymorph , survival of a male subject suffering from prostate cancer hydrate or any combination thereof, represented by a com comprising administering to said subject a therapeutically pound of formula VII : effective amount of a compound or its isomer, pharmaceu tically acceptable salt , pharmaceutical product, polymorph , hydrate or any combination thereof, selected from any one VII of the following structures :

13 ON NH RiT NC

- NH F3C NH MOL US 2019 /0040000 A1 Feb . 7 , 2019

- continued -continued 14

NC

- NH parooF?c Y N sasaF3C N

NC

NH NC FzC

F3C 16 or Das 49 Fac sast MOHN ? ??

F NC

50

F3C N ?? 17a 2 ?? - NO2

NC CF3 [0461 ] In another embodiment, the prostate cancer is CF3 advanced prostate cancer , castration resistant prostate cancer 18 (CRPC ) , metastatic CRPC (mCRPC ) , non -metastatic CRPC - CN (nmCRPC ) , high - risk nmCRPC or any combination thereof. In another embodiment, the prostate cancer depends on AR - FL and /or AR -SV for proliferation . In another embodi F3C NH ment, the subject further receives androgen deprivation Ion L therapy ( ADT ) . In another embodiment, the subject has Ph failed androgen deprivation therapy ( ADT) . In another 19 embodiment, the cancer is resistant to treatment with an androgen receptor antagonist . In another embodiment, the NC CN cancer is resistant to treatment with enzalutamide , bicaluta mide , apalutamide , abiraterone , ARN - 509, AZD - 3514 , galeterone , ASC -J9 , flutamide , hydroxyflutamide, niluta F C NH N ' mide, cyproterone acetate , ketoconazole , spironolactone , or OL any combination thereof. In another embodiment, adminis tering the compound to a subject reduces the levels of AR , AR -full length (AR - FL ) , AR - FL with antiandrogen resis US 2019 /0040000 A1 Feb . 7 , 2019 28 tance - conferring AR -LBD mutations, AR -splice variant [0465 ] In one embodiment, this invention provides a ( AR - SV ) , gene - amplified AR , or any combination thereof, method of treating , suppressing, reducing the incidence , in said subject . reducing the severity , or inhibiting the progression of [0462 ] In one embodiment, the invention is directed to a advanced prostate cancer and its symptoms, or increasing method of treating, suppressing , reducing the incidence , the survival of a male subject suffering from advanced reducing the severity, or inhibiting the progression of AR prostate cancer comprising administering to said subject a positive cancer that is resistant to treatment with an andro therapeutically effective amount of a SARD compound or its gen receptor antagonist and / or a lyase inhibitor, comprising isomer , pharmaceutically acceptable salt , pharmaceutical administering to said subject a therapeutically effective product , polymorph , hydrate or any combination thereof , amount of compound 17 said compound is represented by a compound of formulas I - VII, IA - IB , and IIA - IIB or any one of compounds 13 -21 , 49 , 50 and 17a . 17 [ 0466 ] In one embodiment, this invention provides a method of treating, suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of meta static prostate cancer and its symptoms, or increasing the survival of a male subject suffering from metastatic prostate NC . cancer comprising administering to said subject a therapeu tically effective amount of a SARD compound or its isomer , pharmaceutically acceptable salt , pharmaceutical product, F C N * t polymorph , hydrate or any combination thereof , said com pound is represented by a compound of formulas I - VII, IA - IB , and IIA - IIB or any one of compounds 13 -21 , 49, 50 or its isomer , pharmaceutically acceptable salt, pharmaceu and 17a . tical product , polymorph , hydrate or any combination [ 0467 ] In one embodiment, this invention provides a thereof. method of treating , suppressing , reducing the incidence , [0463 ] In one embodiment, the methods of this invention reducing the severity , or inhibiting the progression of cas are directed to treating , suppressing , reducing the incidence , tration resistant prostate cancer (CRPC ) and its symptoms, reducing the severity , inhibiting, providing palliative care , or or increasing the survival of a male subject suffering from increasing the survival of a subject suffering from prostate castration resistant prostate cancer (CRPC ) comprising cancer . In one embodiment, the methods of this invention administering to said subject a therapeutically effective are directed to methods of treating, suppressing , reducing amount of a SARD compound or its isomer, pharmaceuti the incidence, reducing the severity , inhibiting , providing cally acceptable salt , pharmaceutical product, polymorph , palliative care , or increasing the survival of advanced pros hydrate or any combination thereof, said compound is tate cancer in a subject. In one embodiment, the methods of represented by a compound of formulas I- VII , IA - IB , and this invention are directed to treating, suppressing, reducing IIA - IIB or any one of compounds 13- 21 , 49, 50 and 17a . the incidence , reducing the severity , inhibiting, providing [0468 ] In one embodiment , the SARD compounds as palliative care , or increasing the survival of a subject suf described herein and / or compositions comprising the same fering from castration resistant prostate cancer (CRPC ). In may be used for treating , suppressing , reducing the inci one embodiment , the methods of this invention are directed dence , reducing the severity , or inhibiting the progression of to treating, suppressing , reducing the incidence, reducing the castration resistant prostate cancer (CRPC ) and its symp severity , inhibiting , providing palliative care , or increasing toms, or increasing the survival of men with castration the survival of a subject suffering from metastatic castration resistant prostate cancer. In another embodiment , the CRPC resistant prostate cancer (mCRPC ) . In one embodiment, the is metastatic CRPC (mCRPC ) . In another embodiment, the methods of this invention are directed to treating , suppress CRPC is non -metastatic CRPC (nmCRPC ) . In one embodi ing, reducing the incidence, reducing the severity , inhibiting , ment, the nmCRPC is high - risk nmCRPC . In another providing palliative care , or increasing the survival of a embodiment , the subject further receives androgen depriva subject suffering from non -metastatic castration resistant prostate cancer ( nmCRPC ) . In one embodiment, the tion therapy . nmCRPC is high - risk nmCRPC . In another embodiment, the [0469 ] As used herein , the terms “ increase ” and “ prolong ” subject has high or increasing prostate specific antigen may be used interchangeably having all the samemeanings (PSA ) levels . and qualities , wherein these terms may in one embodiment [ 0464] In one embodiment, this invention provides a refer to a lengthening of time. In another embodiment, as method of treating, suppressing , reducing the incidence , used herein , the terms " increase ” , increasing " " increased ” reducing the severity , or inhibiting the progression of pros may be used interchangeably and refer to an entity becoming tate cancer (PCa ) and its symptoms, or increasing the progressively greater (as in size , amount, number , or inten survival of a male subject suffering from prostate cancer sity ) , wherein for example the entity is sex hormone -binding comprising administering to said subject a therapeutically globulin (SHBG ) or prostate - specific antigen (PSA ). effective amount of a SARD compound or its isomer , [ 0470 ] In one embodiment, the compounds as described pharmaceutically acceptable salt , pharmaceutical product, herein and/ or compositions comprising the same may be polymorph , hydrate or any combination thereof, said com used for increasing metastasis - free survival (MFS ) in a pound is represented by a compound of formulas I - VII , subject suffering from non -metastatic prostate cancer. In one IA - IB , and IIA - IIB or any one of compounds 13 -21 , 49 , 50 embodiment, the non -metastatic prostate cancer is non and 17a . metastatic advanced prostate cancer. In another embodi US 2019 /0040000 A1 Feb . 7 , 2019 ment, the non -metastatic prostate cancer is non -metastatic ( anti- PD - 1 ) drugs ( e . g . , AMP - 224 , nivolumab , pembroli CRPC (nmCRPC ). In one embodiment, the nmCRPC is zumab , pidilizumab , AMP -554 , and the like ) for increasing high -risk nmCRPC . the progression free survival or overall survival of a subject [0471 ] In one embodiment, the SARD compounds as suffering from prostate cancer. In another embodiment, the described herein and / or compositions comprising the same prostate cancer is advanced prostate cancer. In another may be used to provide a dual action , for example treating embodiment, the prostate cancer is castration resistant pros prostate cancer and preventing metastases . In one embodi tate cancer (CRPC ) . In another embodiment, the CRPC is ment, the prostate cancer being treated is advanced prostate metastatic CRPC (mCRPC ) . In another embodiment, the cancer. In one embodiment, the prostate cancer being treated CRPC is non -metastatic CRPC ( nmCRPC ). In one embodi is castration resistant prostate cancer ( CRPC ) . In one ment, the nmCRPC is high - risk nmCRPC . In another embodiment, the prostate cancer being treated is metastatic embodiment, the subject is surgically castrated . In another CRPC (mCRPC ). In one embodiment, the prostate cancer embodiment, the subject is chemically castrated . being treated is non -metastatic CRPC ( nmCRPC ) . In one [0476 ] In one embodiment, the compounds as described embodiment, the nmCRPC is high - risk nmCRPC . herein and / or compositions comprising the same may be [ 0472 ] Men with advanced prostate cancer who are at high used in combination with anti- PD -L1 drugs ( e .g ., BMS risk for progression to castration resistant prostate cancer 936559 , MED14736 , MPDL3280A , MEDI4736 , (CRPC ) , in one embodiment , are men on ADT with serum MSB0010718C , and the like) for increasing the progression total testosterone concentrations greater than 20 ng /dL or in free survival or overall survival of a subject suffering from another embodiment, men with advanced prostate cancer prostate cancer. In another embodiment, the prostate cancer who at the time of starting ADT had either ( 1 ) confirmed is advanced prostate cancer. In another embodiment, the Gleason pattern 4 or 5 prostate cancer , ( 2 ) metastatic pros prostate cancer is castration resistant prostate cancer tate cancer, ( 3 ) a PSA doubling time < 3 months, ( 4 ) a (CRPC ) . In another embodiment, the CRPC is metastatic PSA220 ng /mL , or ( 5 ) a PSA relapse in < 3 years after CRPC (mCRPC ) . In another embodiment, the CRPC is definitive local therapy ( radical prostatectomy or radiation non -metastatic CRPC ( nmCRPC ) . In one embodiment, the therapy ). nmCRPC is high - risk nmCRPC . In another embodiment, the [0473 ] Men with high risk non -metastatic castration resis subject is surgically castrated . In another embodiment, the tant prostate cancer ( high - risk nmCRPC ) may include those subject is chemically castrated . with rapid PSA doubling times, having an expected progres [0477 ] In certain embodiments , treatment of prostate can sion - free survival of approximately 18 months or less cer, advanced prostate cancer , CRPC , mCRPC and /or (Miller K , Moul J W , Gleave M , et al. 2013 . Phase III , nmCRPC may result in clinically meaningful improvement randomized , placebo - controlled study of once - daily oral in prostate cancer related symptoms, function and / or sur zibotentan ( ZD4054 ) in patients with non -metastatic castra vival . Clinically meaningful improvements include but are tion -resistant prostate cancer. Prostate Canc Prost Dis . not limited to increasing radiographic progression free sur February ; 16 : 187 - 192 ) . This relatively rapid progression of vival (rPFS ) if cancer is metastatic , and increasing metas their disease underscores the importance of novel therapies tasis - free survival (MFS ) if cancer is non -metastatic . for these individuals . In one embodiment, the PSA levels are [0478 ] In one embodiment, the compounds as described greater than 8 ng /mL in a subject suffering from high - risk herein and / or compositions comprising the same may be nmCRPC . In one embodiment, the PSA doubling time is less used for increasing the survival of men with castration than 8 months in a subject suffering from high - risk resistant prostate cancer (CRPC ) . In another embodiment, nmCRPC . In another embodiment, the PSA doubling time is the CRPC is metastatic CRPC (mCRPC ) . In another less than 10 months in a subject suffering from high - risk embodiment, the CRPC is non -metastatic CRPC (nm nmCRPC . In one embodiment, the total serum testosterone CRPC ) . In one embodiment, the nmCRPC is high - risk levels are greater than 20 ng /mL in a subject suffering from nmCRPC . In another embodiment, the subject further high - risk nmCRPC . In one embodiment, the serum free receives androgen deprivation therapy . testosterone levels are greater than those observed in an [0479 ] In one embodiment, levels of prostate specific orchiechtomized male in a subject suffering from high - risk antigen ( PSA ) considered normal are age dependent. In one nmCRPC . embodiment, levels of prostate specific antigen (PSA ) con [ 0474 ] In one embodiment, the compounds as described sidered normal are dependent on the size of a male subject ' s herein and / or compositions comprising the same may be prostate. In one embodiment, PSA levels in the range used in combination with LHRH agonist or antagonist for between 2 . 5 - 10 ng /mL are considered “ borderline high " . In increasing the progression free survival or overall survival another embodiment, PSA levels above 10 ng/ mL are con of a subject suffering from prostate cancer . In another sidered “ high ” . embodiment, the prostate cancer is advanced prostate can [0480 ] In one embodiment, the rate of change or “ PSA cer . In another embodiment, the prostate cancer is castration velocity ” is high . In one embodiment, a rate of change or resistant prostate cancer ( CRPC ) . In another embodiment, “ PSA velocity ” greater than 0 .75 / year is considered high . the CRPC is metastatic CRPC (mCRPC ) . In another [0481 ] In one embodiment, this invention provides a embodiment, the CRPC is non -metastatic CRPC ( nm method of lowering serum prostate specific antigen (PSA ) CRPC ) . In one embodiment, the nmCRPC is high - risk levels in a male subject suffering from prostate cancer, nmCRPC . In another embodiment , the subject is surgically advanced prostate cancer, metastatic prostate cancer or castrated . In another embodiment, the subject is chemically castration resistant prostate cancer (CRPC ) , comprising castrated . administering a therapeutically effective amount of a SARD [0475 ] In one embodiment, the compounds as described compound or its isomer , pharmaceutically acceptable salt , herein and / or compositions comprising the same may be pharmaceutical product, polymorph , hydrate or any combi used in combination with anti -programmed death receptor 1 nation thereof, said compound is represented by the struc US 2019 /0040000 A1 Feb . 7 , 2019 30 ture of formulas I -VII , IA - IB , and IIA - IIB or any one of gression free survival ( rPFS ) in a subject suffering from a compounds 13 - 21, 49 , 50 and 17a . metastatic cancer. In another embodiment, the method fur [ 0482 ] In one embodiment , this invention is directed to ther increases metastasis - free survival (MFS ) in a subject treatment of a subject with high or increasing PSA levels suffering from non -metastatic cancer. In one embodiment, comprising administering a SARD compound of this inven the method may be used to provide a dual action , for tion . In one embodiment, this invention is directed to example treating prostate cancer and preventing metastases . treatment of a subject with high or increasing PSA levels In another embodiment , the subject has failed androgen despite ongoing ADT or a history of ADT, surgical castration deprivation therapy (ADT ) . In another embodiment, the or despite treatment with antiandrogens and /or LHRH ago subject further receives androgen deprivation therapy nist . In another embodiment, the treatment makes use of (ADT ) . In another embodiment, the subject further receives compounds of formulas I -VII , IA - IB , and IIA -IIB or any one LHRH agonist or antagonist . In another embodiment, the of compounds 13 - 21 , 49 , 50 and 17a . LHRH agonist is leuprolide acetate . In another embodiment, [0483 ] In one embodiment, this invention provides a the subject had undergone orchidectomy. In another embodi method of treating , suppressing , reducing the incidence , ment, the subject has high or increasing prostate specific reducing the severity , or inhibiting the progression of cas antigen (PSA ) levels . In another embodiment, the subject is tration resistant prostate cancer ( CRPC ) and its symptoms, a prostate cancer patient. In another embodiment, the subject or increasing the survival of men with castration resistant is a prostate cancer patient on ADT. In another embodiment, prostate cancer comprising administering a therapeutically the subject is a prostate cancer patient on ADT with castrate effective amount of a compound of formulas I - VII , IA - IB , levels of total T . In another embodiment, the subject is an and IIA - IIB or its isomer , pharmaceutically acceptable salt , advanced prostate cancer patient . In another embodiment, pharmaceutical product, polymorph , hydrate or any combi the subject is an advanced prostate cancer patient on ADT. nation thereof. In another embodiment, the compound is In another embodiment, the subject is an advanced prostate compound 13 . In another embodiment , the compound is cancer patient on ADT with castrate levels of total T. In compound 14 . In another embodiment, the compound is another embodiment, the subject is a CRPC patient. In compound 15 . In another embodiment, the compound is another embodiment, the subject is a CRPC patient on ADT. compound 16 . In another embodiment , the compound is In another embodiment, the subject is a CRPC patient on compound 17 . In another embodiment , the compound is ADT with castrate levels of total T . In another embodiment, compound 17a . In another embodiment , the compound is the subject is a metastatic castration resistant prostate cancer compound 18 . In another embodiment, the compound is (mCRPC ) patient. In another embodiment , the subject is a compound 19 . In another embodiment, the compound is mCRPC patient maintained on ADT. In another embodi compound 20 . In another embodiment, the compound is ment, the subject is a mCRPC patient maintained on ADT compound 21. In another embodiment , the compound is with castrate levels of total T . In another embodiment, the compound 49. In another embodiment, the compound is subject is a non -metastatic castration resistant prostate can compound 50 . cer (nmCRPC ) patient. In another embodiment, the subject is an nmCRPC patient maintained on ADT. In another [0484 ] In one embodiment , this invention provides a embodiment, the subject is an nmCRPC patient maintained method of secondary hormonal therapy that reduces serum on ADT with castrate levels of total T . In one embodiment , PSA in a male subject suffering from castration resistant the nmCRPC is high -risk nmCRPC . In another embodiment , prostate cancer ( CRPC ) comprising administering a thera the method further treats, suppresses , reduces the incidence , peutically effective amount of a compound of formulas I - VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically reduces the severity , or inhibits advanced prostate cancer. In acceptable salt , pharmaceutical product , polymorph , hydrate another embodiment, the method further provides palliative or any combination thereof. In another embodiment, the treatment of advanced prostate cancer . castration is surgical castration . In another embodiment, [0485 ] In one embodiment , this invention is directed to a with regards to the methods described above, the prostate method of reducing the levels of AR , AR - full length , AR - FL cancer depends on AR -FL and / or AR -SV for proliferation . with antiandrogen resistance- conferring AR -LBD muta In another embodiment, the cancer is resistant to treatment tions, and / or AR - splice variants in a subject , comprising with an androgen receptor antagonist. In another embodi administering to said subject a therapeutically effective ment, the cancer is resistant to treatment with enzalutamide , amount of a SARD compound according to this invention , bicalutamide , apalutamide , abiraterone , ARN - 509 , AZD or its isomer, pharmaceutically acceptable salt , pharmaceu 3514 , galeterone , ASC - J9 , flutamide , hydroxyflutamide , tical product , polymorph , hydrate or any combination , cyproterone acetate , ketoconazole , spironolac thereof. In another embodiment, the reduction is achieved by tone, or any combination thereof. In another embodiment, degradation of said AR , AR - full length ( AR - FL ) and /or administration of the compounds of formulas I - VII , IA - IB , AR - splice variants (AR -SV ). In another embodiment, the and IIA - IIB reduces the levels of AR , AR - full length ( AR reduction is achieved by inhibition of said AR , AR - full FL ), AR - FL with antiandrogen resistance - conferring AR length (AR - FL ) and /or AR - splice variants (AR - SV ) . In LBD mutations, AR - splice variant (AR -SV ) , amplications another embodiment, the reduction is achieved by dual of the AR gene within the tumor, or any combination AR -SVIAR - FL degradation and AR -SVIAR - FL inhibitory thereof, in the subject. In another embodiment, the castration functions. is surgical castration . In another embodiment, the castration [ 0486 ] In one embodiment , this invention is directed to a is chemical castration . In another embodiment, the CRPC is method of reducing the levels of AR - splice variants in a metastatic CRPC (mCRPC ) . In another embodiment, the subject , comprising administering to said subject a thera CRPC is non -metastatic CRPC (nmCRPC ). In one embodi peutically effective amount of a SARD compound according ment, the nmCRPC is high - risk nmCRPC . In another to this invention , or its isomer, pharmaceutically acceptable embodiment, the method further increases radiographic pro - salt , pharmaceutical product, polymorph , hydrate or any US 2019 /0040000 A1 Feb . 7 , 2019 31 combination thereof. In another embodiment, the method includes leuprolide acetate (Lupron® ) ( U . S . Pat . No. 5 , 480 , further reduces the levels of AR - full length (AR - FL ) in the 656 ; U . S . Pat. Nos. 5, 575 , 987; 5 ,631 , 020 ; 5 ,643 ,607 ; 5 ,716 , subject. In another embodiment, the reduction is achieved by 640 ; 5 , 814 , 342 ; 6 ,036 ,976 which are all incorporated by degradation of said AR -splice variants ( AR - SV ) . In another reference herein ) or goserelin acetate ( Zoladex® ) ( U . S . Pat . embodiment, the reduction is further achieved by degrada Nos. 7 , 118, 552 ; 7 , 220 ,247 ; 7 ,500 , 964 which are all incor tion of said AR - FL . In another embodiment, the reduction is porated by reference herein ). In one embodiment, forms of achieved by inhibition of said AR -splice variants (AR - SV ) . ADT include an LHRH antagonist. In another embodiment, In another embodiment, the reduction is further achieved by the LHRH antagonist includes degarelix . In one embodi inhibition of said AR - FL . In another embodiment, the reduc ment, forms of ADT include reversible antiandrogens . In tion is achieved by dual AR - SV degradation and AR -SV another embodiment, the antiandrogens include bicaluta inhibitory functions . In another embodiment , the reduction mide , apalutamide, flutamide, finasteride, , is achieved by dual AR - FL degradation and AR - FL inhibi- enzalutamide , nilutamide , chlormadinone , abiraterone or tory functions. any combination thereof. In one embodiment, forms of ADT [ 0487 ] In one embodiment , “ a subject suffering from cas include bilateral orchidectomy. tration resistant prostate cancer ” refers to a subject which [0493 ] In one embodiment, this invention provides a has been previously treated with androgen deprivation method of treating , suppressing , reducing the incidence , therapy (ADT ) , has responded to the ADT and currently has reducing the severity , or inhibiting the progression of cas a serum PSA > 2 ng /mL or > 2 ng /mL and representing a 25 % tration resistant prostate cancer (CRPC ) and its symptoms, increase above the nadir achieved on the ADT. In another or increasing the survival of men with castration resistant embodiment, the term refers to a subject which despite being prostate cancer comprising administering a therapeutically maintained on androgen deprivation therapy is diagnosed to effective amount of a combination of one or more forms of have serum PSA progression . In another embodiment, the ADT and a compound of formulas I -VII , IA - IB , and IIA - IIB subject has a castrate level of serum total testosterone ( < 50 or its isomer, pharmaceutically acceptable salt, pharmaceu ng / dL ) . In another embodiment , the subject has a castrate tical product, polymorph , hydrate or any combination level of serum total testosterone ( < 20 ng /dL ) . In another thereof. In another embodiment, the subject has failed embodiment, the subject has rising serum PSA on two androgen deprivation therapy (ADT ) . successive assessments at least 2 weeks apart. In another 10494 ]. In one embodiment, this invention provides a embodiment, the subject had been effectively treated with method of lowering serum PSA levels in a male subject ADT. In another embodiment, the subject has a history of suffering from castration resistant prostate cancer (CRPC ) serum PSA response after initiation of ADT. In another comprising administering a therapeutically effective amount embodiment, the subject has been treated with ADT and had of a combination of one or more forms of ADT and a an initial serum PSA response , but now has a serum PSA > 2 compound of formulas I - VII , IA - IB , and IIA - IIB or its ng /mL and a 25 % increase above the nadir observed on isomer, pharmaceutically acceptable salt , pharmaceutical ADT. In one embodiment, the CRPC is metastatic CRPC product , polymorph ,hydrate or any combination thereof. In (mCRPC ) . In another embodiment, the CRPC is non -meta another embodiment, the subject has failed androgen depri static CRPC ( nmCRPC ) . In one embodiment , the nmCRPC vation therapy (ADT ) . is high -risk nmCRPC . [ 0495 ] In one embodiment, the methods of this invention [0488 ] The term “ serum PSA response ” refers to , in one comprise administering a therapeutically effective amount embodiment, at least 90 % reduction in serum PSA value of an antiandrogen and a compound of this invention . In one prior to the initiation of ADT, to < 10 ng /mL OR undetectable embodiment, the methods of this invention comprise admin level of serum PSA ( < 0 . 2 ng /mL ) at any time, or in another istering a therapeutically effective amount of an LHRH embodiment to at least 50 % decline from baseline in serum agonist and a compound of this invention . In one embodi PSA , or in another embodiment to at least 90 % decline from ment, the methods of this invention comprise administering baseline in serum PSA , or in another embodiment to at least a therapeutically effective amount of an antiandrogen , 30 % decline from baseline in serum PSA , or in another LHRH agonist and a compound of this invention . In another embodiment to at least 10 % decline from baseline in serum embodiment, the compound is compound of formulas I - VII , PSA . IA - IB , and IIA - IIB . In another embodiment, the compound [0489 ] The term “ serum PSA progression ” refers to in one is any one of compounds 13 - 21, 49, 50 and 17a . embodiment, a 25 % or greater increase in serum PSA and an [0496 ] In one embodiment, the methods of this invention absolute increase of 2 ng /ml or more from the nadir ; or in comprise administering a therapeutically effective amount another embodiment, to serum PSA > 2 ng /mL , or > 2 ng /mL of a lyase inhibitor ( e . g . , abiraterone ) and a compound of and a 25 % increase above the nadir after the initiation of this invention . In another embodiment, the compound is a androgen deprivation therapy (ADT ) . compound of formulas I -VII , IA - IB , and IIA - IIB . In another [0490 ] In another embodiment, the term “ nadir ” refers to embodiment, the compound is any one of compounds 13 - 21 , the lowest PSA level while a patient is undergoing ADT. 49 , 50 and 17a. [0491 ] Testosterone can be measured as " free ” (that is , [0497 ] In another embodiment, this invention provides a bioavailable and unbound ) or as " total” ( including the method for androgen deprivation therapy (ADT ) in a sub percentage which is protein bound and unavailable ) serum ject, comprising administering a therapeutically effective levels . In one embodiment, total serum testosterone com amount of a compound of formulas I - VII, IA - IB , and prises free testosterone and bound testosterone . IIA - IIB or its isomer, pharmaceutically acceptable salt , [0492 ] The methods of this invention comprise adminis pharmaceutical product, polymorph , hydrate or any combi tering a combination of forms of ADT and a compound of nation thereof. In another embodiment, said subject has this invention . In one embodiment, forms of ADT include a prostate cancer. In another embodiment, the prostate cancer LHRH agonist. In another embodiment, the LHRH agonist is castration resistant prostate cancer (CRPC ) . In another US 2019 /0040000 A1 Feb . 7 , 2019 32 embodiment, the CRPC is metastatic CRPC (mCRPC ). In or progressing while the patient remains on ADT or other one embodiment, the CRPC is non -metastatic castration therapies to reduce testosterone , or prostate cancer which is resistant prostate cancer ( nmCRPC ) . In one embodiment, the considered hormone refractory , hormone naïve, androgen nmCRPC is high -risk nmCRPC . In another embodiment, the independent or chemical or surgical castration resistant. In compound is any one of compounds 13 - 21, 49 , 50 and 17a . another embodiment , CRPC is a result of AR activation by In another embodiment, the subject has failed androgen intracrine androgen synthesis. In another embodiment, deprivation therapy (ADT ) . In another embodiment, the CRPC is a result of expression of AR splice variants subject further receives androgen deprivation therapy ( AR - SV ) that lack ligand binding domain (LBD ) . In another ( ADT) . embodiment, CRPC is a result of expression of AR -LBD [0498 ] In one embodiment, this invention provides a mutations with potential to resist antagonists . In another method of treating prostate cancer or delaying the progres embodiment, castration resistant prostate cancer (CRPC ) is sion of prostate cancer comprising administering a SARD an advanced prostate cancer which developed despite ongo compound of this invention . In one embodiment, this inven ing ADT and /or surgical castration . In one embodiment, tion provides a method of preventing and /or treating the castration resistant prostate cancer is defined as prostate recurrence of prostate cancer comprising administering a cancer that continues to progress or worsen or adversely SARD compound of this invention . In another embodiment, affect the health of the patient despite prior surgical castra the prostate cancer is castration resistant prostate cancer tion , continued treatment with releasing hor (CRPC ) . In another embodiment , the CRPC is metastatic mone agonists ( e . g . , leuprolide ) or antagonists ( e . g . , CRPC (mCRPC ) . In one embodiment, the CRPC is non degarelix ), antiandrogens (e .g . , bicalutamide , apalutamide, metastatic castration resistant prostate cancer (nmCRPC ) . In flutamide, enzalutamide, ketoconazole , aminogluteth one embodiment, the nmCRPC is high - risk nmCRPC . amide ) , chemotherapeutic agents ( e . g . , docetaxel, paclitaxel, [0499 ] In one embodiment , this invention provides a cabazitaxel, adriamycin , mitoxantrone , estramustine , cyclo method of increasing the survival of a subject having phosphamide ) , kinase inhibitors ( imatinib (Gleevec® ) or prostate cancer, advanced prostate cancer, castration resis gefitinib (Iressa® ), cabozantinib ( CometrigTM , also known tant prostate cancer or metastatic castration resistant prostate as XL184 )) or other prostate cancer therapies ( e . g ., vaccines cancer or non -metastatic castration resistant prostate cancer ( sipuleucel - T (Provenge® ) ,GVAX , etc . ), herbal (PC - SPES ) or high - risk non -metastatic castration resistant prostate can and lyase inhibitor ( abiraterone )) as evidenced by increasing cer , comprising administering a compound of this invention . or higher serum levels of prostate specific antigen ( PSA ) , In another embodiment, administering a compound of this metastasis , bone metastasis , pain , lymph node involvement, invention in combination with LHRH analogs, reversible increasing size or serum markers for tumor growth , wors antiandrogens (such as bicalutamide, apalutamide , fluta ening diagnostic markers of prognosis , or patient condition . mide , or enzalutamide ) , anti -estrogens , anticancer drugs , [0504 ] In one embodiment, castration resistant prostate 5 - alpha reductase inhibitors , aromatase inhibitors , proges cancer is defined as hormone naïve prostate cancer. tins, selective androgen receptor modulators ( SARMs) or [0505 ] Many early prostate cancers require androgens for agents acting through other nuclear hormone receptors . In growth , but advanced prostate cancers are in some embodi another embodiment, the subject has failed androgen depri ments , androgen - independent, or hormone naïve . In one vation therapy ( ADT ) . In another embodiment the com embodiment, in men with castration resistant prostate can pound is any one of compounds 13 - 21 , 49 , 50 and 17a . cer , the tumor cells may have the ability to grow in the [0500 ] The term “ advanced prostate cancer” refers to absence of androgens (hormones that promote the develop metastatic cancer having originated in the prostate , and ment and maintenance of male sex characteristics ) . having widely metastasized to beyond the prostate such as [ 0506 ] In one embodiment, the term “ androgen depriva the surrounding tissues to include the seminal vesicles the tion therapy ” (ADT ) or “ traditional androgen deprivation pelvic lymph nodes or bone , or to other parts of the body. therapy ” is directed to orchiectomy ( surgical castration ) Prostate cancer pathologies are graded with a Gleason wherein the surgeon removes the testicles. In another grading from 1 to 5 in order of increasing malignancy . In embodiment, the term “ androgen deprivation therapy ” or another embodiment, patients with significant risk of pro “ traditional androgen deprivation therapy” is directed to gressive disease and / or death from prostate cancer should be administering luteinizing hormone -releasing hormone included in the definition and that any patient with cancer (LHRH ) analogs : these drugs lower the amount of testos outside the prostate capsule with disease stages as low as IIB terone made by the testicles . Examples of LHRH analogs clearly has " advanced ” disease . In another embodiment, available in the United States include leuprolide (Lupron® , " advanced prostate cancer” can refer to locally advanced Viadur® , Eligard® ) , goserelin (Zoladex® ) , triptorelin ( Trel prostate cancer. star® ) , and histrelin ( Vantas® ) . In another embodiment, the [0501 ] Men with advanced prostate cancer often receive term “ androgen deprivation therapy ” or “ traditional andro treatment to block the production of androgens , which are gen deprivation therapy ” is directed to administering anti male sex hormones that may help prostate tumors grow . androgens: Antiandrogens block the body ' s ability to use However, prostate cancers that initially respond to antian any androgens . Even after orchiectomy or during treatment drogen therapy eventually develop the ability to grow with with LHRH analogs, a small amount of androgens is still out androgens . Such cancers are often referred to as hor made by the adrenal glands . Examples of antiandrogens mone refractory, androgen independent, or castration drugs include enzalutamide ( Xtandi® ) , flutamide (Eu resistant . lexin® ) , bicalutamide ( Casodex® ) , apalutamide, and nilu [ 0502] In one embodiment, the advanced prostate cancer tamide (Nilandron® ) . In another embodiment, the term is castration resistant prostate cancer. " androgen deprivation therapy ” or “ traditional androgen 0503 ] The term “ castration resistant prostate cancer" deprivation therapy ” is directed to administering luteinizing ( CRPC ) refers to advanced prostate cancer that is worsening hormone -releasing hormone (LHRH ) antagonists such as US 2019 /0040000 A1 Feb . 7 , 2019 33 abarelix (Plenaxis® ) or degarelix ( Firmagon® ) ( approved setting , or as monotherapy, or when castration -sensitive for use by the FDA in 2008 to treat advanced prostate prostate cancer tumor is resistant to enzalutamide , apaluta cancer ) . In another embodiment, the term " androgen depri mide , and/ or abiraterone. vation therapy " or " traditional androgen deprivation [0513 ] In one embodiment, this invention provides a therapy ” is directed to administering 5a - reductase inhibitors method of treating AR overexpressing prostate cancer in a such as finasteride ( Proscar® ) and dutasteride (Avodart® ) : subject in need thereof, comprising administering to the 5a - reductase inhibitors block the body ' s ability to convert subject a therapeutically effective amount of a selective testosterone to the more active androgen , 5a -dihydrotestos androgen receptor degrader (SARD ) compound , or its iso terone (DHT ) . In another embodiment, the term “ androgen mer, pharmaceutically acceptable salt , pharmaceutical prod deprivation therapy ” or “ traditional androgen deprivation uct , polymorph , hydrate or any combination thereof, therapy ” is directed to administering inhibitors of testoster wherein said SARD compound is represented by the struc one biosynthesis such as ketoconazole (Nizoral® ) . In ture of formula I -VII , IA - IB , and IIA - IIB or its isomer , another embodiment, the term " androgen deprivation pharmaceutically acceptable salt , pharmaceutical product , therapy ” or “ traditional androgen deprivation therapy ” is polymorph , hydrate or any combination thereof. In another directed to administering estrogens such as embodiment, the compound is any one of compounds 13 - 21, or 17ß - estradiol. In another embodiment, the term “ andro 49 , 50 and 17a . gen deprivation therapy ” or “ traditional androgen depriva [0514 ] In one embodiment, this invention provides a tion therapy” is directed to administering 17a -hydroxylase ! method of treating castration -resistant prostate cancer in a C17, 20 lyase (CYP17A1 ) inhibitors such as abiraterone subject in need thereof, comprising administering to the ( Zytiga® ). subject a therapeutically effective amount of a selective 10507 ] In one embodiment, this invention provides a androgen receptor degrader (SARD ) compound , or its iso method of treating, suppressing, reducing the incidence , mer , pharmaceutically acceptable salt , pharmaceutical prod reducing the severity , increasing the survival , or inhibiting uct, polymorph , hydrate or any combination thereof, an antiandrogen -resistant prostate cancer. In another wherein said SARD compound is represented by the struc embodiment, the antiandrogen is bicalutamide , apalutamide , ture of I -VII , IA - IB , and IIA - IIB or its isomer, pharmaceu hydroxyflutamide , flutamide, or enzalutamide . tically acceptable salt , pharmaceutical product , polymorph , [0508 ] In one embodiment , this invention provides a hydrate method of treating, suppressing , reducing the incidence , [0515 ] In one embodiment, the castration -resistant pros reducing the severity , increasing the survival , or inhibiting tate cancer is AR overexpressing castration - resistant pros an abiraterone- resistant prostate cancer . tate cancer, F876L mutation expressing castration - resistant [0509 ] In one embodiment , this invention provides a prostate cancer, F876L _ T877A double mutation expressing method of treating prostate cancer in a subject in need castration - resistant prostate cancer , AR - V7 expressing cas thereof, wherein said subject has AR overexpressing pros tration -resistant prostate cancer, d567ES expressing castra tate cancer, castration - resistant prostate cancer, castration tion - resistant prostate cancer, and /or castration - resistant sensitive prostate cancer, AR - V7 expressing prostate cancer, prostate cancer characterized by intratumoral androgen syn or d567ES expressing prostate cancer , comprising adminis thesis . tering to the subject a therapeutically effective amount of a [0516 ] In one embodiment, this invention provides a selective androgen receptor degrader (SARD ) compound , or method of treating castration - sensitive prostate cancer in a its isomer , pharmaceutically acceptable salt, pharmaceutical subject in need thereof, comprising administering to the product, polymorph , hydrate or any combination thereof, subject a therapeutically effective amount of a selective wherein said SARD compound is represented by the struc androgen receptor degrader (SARD ) compound , or its iso ture of formula I - VII, IA - IB , and IIA - IIB or its isomer, mer, pharmaceutically acceptable salt , pharmaceutical prod pharmaceutically acceptable salt , pharmaceutical product, uct , polymorph , hydrate or any combination thereof, polymorph , hydrate or any combination thereof. In another wherein said SARD compound is represented by the struc ture of formula I - VII, IA - IB , and IIA - IIB or its isomer, embodiment, the compound is any one of compounds 13 - 21 , pharmaceutically acceptable salt , pharmaceutical product , 49 , 50 and 17a . polymorph , hydrate or any combination thereof. In another [0510 ] In one embodiment, the castration - resistant pros embodiment, the compound is any one of compounds 13 - 21, tate cancer is AR overexpressing castration -resistant pros 49 , 50 and 17a . In one embodiment, the castration -sensitive tate cancer, F876L mutation expressing castration - resistant prostate cancer is F876L mutation expressing castration prostate cancer , F876L _ T877A double mutation expressing sensitive prostate cancer, F876L _ T877A double mutation castration - resistant prostate cancer , AR - V7 expressing cas castration - sensitive prostate cancer, and/ or castration - sensi tration -resistant prostate cancer, d567ES expressing castra tive prostate cancer characterized by intratumoral androgen tion - resistant prostate cancer, and / or castration -resistant synthesis . In one embodiment, the treating of castration prostate cancer characterized by intratumoral androgen syn sensitive prostate cancer is conducted in a non -castrate thesis . setting , or as monotherapy , or when castration -sensitive [0511 ] In one embodiment, the castration -sensitive pros prostate cancer tumor is resistant to enzalutamide , apaluta tate cancer is F876L mutation expressing castration -sensi mide , and /or abiraterone . tive prostate cancer, F876L _ T877A double mutation castra [0517 ] In one embodiment, this invention provides a tion - sensitive prostate cancer , and /or castration - sensitive method of treating AR - V7 expressing prostate cancer in a prostate cancer characterized by intratumoral androgen syn subject in need thereof, comprising administering to the thesis . subject a therapeutically effective amount of a selective 10512 ] In one embodiment , the treating of castration - androgen receptor degrader (SARD ) compound , or its iso sensitive prostate cancer is conducted in a non - castrate mer, pharmaceutically acceptable salt , pharmaceutical prod US 2019 /0040000 A1 Feb . 7 , 2019 34 uct, polymorph , hydrate or any combination thereof, mer, pharmaceutically acceptable salt , pharmaceutical prod wherein said SARD compound is represented by the struc uct, polymorph , hydrate or any combination thereof, ture of formula I - VII , IA - IB , and IIA - IIB or its isomer, wherein said SARD compound is represented by the struc pharmaceutically acceptable salt, pharmaceutical product , ture of formula I - VII , IA - IB , and IIA - IIB or its isomer , polymorph , hydrate or any combination thereof. In another pharmaceutically acceptable salt , pharmaceutical product , embodiment, the compound is any one of compounds 13 - 21, polymorph , hydrate or any combination thereof. In another 49 , 50 and 17a . embodiment, the compound is any one of compounds 13 -21 , [ 0518 ] In one embodiment, this invention provides a 49 , 50 and 17a . method of treating d567ES expressing prostate cancer in a [0523 ] In one embodiment, this invention provides a subject in need thereof, comprising administering to the method of treating, suppressing , reducing the incidence , subject a therapeutically effective amount of a selective reducing the severity, or inhibiting the progression of a androgen receptor degrader (SARD ) compound , or its iso hormonal condition in a male in need thereof, comprising mer , pharmaceutically acceptable salt, pharmaceutical prod administering to the subject a therapeutically effective uct , polymorph , hydrate or any combination thereof, amount of a selective androgen receptor degrader ( SARD ) wherein said SARD compound is represented by the struc compound , or its isomer , pharmaceutically acceptable salt , ture of formula I- VII , IA - IB , and IIA - IIB or its isomer, pharmaceutical product, polymorph , hydrate or any combi pharmaceutically acceptable salt , pharmaceutical product , nation thereof, wherein said SARD compound is represented polymorph , hydrate or any combination thereof. In another by the structure of formula I - VII , IA - IB , and IIA - IIB or its embodiment, the compound is any one of compounds 13 -21 , isomer , pharmaceutically acceptable salt , pharmaceutical 49 , 50 and 17a . product , polymorph ,hydrate or any combination thereof. In [ 0519 ] In one embodiment, this invention provides a another embodiment, the compound is any one of com method of treating breast cancer in a subject in need thereof, pounds 13 - 21 , 49 , 50 and 17a . wherein said subject has AR expressing breast cancer, [0524 ] In one embodiment, the condition is hypergonad AR - SV expressing breast cancer , and / or AR -V7 expressing ism , hypersexuality , sexual dysfunction , gynecomastia , pre breast cancer, comprising administering to the subject a cocious puberty in a male , alterations in cognition and therapeutically effective amount of a selective androgen mood , depression , hair loss , hyperandrogenic dermatologi receptor degrader (SARD ) compound , or its isomer, phar cal disorders , pre -cancerous lesions of the prostate , benign maceutically acceptable salt , pharmaceutical product, poly prostate hyperplasia , prostate cancer and /or other androgen morph , hydrate or any combination thereof, wherein said dependent cancers . SARD compound is represented by the structure of formula [ 0525 ] Muscle atrophy (MA ) is characterized by wasting I - VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically away or diminution of muscle and a decrease in muscle acceptable salt , pharmaceutical product, polymorph , hydrate mass . For example , post - polio MA is a muscle wasting that or any combination thereof. In another embodiment, the occurs as part of the post - polio syndrome (PPS ) . The atro compound is any one of compounds 13 -21 , 49, 50 and 17a . phy includes weakness , muscle fatigue, and pain . [0520 ] In one embodiment, this invention provides a 105261. Another type of MA is X - linked spinal- bulbar method of treating AR expressing breast cancer in a subject muscular atrophy ( SBMA also known as Kennedy ' s Dis in need thereof, comprising administering to the subject a ease ). This disease arises from a defect in the androgen therapeutically effective amount of a selective androgen receptor gene on the X chromosome, affects only males, and receptor degrader (SARD ) compound , or its isomer , phar its onset is in late adolescence to adulthood . Proximal limb maceutically acceptable salt , pharmaceutical product , poly and bulbar muscle weakness results in physical limitations morph , hydrate or any combination thereof, wherein said including dependence on a wheelchair in some cases . The SARD compound is represented by the structure of formula mutation results in an extended polyglutamine tract at the I - VII , IA -IB , and IIA - IIB or its isomer , pharmaceutically N - terminal domain of the androgen receptor (polyQ AR ) . acceptable salt, pharmaceutical product , polymorph , hydrate Binding and activation of the polyQ AR by endogeneous or any combination thereof. In another embodiment, the androgens ( testosterone and DHT) results in unfolding and compound is any one of compounds 13 -21 , 49, 50 and 17a. nuclear translocation of the mutant androgen receptor. These 0521 ] In one embodiment , this invention provides a steps are required for pathogenesis and results in partial loss method of treating AR - SV expressing breast cancer in a of transactivation function ( i . e . , an androgen insensitivity ) subject in need thereof, comprising administering to the and a poorly understood neuromuscular degeneration . Cur subject a therapeutically effective amount of a selective rently there are no disease -modifying treatments but rather androgen receptor degrader (SARD ) compound , or its iso only symptom directed treatments . Efforts to target the mer , pharmaceutically acceptable salt, pharmaceutical prod polyQ AR as the proximal mediator of toxicity by harness uct, polymorph , hydrate or any combination thereof , ing cellular machinery to promote its degradation hold wherein said SARD compound is represented by the struc promise for therapeutic intervention . Selective androgen ture of formula I - VII, IA - IB , and IIA - IIB or its isomer, receptor degraders such as those reported herein bind to and pharmaceutically acceptable salt , pharmaceutical product , degrade a variety of androgen receptors ( full length , splice polymorph , hydrate or any combination thereof. In another variant, antiandrogen resistance mutants , etc . ), indicating embodiment, the compound is any one of compounds 13 - 21, that they are promising leads for treatment of SBMA . This 49 , 50 and 17a . view is supported by the observation that peripheral polyQ [0522 ] In one embodiment, this invention provides a AR anti -sense therapy rescues disease in mouse models of method of treating AR - V7 expressing breast cancer in a SBMA ( Cell Reports 7 , 774 - 784 , May 8 , 2014 ) . subject in need thereof, comprising administering to the [0527 ] In one embodiment, this invention is directed to a subject a therapeutically effective amount of a selective method of treating, suppressing, reducing the incidence , androgen receptor degrader (SARD ) compound , or its iso reducing the severity , or inhibiting the progression of the US 2019 /0040000 A1 Feb . 7 , 2019 35

Kennedy ' s disease comprising administering therapeutically polymorph , hydrate or any combination thereof. In another effective amount of a compound of formulas I - VII , IA , IIA embodiment, the compound is any one of compounds 13 - 21 , or its isomer , pharmaceutically acceptable salt , pharmaceu 49 , 50 and 17a . tical product, polymorph , hydrate or any combination [0533 ] The effect of the AR on the skin is apparent in the thereof. In another embodiment, the compound is any one of gender dimorphism and puberty related dermatological compounds 13- 21, 49 , 50 and 17a . problems common to teens and early adults . The hyperan [0528 ] In one embodiment , this invention is directed to a drogenism of puberty stimulates terminal hair growth , method of treating, suppressing , reducing the incidence , sebum production , and predisposes male teens to acne , acne reducing the severity, or inhibiting the progression of Ken vulgaris , seborrhea , excess sebum , hidradenitis suppurativa , nedy ' s disease in a subject , comprising administering to said hirsutism , hypertrichosis , hyperpilosity , androgenic alope subject a therapeutically effective amount of compound 17 cia , male pattern baldness , and other dermatological mala dies. Although antiandrogens theoretically should prevent the hyperandrogenic dermatological diseases discussed , they are limited by toxicities , sexual side effects , and lack of efficacy when topically applied . The SARDs of this inven tion potently inhibit ligand - dependent and ligand - indepen dent AR activation , and have short biological half - lives in the serum , suggesting that topically formulated SARDs of NC . this invention could be applied to the areas affected by acne , seborrheic dermatitis , and /or hirsutism without risk of sys temic side effects . F3C [0534 ] In one embodiment, this invention is directed to a 1 method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of acne comprising administering a therapeutically effective amount or its isomer, pharmaceutically acceptable salt , pharmaceu of a compound of formulas I -VII , IA - IB , and IIA - IIB or its tical product, polymorph , hydrate or any combination isomer , pharmaceutically acceptable salt , pharmaceutical thereof. product, polymorph , hydrate or any combination thereof. In [0529 ] As used herein , “ androgen receptor associated con another embodiment, the compound is any one of com ditions " or " androgen sensitive diseases or disorders ” are pounds 13 -21 , 49 , 50 and 17a . conditions, diseases , or disorders that are modulated by or [0535 ] In one embodiment, this invention is directed to a whose pathogenesis is dependent upon the activity of the method of treating, suppressing, reducing the incidence , androgen receptor. The androgen receptor is expressed in reducing the severity , or inhibiting the progression of acne most tissues of the body however it is overexpressed in , inter vulgaris comprising administering a therapeutically effec alia , the prostate and skin . ADT has been the mainstay of tive amount of a compound of formulas I -VII , IA - IB , and prostate cancer treatment for many years, and SARD may IIA - IIB or its isomer , pharmaceutically acceptable salt , also be useful also in treating various prostate cancers , pharmaceutical product, polymorph , hydrate or any combi benign prostatic hypertrophy, prostamegaly , and other mala nation thereof. In another embodiment, the compound is any dies of the prostate . one of compounds 13 - 21 , 49 , 50 and 17a . [0530 ] In one embodiment, this invention is directed to a [0536 ] In one embodiment, this invention is directed to a method of treating , suppressing , reducing the incidence , method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression ofbenign reducing the severity , or inhibiting the progression of seb prostatic hypertrophy comprising administering a therapeu orrhea comprising administering a therapeutically effective tically effective amount of a compound of formulas I - VII , amount of a compound of formulas I - VII , IA -IB , and IA , IIA or its isomer , pharmaceutically acceptable salt, IIA - IIB or its isomer , pharmaceutically acceptable salt , pharmaceutical product, polymorph , hydrate or any combi pharmaceutical product, polymorph , hydrate or any combi nation thereof. In another embodiment, the compound is any nation thereof. In another embodiment, the compound is any one of compounds 13 -21 , 49 , 50 and 17a . one of compounds 13 - 21 , 49 , 50 and 17a . [ 0531 ] In one embodiment , this invention is directed to a 105371. In one embodiment, this invention is directed to a method of treating , suppressing , reducing the incidence , method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of pros reducing the severity , or inhibiting the progression of seb tamegaly comprising administering a therapeutically effec orrheic dermatitis comprising administering a therapeuti tive amount of a compound of formulas I - VII , IA , IIA or its cally effective amount of a compound of formulas I - VII, isomer , pharmaceutically acceptable salt , pharmaceutical IA - IB , and IIA - IIB or its isomer, pharmaceutically accept product , polymorph , hydrate or any combination thereof. In able salt, pharmaceutical product, polymorph , hydrate or another embodiment, the compound is any one of com any combination thereof. In another embodiment, the com pounds 13 -21 , 49 , 50 and 17a . pound is any one of compounds 13 - 21, 49, 50 and 17a . [0532 ] In one embodiment , this invention is directed to a [0538 ] In one embodiment, this invention is directed to a method of treating, suppressing , reducing the incidence , method of treating, suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of hyper reducing the severity , or inhibiting the progression of proliferative prostatic disorders and diseases comprising hidradenitis supporativa comprising administering a thera administering a therapeutically effective amount of a com peutically effective amount of a compound of formulas pound of formulas I - VII , IA - IB , and IIA - IIB or its isomer, I - VII, IA - IB , and IIA - IIB or its isomer, pharmaceutically pharmaceutically acceptable salt, pharmaceutical product, acceptable salt , pharmaceutical product , polymorph , hydrate US 2019 /0040000 A1 Feb . 7 , 2019 36 or any combination thereof . In another embodiment, the polycystic ovary syndrome, pre- eclampsia , eclampsia of compound is any one of compounds 13 -21 , 49, 50 and 17a . pregnancy , preterm labor, premenstrual syndrome, and vagi 10539 ] In one embodiment, this invention is directed to a nal dryness . method of treating , suppressing , reducing the incidence , [0546 ] In one embodiment, this invention is directed to a reducing the severity , or inhibiting the progression of hir method of treating, suppressing , reducing the incidence , sutism comprising administering a therapeutically effective reducing the severity , or inhibiting the progression of pre amount of a compound of formulas I - VII , IA - IB , and cocious puberty or early puberty comprising administering a IIA - IIB or its isomer, pharmaceutically acceptable salt , therapeutically effective amount of a compound of formulas pharmaceutical product, polymorph , hydrate or any combi I -VII , IA - IB , and IIA - IIB or its isomer, pharmaceutically nation thereof. In another embodiment, the compound is any acceptable salt , pharmaceutical product, polymorph , hydrate one of compounds 13 -21 , 49 , 50 and 17a . or any combination thereof. In another embodiment, the [ 0540 ] In one embodiment, this invention is directed to a compound is any one of compounds 13 - 21, 49 , 50 and 17a . method of treating , suppressing , reducing the incidence , [0547 ] In one embodiment, the invention is directed to a reducing the severity , or inhibiting the progression of hyper method of treating, suppressing , reducing the incidence , trichosis comprising administering a therapeutically effec reducing the severity , or inhibiting the progression of a tive amount of a compound of formulas I - VII , IA , IIAor its hyperandrogenic hormonal condition in a female , compris isomer , pharmaceutically acceptable salt, pharmaceutical ing administering to said subject a therapeutically effective product , polymorph , hydrate or any combination thereof. In amount of compound 17 another embodiment, the compound is any one of com pounds 13 - 21 , 49 , 50 and 17a . [ 0541] In one embodiment, this invention is directed to a 17 method of treating, suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of hyp erpilosity comprising administering a therapeutically effec tive amount of a compound of formulas I -VII , IA - IB , and IIA - IIB or its isomer, pharmaceutically acceptable salt , NC . pharmaceutical product, polymorph , hydrate or any combi nation thereof. In another embodiment, the compound is any one of compounds 13 -21 , 49 , 50 and 17a . F3C ZI [0542 ] In one embodiment, this invention is directed to a method of treating, suppressing , reducing the incidence, reducing the severity , or inhibiting the progression of alo or its isomer, pharmaceutically acceptable salt , pharmaceu pecia comprising administering a therapeutically effective tical product , polymorph , hydrate or any combination amount of a compound of formulas I - VII, IA - IB , and thereof. IIA - IIB or its isomer , pharmaceutically acceptable salt , [0548 ] In one embodiment, the hyperandrogenic hormonal pharmaceutical product, polymorph , hydrate or any combi condition in a female is precocious puberty , early puberty , nation thereof. In another embodiment, the compound is any dysmenorrhea , amenorrhea , multilocular uterus syndrome, one of compounds 13 -21 , 49 , 50 and 17a . endometriosis , hysteromyoma , abnormal uterine bleeding , [0543 ] In some embodiments , the compounds as described early menarche, fibrocystic breast disease , fibroids of the herein and /or compositions may be used for applications in uterus, ovarian cysts, polycystic ovary syndrome, pre - ec or treating hair loss , alopecia , androgenic alopecia , alopecia lampsia , eclampsia of pregnancy , preterm labor , premen areata , alopecia secondary to chemotherapy , alopecia sec strual syndrome, and /or vaginal dryness . ondary to radiation therapy, alopecia induced by scarring or [05491 . In one embodiment, this invention is directed to a alopecia induced by stress. In one embodiment, " hair loss” , method of treating, suppressing , reducing the incidence , or “ alopecia ” , refers to baldness as in the very common type reducing the severity , or inhibiting the progression of dys of male -pattern baldness . Baldness typically begins with menorrhea or amenorrhea comprising administering a thera patch hair loss on the scalp and sometimes progresses to peutically effective amount of a compound of formulas complete baldness and even loss of body hair . Hair loss I - VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically affects both males and females. acceptable salt , pharmaceutical product , polymorph , hydrate [ 0544 ] In one embodiment, this invention is directed to a or any combination thereof. In another embodiment, the method of treating , suppressing , reducing the incidence , compound is any one of compounds 13 - 21, 49 , 50 and 17a . reducing the severity, or inhibiting the progression of andro [0550 ] In one embodiment, this invention is directed to a genic alopecia comprising administering a therapeutically method of treating , suppressing , reducing the incidence , effective amount of a compound of formula I - VII , IA - IB , reducing the severity , or inhibiting the progression of mul and IIA -IIB or its isomer , pharmaceutically acceptable salt , tilocular uterus syndrome, endometriosis , hysteromyoma, or pharmaceutical product, polymorph , hydrate or any combi abnormal uterine bleeding comprising administering a thera nation thereof. In another embodiment, the compound is any peutically effective amount of a compound of formulas one of compounds 13 -21 , 49 , 50 and 17a . I - VII, IA - IB , and IIA - IIB or its isomer, pharmaceutically 105451 SARDs of this invention may also be useful in the acceptable salt , pharmaceutical product, polymorph , hydrate treatment of hormonal conditions in females such as preco or any combination thereof. In another embodiment, the cious puberty , early puberty , dysmenorrhea , amenorrhea , compound is any one of compounds 13 - 21, 49 , 50 and 17a . multilocular uterus syndrome, endometriosis , hystero [0551 ] In one embodiment, this invention is directed to a myoma, abnormal uterine bleeding, early menarche, fibro method of treating , suppressing , reducing the incidence , cystic breast disease , fibroids of the uterus, ovarian cysts , reducing the severity , or inhibiting the progression of any US 2019 /0040000 A1 Feb . 7 , 2019 37 hyper - androgenic diseases ( for example polycystic ovary gen insensitivity syndromes comprising administering a syndrome (PCOS ) ) comprising administering a therapeuti therapeutically effective amount of a compound of formulas cally effective amount of a compound of formulas I - VII, IA , I - VII , IA - IB , and IIA - IIB or its isomer, pharmaceutically IIA or its isomer, pharmaceutically acceptable salt , pharma acceptable salt, pharmaceutical product , polymorph , hydrate ceutical product, polymorph , hydrate or any combination or any combination thereof. In another embodiment , the thereof. In another embodiment, the compound is any one of compound is any one of compounds 13 - 21 , 49 , 50 and 17a . compounds 13 - 21, 49, 50 and 17a . In one embodiment, the androgen insensitivity syndrome is 10552] In one embodiment, this invention is directed to a a complete androgen insensitivity syndrome. In another method of treating , suppressing , reducing the incidence , embodiment, the androgen insensitivity syndrome is a par reducing the severity, or inhibiting the progression of fibro tial androgen insensitivity syndrome. cystic breast disease , fibroids of the uterus, ovarian cysts , or 0559 ] In one embodiment, this invention is directed to a polycystic ovary syndrome comprising administering a method of increasing, modulating , or improving ovulation in therapeutically effective amount of a compound of formulas an animal comprising administering a therapeutically effec I -VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically tive amount of a compound of formulas I - VII , IA - IB , and acceptable salt , pharmaceutical product , polymorph , hydrate IIA - IIB or its isomer, pharmaceutically acceptable salt, or any combination thereof. In another embodiment , the pharmaceutical product , polymorph , hydrate or any combi compound is any one of compounds 13 - 21 , 49, 50 and 17a . nation thereof. In another embodiment, the compound is any (0553 ] In one embodiment, this invention is directed to a one of compounds 13 - 21 , 49 , 50 and 17a . method of treating , suppressing , reducing the incidence , [0560 ] SARDs of this invention may also be useful for the reducing the severity , or inhibiting the progression of pre treating of hormone -dependent cancers such as prostate eclampsia , eclampsia of pregnancy , preterm labor, premen cancer, breast cancer, testicular cancer , ovarian cancer, strual syndrome, or vaginal dryness comprising administer hepatocellular carcinoma , urogenital cancer , etc . Further , ing a therapeutically effective amount of a compound of local or systemic SARD administration may be useful for formulas I - VII, IA - IB , and IIA - IIB or its isomer , pharma treatment of precursors of hormone dependent cancers such ceutically acceptable salt, pharmaceutical product, poly as prostatic intraepithelial neoplasia (PIN ) and atypical morph , hydrate or any combination thereof. In another small acinar proliferation ( ASAP ) . embodiment, the compound is any one of compounds 13 - 21 , 10561] In one embodiment, this invention is directed to a 49 , 50 and 17a . method of treating, suppressing , reducing the incidence , [ 0554 ] SARDS of this invention may also find utility in reducing the severity , or inhibiting the progression of breast treatment of sexual perversion , hypersexuality , paraphilias, cancer comprising administering a therapeutically effective androgen psychosis , virilization , androgen insensitivity syn amount of a compound of formulas I - VII , IA - IB , and dromes (AIS ) such as complete MS (CMS ) and partial MS IIA - IIB or its isomer, pharmaceutically acceptable salt , ( PAIS ), and improving ovulation in an animal. pharmaceutical product, polymorph , hydrate or any combi [0555 ] In one embodiment, this invention is directed to a nation thereof. In another embodiment, the compound is any method of treating, suppressing, reducing the incidence , one of compounds 13 - 21 , 49 , 50 and 17a . reducing the severity , or inhibiting the progression of sexual 10562 ] In one embodiment, this invention is directed to a perversion , hypersexuality , or paraphilias comprising method of treating , suppressing , reducing the incidence , administering a therapeutically effective amount of a com reducing the severity , or inhibiting the progression of tes pound of formulas I - VII , IA - IB , and IIA - IIB or its isomer, ticular cancer comprising administering a therapeutically pharmaceutically acceptable salt, pharmaceutical product, effective amount of a compound of formulas I- VII , IA -IB , polymorph , hydrate or any combination thereof. In another and IIA - IIB or its isomer, pharmaceutically acceptable salt , embodiment, the compound is any one of compounds 13 - 21 , pharmaceutical product, polymorph , hydrate or any combi 49 , 50 and 17a . nation thereof. In another embodiment, the compound is any [ 0556 ] In one embodiment, this invention is directed to a one of compounds 13 - 21, 49 , 50 and 17a . method of treating , suppressing , reducing the incidence , [0563 ] In one embodiment, this invention is directed to a reducing the severity, or inhibiting the progression of andro method of treating , suppressing , reducing the incidence , gen psychosis comprising administering a therapeutically reducing the severity , or inhibiting the progression of uterine effective amount of a compound of formulas I -VII , IA - IB , cancer comprising administering a therapeutically effective and IIA - IIB or its isomer , pharmaceutically acceptable salt, amount of a compound of formulas I- VII , IA -IB , and pharmaceutical product, polymorph , hydrate or any combi IIA - IIB or its isomer , pharmaceutically acceptable salt, nation thereof. In another embodiment, the compound is any pharmaceutical product, polymorph , hydrate or any combi one of compounds 13 -21 , 49 , 50 and 17a . nation thereof. In another embodiment, the compound is any [ 0557 ] In one embodiment, this invention is directed to a one of compounds 13 - 21 , 49 , 50 and 17a . method of treating , suppressing , reducing the incidence , 10564 ] In one embodiment, this invention is directed to a reducing the severity , or inhibiting the progression of viril method of treating, suppressing , reducing the incidence , ization comprising administering a therapeutically effective reducing the severity , or inhibiting the progression of ovar amount of a compound of formulas I - VII , IA - IB , and ian cancer comprising administering a therapeutically effec IIA - IIB or its isomer, pharmaceutically acceptable salt , tive amount of a compound of formulas I - VII, IA - IB , and pharmaceutical product, polymorph , hydrate or any combi IIA - IIB or its isomer , pharmaceutically acceptable salt , nation thereof. In another embodiment , the compound is any pharmaceutical product, polymorph , hydrate or any combi one of compounds 13 - 21, 49 , 50 and 17a . nation thereof. In another embodiment, the compound is any [0558 ] In one embodiment, this invention is directed to a one of compounds 13 - 21, 49 , 50 and 17a . method of treating , suppressing , reducing the incidence , [0565 ] In one embodiment, this invention is directed to a reducing the severity , or inhibiting the progression of andro method of treating, suppressing , reducing the incidence , US 2019 /0040000 A1 Feb . 7 , 2019 38 reducing the severity , or inhibiting the progression of uro nation thereof. In another embodiment , the compound is any genital cancer comprising administering a therapeutically one of compounds 13 - 21, 49 , 50 and 17a . effective amount of a compound of formulas I - VII, IA - IB , [0572 ] In one embodiment, this invention is directed to a and IIA - IIB or its isomer, pharmaceutically acceptable salt, method of treating , suppressing , reducing the incidence , pharmaceutical product, polymorph , hydrate or any combi reducing the severity , or inhibiting the progression of skin nation thereof. In another embodiment, the compound is any cancer comprising administering a therapeutically effective one of compounds 13 -21 , 49, 50 and 17a . amount of a compound of formulas I - VII , IA - IB , and [0566 ] In one embodiment , this invention is directed to a IIA - IIB or its isomer, pharmaceutically acceptable salt , method of treating, suppressing , reducing the incidence , pharmaceutical product , polymorph , hydrate or any combi reducing the severity , or inhibiting the progression of pre nation thereof. In another embodiment, the compound is any cursors of prostate cancer comprising local or systemic one of compounds 13 -21 , 49 , 50 and 17a . administration of a therapeutically effective amount of a [0573 ] In one embodiment, this invention is directed to a compound of formulas I - VII , IA - IB , and IIA - IIB or its method of treating , suppressing , reducing the incidence , isomer , pharmaceutically acceptable salt , pharmaceutical reducing the severity , or inhibiting the progression of ovar product , polymorph , hydrate or any combination thereof. In ian cancer comprising administering a therapeutically effec another embodiment, the compound is any one of com tive amount of a compound of formulas I -VII , IA - IB , and pounds 13 - 21 , 49 , 50 and 17a . In one embodiment , the IIA - IIB or its isomer, pharmaceutically acceptable salt, precursor of prostate cancers is pro static intraepithelial pharmaceutical product , polymorph , hydrate or any combi neoplasia ( PIN ) . In another embodiment, the precursor of nation thereof. In another embodiment, the compound is any prostate cancer is atypical small acinar proliferation one of compounds 13 - 21 , 49 , 50 and 17a . ( ASAP ). [0574 ] In one embodiment, this invention is directed to a 05671. In one embodiment, this invention is directed to a method of treating , suppressing, reducing the incidence , method of treating, suppressing, reducing the incidence , reducing the severity , or inhibiting the progression of blad reducing the severity , or inhibiting the progression of AR der cancer comprising administering a therapeutically effec related solid tumors. In another embodiment, the tumor is tive amount of a compound of formulas I - VII , IA - IB , and hepatocellular carcinoma (HCC ) . In another embodiment, IIA - IIB or its isomer, pharmaceutically acceptable salt , the tumor is bladder cancer . Serum testosterone may be pharmaceutical product, polymorph , hydrate or any combi positively linked to the development of HCC . Based on nation thereof. In another embodiment, the compound is any epidemiologic , experimental observations, and notably the one of compounds 13 -21 , 49 , 50 and 17a . fact that men have a substantially higher risk of bladder [0575 ] In one embodiment, this invention is directed to a cancer than women , androgens and /or the AR also play a method of treating , suppressing , reducing the incidence , role in bladder cancer initiation . reducing the severity, or inhibiting the progression of lym [0568 ] SARD of this invention may also be useful for the phoma comprising administering a therapeutically effective treating other cancers containing AR such as breast, brain , amount of a compound of formulas I - VII , IA - IB , and skin , ovarian , bladder, lymphoma, liver , kidney , pancreas , IIA - IIB or its isomer , pharmaceutically acceptable salt, endometrium , lung ( e . g ., NSCLC ) , colon , perianal adenoma , pharmaceutical product , polymorph , hydrate or any combi osteosarcoma, CNS, melanoma, hypercalcemia of malig nation thereof. In another embodiment, the compound is any nancy and metastatic bone disease etc . one of compounds 13 - 21 , 49 , 50 and 17a . [0569 ] In one embodiment, this invention is directed to a [0576 ] In one embodiment, this invention is directed to a method of treating, suppressing , reducing the incidence , method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of hyper reducing the severity , or inhibiting the progression of liver calcemia of malignancy comprising administering a thera cancer comprising administering a therapeutically effective peutically effective amount of a compound of formulas amount of a compound of formulas I -VII , IA - IB , and I - VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically IIA - IIB or its isomer, pharmaceutically acceptable salt , acceptable salt , pharmaceutical product , polymorph , hydrate pharmaceutical product , polymorph , hydrate or any combi or any combination thereof. In another embodiment, the nation thereof. In another embodiment, the compound is any compound is any one of compounds 13- 21 , 49, 50 and 17a . one of compounds 13 - 21 , 49 , 50 and 17a . [0570 ] In one embodiment, this invention is directed to a [0577 ] In one embodiment , this invention is directed to a method of treating, suppressing , reducing the incidence , method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression ofmeta reducing the severity, or inhibiting the progression of renal static bone disease comprising administering a therapeuti cancer comprising administering a therapeutically effective cally effective amount of a compound of formulas I - VII , amount of a compound of formulas I - VII , IA - IB , and IA - IB , and IIA - IIB or its isomer , pharmaceutically accept- IIA - IIB or its isomer , pharmaceutically acceptable salt, able salt , pharmaceutical product, polymorph , hydrate or pharmaceutical product, polymorph , hydrate or any combi any combination thereof. In another embodiment, the com nation thereof. In another embodiment, the compound is any pound is any one of compounds 13 -21 , 49 , 50 and 17a . one of compounds 13 - 21 , 49, 50 and 17a . [0571 ] In one embodiment , this invention is directed to a [0578 ] In one embodiment, this invention is directed to a method of treating, suppressing , reducing the incidence , method of treating, suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of brain reducing the severity , or inhibiting the progression of osteo cancer comprising administering a therapeutically effective sarcoma comprising administering a therapeutically effec amount of a compound of formulas I- VII , IA -IB , and tive amount of a compound of formulas I - VII, IA - IB , and IIA - IIB or its isomer, pharmaceutically acceptable salt, IIA - IIB or its isomer, pharmaceutically acceptable salt , pharmaceutical product, polymorph , hydrate or any combi pharmaceutical product, polymorph , hydrate or any combi US 2019 /0040000 A1 Feb . 7 , 2019 39 nation thereof. In another embodiment , the compound is any duct carcinoma. In another embodiment , the SARDs of this one of compounds 13 - 21, 49 , 50 and 17a . invention are used for treating bladder cancer. In another 10579 ]. In one embodiment, this invention is directed to a embodiment, the SARDs of this invention are used for method of treating , suppressing , reducing the incidence , treating esophageal cancer. In another embodiment, the reducing the severity , or inhibiting the progression of pan SARDs of this invention are used for treating pancreatic creatic cancer comprising administering a therapeutically cancer. In another embodiment, the SARDs of this invention effective amount of a compound of formulas I -VII , IA - IB , are used for treating colon cancer. In another embodiment, and IIA - IIB or its isomer , pharmaceutically acceptable salt , the SARDs of this invention are used for treating non - small pharmaceutical product, polymorph , hydrate or any combi cell lung cancer. In another embodiment, the SARDs of this nation thereof . In another embodiment , the compound is any invention are used for treating renal cell carcinoma. one of compounds 13 - 21, 49 , 50 and 17a . [0587 ] AR plays a role in cancer initiation in hepatocel [0580 ] In one embodiment, this invention is directed to a lular carcinoma (HCC ) . Therefore , targeting AR may be method of treating, suppressing , reducing the incidence , appropriate treatment for patients with early stage HCC . In reducing the severity , or inhibiting the progression of endo late - stage HCC disease , there is evidence that metastasis is metrial cancer comprising administering a therapeutically suppressed by androgens . In another embodiment, the effective amount of a compound of formulas I - VII, IA - IB , and IIA - IIB or its isomer , pharmaceutically acceptable salt, SARDs of this invention are used for treating hepatocellular pharmaceutical product , polymorph , hydrate or any combi carcinoma (HCC ) . nation thereof. In another embodiment , the compound is any [ 0588 ] Locati et al . (Head & Neck , 2016 , 724 -731 ) dem one of compounds 13 -21 , 49 , 50 and 17a . onstrated the use of androgen deprivation therapy (ADT ) in [ 0581 ] In one embodiment, this invention is directed to a AR -expressing recurrent/ metastatic salivary gland cancers method of treating, suppressing , reducing the incidence , was confirmed to improve progression free survival and reducing the severity , or inhibiting the progression of lung overall survival endpoints . In another embodiment, the cancer comprising administering a therapeutically effective SARDs of this invention are used for treating salivary gland amount of a compound of formulas I - VII , IA -IB , and cancer. IIA - IIB or its isomer, pharmaceutically acceptable salt , [ 0589 ] Kawahara et al. (Oncotarget , 2015, 6 ( 30 ), 29860 pharmaceutical product, polymorph , hydrate or any combi 29876 ) demonstrated that ELK1 inhibition , together with nation thereof. In another embodiment, the compound is any AR inactivation , has the potential of being a therapeutic one of compounds 13 -21 , 49 , 50 and 17a . In one embodi approach for bladder cancer. McBeth et al. ( Int. J Endocri ment, the lung cancer is non -small cell lung cancer nology , 2015 , Vol 2015 1 - 10 ) suggested that the combination (NSCLC ) . of anti -androgen therapy plus glucocorticoids since bladder [ 0582] In one embodiment , this invention is directed to a cancer is believed to have an inflammatory etiology. In method of treating, suppressing, reducing the incidence , another embodiment, the SARDs of this invention are used reducing the severity , or inhibiting the progression of a for treating bladder cancer . central nervous system cancer comprising administering a [0590 ] In one embodiment, the invention is directed to a therapeutically effective amount of a compound of formulas method of treating , suppressing , reducing the incidence , I - VII , IA - IB , and IIA - IIB or its isomer , pharmaceutically reducing the severity , or inhibiting the progression of AR acceptable salt , pharmaceutical product, polymorph , hydrate expressing cancer in a subject , comprising administering to or any combination thereof. In another embodiment, the said subject a therapeutically effective amount of compound compound is any one of compounds 13 - 21 , 49 , 50 and 17a . 17 [0583 ] In one embodiment, this invention is directed to a method of treating , suppressing , reducing the incidence , reducing the severity , or inhibiting the progression of colon 17 cancer comprising administering a therapeutically effective amount of a compound of formulas I- VII , IA -IB , and IIA - IIB or its isomer , pharmaceutically acceptable salt , pharmaceutical product, polymorph , hydrate or any combi nation thereof. In another embodiment , the compound is any NC one of compounds 13 - 21 , 49, 50 and 17a . [0584 ] In one embodiment, this invention is directed to a method of treating, suppressing , reducing the incidence , Fac reducing the severity , or inhibiting the progression of mela noma comprising administering a therapeutically effective amount of a compound of formulas I - VII, IA - IB , and IIA - IIB or its isomer , pharmaceutically acceptable salt , or its isomer, pharmaceutically acceptable salt, pharmaceu pharmaceutical product, polymorph , hydrate or any combi tical product, polymorph , hydrate or any combination nation thereof. In another embodiment, the compound is any thereof. one of compounds 13 -21 , 49 , 50 and 17a . [ 0591 ] In one embodiment, AR -expressing cancer is a [0585 ] SARDs of this invention may also be useful for the cancer associated with partial androgen insensitivity syn treating of non -hormone - dependent cancers . Non -hormone dromes (PAIS ), cancer of the fallopian tubes or peritoneum , dependent cancers include liver, salivary duct, etc . salivary gland cancer, esophageal cancer , bladder cancer, [0586 ] In one embodiment, the SARDs of this invention melanoma, mantle cell lymphoma, hepatocellular carci are used for treating gastric cancer . In another embodiment, noma, renal cell carcinoma , non - small cell lung cancer the SARDs of this invention are used for treating salivary (NSCLC ) , gastric cancer, and / or colon cancer. In one US 2019 /0040000 A1 Feb . 7 , 2019 40 embodiment, the cancer associated with partial androgen [0596 ] In one embodiment, this invention provides a insensitivity syndromes ( PAIS ) is gonadal tumors and /or method of treating a subject suffering from a wound , or seminoma . reducing the incidence of, or mitigating the severity of , or [0592 ] In one embodiment, this invention is directed to a enhancing or hastening healing of a wound in a subject, the method of treating, suppressing , reducing the incidence , method comprises administering to said subject a therapeu reducing the severity , or inhibiting the progression of amyo tically effective amount of a compound of formulas I - VII , trophic lateral sclerosis ( ALS ) in a subject , comprising IA - IB , and IIA - IIB or its isomer , pharmaceutically accept administering a therapeutically effective amount of the com able salt , pharmaceutical product, polymorph , hydrate or pound of formulas I - VII, IA - IB , and IIA - IIB or its isomer, pharmaceutically acceptable salt, pharmaceutical product , any combination thereof. In another embodiment, the com polymorph , hydrate or any combination thereof. In another pound is any one of compounds 13 -21 , 49, 50 and 17a . embodiment, the compound is any one of compounds 13 -21 , [0597 ] In one embodiment, this invention provides a 49 , 50 and 17a . method of treating a subject suffering from a burn , or [0593 ] In one embodiment, this invention is directed to a reducing the incidence of, or mitigating the severity of, or method of treating, suppressing , reducing the incidence , enhancing or hastening healing of a burn in a subject, the reducing the severity , or inhibiting the progression of amyo method comprises administering to said subject a therapeu trophic lateral sclerosis ( ALS ) in a subject , comprising tically effective amount of a compound of formulas I -VII , administering to said subject a therapeutically effective IA , IIA or its isomer, pharmaceutically acceptable salt , amount of compound 17 pharmaceutical product, polymorph , hydrate or any combi nation thereof. In another embodiment, the compound is any one of compounds 13- 21 , 49 , 50 and 17a . [ 0598 ] Wounds and / or ulcers are normally found protrud ing from the skin or on a mucosal surface or as a result of an infarction in an organ . A wound may be a result of a soft tissue defect or a lesion or of an underlying condition . In one embodiment, the term " wound ” denotes a bodily injury with disruption of the normal integrity of tissue structures . The term is also intended to encompass the terms “ sore ” , Fac NH TOH “ lesion ” , “ necrosis ” and “ ulcer” . In one embodiment, the term “ sore ” refers to any lesion of the skin or mucous membranes and the term " ulcer ” refers to a local defect, or or its isomer , pharmaceutically acceptable salt , pharmaceu excavation , of the surface of an organ or tissue , which is tical product, polymorph , hydrate or any combination produced by the sloughing of necrotic tissue . Lesion gen thereof. erally relates to any tissue defect. Necrosis is related to dead [ 0594 ] In one embodiment, the invention is directed to a tissue resulting from infection , injury , inflammation or method of treating abdominal aortic aneurysm ( AAA ) in a infarctions . All of these are encompassed by the term subject, comprising administering to said subject a thera " wound ” , which denotes any wound at any particular stage peutically effective amount of compound 17 in the healing process including the stage before any healing has initiated or even before a specific wound like a surgical incision is made (prophylactic treatment) . 17 [0599 ] Examples of wounds which can be prevented and or treated in accordance with the present invention are , e . g . , aseptic wounds, contused wounds, incised wounds, lacer ated wounds , non -penetrating wounds ( i. e . wounds in which NC . there is no disruption of the skin but there is injury to underlying structures ) , open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, sub cutaneous wounds , etc . Examples of sores are bed sores , F3C NH canker sores, chrome sores, cold sores , pressure sores etc . Examples of ulcers are , e . g . , peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer , diabetic ulcer, hypertensive isch or its isomer , pharmaceutically acceptable salt, pharmaceu emic ulcer, stasis ulcer , ulcus cruris ( venous ulcer ) , sublin tical product, polymorph , hydrate or any combination gual ulcer , submucous ulcer, symptomatic ulcer, trophic thereof. ulcer, tropical ulcer , veneral ulcer, e . g . caused by gonorrhoea 10595 ) In one embodiment, this invention is directed to a ( including urethritis , endocervicitis and proctitis ) . Condi method of treating, suppressing , reducing the incidence , tions related to wounds or sores which may be successfully reducing the severity , or inhibiting the progression of uterine treated according to the invention are burns, anthrax , teta fibroids in a subject, comprising administering a therapeu nus , gas gangrene , scalatina , erysipelas , sycosis barbae , tically effective amount of the compound of formulas I - VII, folliculitis , impetigo contagiosa , or impetigo bullosa , etc . IA - IB , and IIA - IIB or its isomer, pharmaceutically accept There is often a certain overlap between the use of the terms able salt, pharmaceutical product , polymorph , hydrate or “ wound ” and “ ulcer ” and “ wound ” and “ sore ” and , further any combination thereof. In another embodiment, the com more , the terms are often used at random . Therefore , as pound is any one of compounds 13- 21, 49 , 50 and 17a. mentioned above , in the present context the term “ wounds” US 2019 /0040000 A1 Feb . 7 , 2019 encompasses the term “ ulcer” , “ lesion ” , “ sore” and “ infarc Injuries on soft tissues including mucosalmembranes and /or tion ” , and the terms are indiscriminately used unless other skin are especially relevant in connection with the present wise indicated . invention . [ 0600 ] The kinds of wounds to be treated according to the [0608 ] Healing of a wound on the skin or on a mucosal invention include also i ) general wounds such as , e . g ., membrane undergoes a series of stages that results either in surgical, traumatic , infectious, ischemic , thermal, chemical repair or regeneration of the skin or mucosal membrane . In and bullous wounds ; ii ) wounds specific for the oral cavity recent years , regeneration and repair have been distin such as , e . g. , post- extraction wounds, endodontic wounds guished as the two types of healing that may occur . Regen especially in connection with treatment of cysts and eration may be defined as a biological process whereby the abscesses, ulcers and lesions of bacterial, viral or autoim architecture and function of lost tissue are completely munological origin , mechanical , chemical, thermal, infec renewed . Repair , on the other hand , is a biological process tious and lichenoid wounds; herpes ulcers, stomatitis aph whereby continuity of disrupted tissue is restored by new thosa , acute necrotising ulcerative gingivitis and burning tissues which do not replicate the structure and function of mouth syndrome are specific examples ; and iii ) wounds on the lost ones . the skin such as, e .g ., neoplasm , burns (e . g . chemical , [ 0609 ] The majority of wounds heal through repair, mean thermal) , lesions ( bacterial , viral, autoimmunological) , bites ing that the new tissue formed is structurally and chemically and surgical incisions. Another way of classifying wounds is unlike the original tissue (scar tissue) . In the early stage of as i) small tissue loss due to surgical incisions, minor the tissue repair , one process which is almost always abrasions and minor bites , or as ii ) significant tissue loss . involved is the formation of a transient connective tissue in The latter group includes ischemic ulcers , pressure sores , the area of tissue injury . This process starts by formation of fistulae, lacerations, severe bites, thermal burns and donor a new extracellular collagen matrix by fibroblasts . This new site wounds ( in soft and hard tissues ) and infarctions . extracellular collagen matrix is then the support for a [ 0601] In other aspects of the invention , the wound to be connective tissue during the final healing process. The final prevented and / or treated is selected from the group consist healing is, in most tissues , a scar formation containing ing of aseptic wounds, infarctions, contused wounds , incised connective tissue . In tissues which have regenerative prop wounds , lacerated wounds , non -penetrating wounds , open erties , such as , e . g . , skin and bone, the final healing includes wounds, penetrating wounds, perforating wounds, puncture regeneration of the original tissue. This regenerated tissue wounds , septic wounds and subcutaneous wounds . has frequently also some scar characteristics , e . g . a thick [0602 ] Other wounds which are of importance in connec ening of a healed bone fracture . tion with the present invention are wounds like ischemic 10610 ]. Under normal circumstances , the body provides ulcers, pressure sores, fistulae , severe bites, thermal burns mechanisms for healing injured skin or mucosa in order to and donor site wounds . restore the integrity of the skin barrier or the mucosa . The 0603 ] Ischemic ulcers and pressure sores are wounds, repair process for even minor ruptures or wounds may take which normally only heal very slowly and especially in such a period of time extending from hours and days to weeks. cases an improved and more rapid healing is of course of However, in ulceration , the healing can be very slow and the great importance for the patient. Furthermore , the costs wound may persist for an extended period of time, i. e. involved in the treatment of patients suffering from such months or even years . wounds are markedly reduced when the healing is improved [0611 ] Burns are associated with reduced testosterone and takes place more rapidly . levels, and hypogonadism is associated with delayed wound [ 0604 ] Donor site wounds are wounds which e. g . occur in healing . In one embodiment, the methods of this invention , connection with removal of hard tissue from one part of the provide for treating a subject suffering from a wound or a body to another part of the body e . g . in connection with burn via the administration of a SARD according to this transplantation . The wounds resulting from such operations invention . In one embodiment, the SARD promotes resolv are very painful and an improved healing is therefore most ing of the burn or wound , or in another embodiment, valuable . participates in the healing process of a burn or a wound , or [ 0605 ] The term “ skin ” is used in a very broad sense in another embodiment, treats a secondary complication of embracing the epidermal layer of the skin and in those cases a burn or wound . where the skin surface is more or less injured also the dermal 10612 ] In one embodiment, the treatment of burns or layer of the skin . Apart from the stratum corneum , the wounds further incorporates the use of additional growth epidermal layer of the skin is the outer ( epithelial) layer and factors like epidermal growth factor ( EGF) , transforming the deeper connective tissue layer of the skin is called the growth factor - a ( TGF - a ), platelet derived growth factor dermis . (PDGF ) , fibroblast growth factors (FGFs ) including acidic [ 0606 ] Since the skin is the most exposed part of the body, fibroblast growth factor ( a - FGF) and basic fibroblast growth it is particularly susceptible to various kinds of injuries such factor ( B -FGF ), transforming growth factor- B ( TGF - B ) and as , e . g ., ruptures, cuts , abrasions, burns and frostbites or insulin like growth factors ( IGF - 1 and IGF - 2 ) , or any injuries arising from various diseases . Furthermore , much combination thereof, which are promoters ofwound healing . skin is often destroyed in accidents. However, due to the [ 0613] Wound healing may be measured by many proce important barrier and physiologic function of the skin , the dures known in the art , including wound tensile strength , integrity of the skin is important to the well -being of the hydroxyproline or collagen content, procollagen expression , individual, and any breach or rupture represents a threat that and re - epithelialization . As an example , a SARD as must be met by the body in order to protect its continued described herein is administered orally or topically , at a existence . dosage of about 0 . 1 - 1 mg per day. Therapeutic effectiveness [ 0607 ] Apart from injuries on the skin , injuries may also is measured as effectiveness in enhancing wound healing . be present in all kinds of tissues ( i. e . soft and hard tissues ). Enhanced wound healing may be measured by known US 2019 /0040000 A1 Feb . 7 , 2019 techniques such as decrease in healing time, increase in herein refers to that amount which provides a therapeutic collagen density , increase in hydroxyproline , reduction in effect for a given condition and administration regimen . complications , increase in tensile strength , and increased [0618 ] As used herein , the term “ administering ” refers to cellularity of scar tissue . bringing a subject in contact with a compound of the present [0614 ] In one embodiment , the terms “ treating ” or “ treat invention . As used herein , administration can be accom ment” includes preventative as well as disorder remitative plished in vitro , i . e . in a test tube, or in vivo , i. e . in cells or treatment. The terms “ reducing ” , “ suppressing ” and “ inhib tissues of living organisms, for example humans. In one iting ” have their commonly understood meaning of lessen embodiment, the present invention encompasses adminis ing or decreasing , in another embodiment , or delaying, in tering the compounds of the present invention to a male another embodiment, or reducing, in another embodiment subject . In one embodiment, the present invention encom the incidence , severity or pathogenesis of a disease , disorder passes administering the compounds of the present invention or condition . In some embodiments , the term treatment to a female subject . refers to delayed progression of, prolonged remission of, 10619 ). This invention provides , in other embodiments , reduced incidence of, or amelioration of symptoms associ pharmaceutical products of the compounds described herein . ated with the disease , disorder or condition . In one embodi The term “ pharmaceutical product ” refers , in other embodi ment, the terms " treating ” “ reducing ” , “ suppressing ” or ments , to a composition suitable for pharmaceutical use " inhibiting ” refer to a reduction in morbidity , mortality , or a (pharmaceutical composition ) , for example , as described combination thereof, in association with the indicated dis herein . ease , disorder or condition . In one embodiment, the term 10620 ] The compounds of the invention can be adminis " progression ” refers to an increasing in scope or severity , tered alone or as an active ingredient of a formulation . Thus , advancing , growing or becoming worse . The term “ recur the present invention also includes pharmaceutical compo rence ” means, in another embodiment , the return of a sitions of compounds of formulas I- VII, IA - IB , and IIA - IIB , disease after a remission . In one embodiment, the methods containing , for example , one or more pharmaceutically of treatment of the invention reduce the severity of the acceptable carriers. disease, or in another embodiment, symptoms associated [0621 ] Numerous standard references are available that with the disease , or in another embodiment, reduces the describe procedures for preparing various formulations suit number of biomarkers expressed during disease . able for administering the compounds according to the [ 0615 ] In one embodiment, the term “ treating ” and its invention . Examples of potential formulations and prepara included aspects , refers to the administration to a subject tions are contained , for example, in the Handbook of Phar with the indicated disease , disorder or condition , or in some maceutical Excipients , American Pharmaceutical Associa embodiments , to a subject predisposed to the indicated tion (current edition ); Pharmaceutical Dosage Forms: disease , disorder or condition . The term “ predisposed to ” is Tablets (Lieberman , Lachman and Schwartz , editors ) cur to be considered to refer to , inter alia , a genetic profile or rent edition , published by Marcel Dekker, Inc. , as well as familial relationship which is associated with a trend or Remington ' s Pharmaceutical Sciences ( Arthur Osol, editor ) , statistical increase in incidence , severity , etc . of the indicated 1553 - 1593 ( current edition ) . disease . In some embodiments , the term " predisposed to ” is [0622 ] The mode of administration and dosage form are to be considered to refer to inter alia , a lifestyle which is closely related to the therapeutic amounts of the compounds associated with increased risk of the indicated disease . In or compositions which are desirable and efficacious for the some embodiments , the term “ predisposed to ” is to be given treatment application . considered to refer to inter alia , the presence of biomarkers [0623 ] The pharmaceutical compositions containing a which are associated with the indicated disease , for example , compound of this invention can be administered to a subject in cancer, the term “ predisposed to ” the cancer may com by any method known to a person skilled in the art , such as prise the presence of precancerous precursors for the indi orally, parenterally, intravascularly , paracancerally , trans cated cancer. muco sally , transdermally , intramuscularly , intranasally , [0616 ] In some embodiments , the term “ reducing the intravenously , intradermally , subcutaneously , sublingually , pathogenesis” is to be understood to encompass reducing intraperitoneally , intraventricularly , intracranially , intravagi tissue damage , or organ damage associated with a particular nally , by inhalation , rectally , intratumorally , or by any means disease , disorder or condition . In another embodiment, the in which the composition can be delivered to tissue ( e . g . , term “ reducing the pathogenesis ” is to be understood to needle or catheter ) . Alternatively , topical administration encompass reducing the incidence or severity of an associ may be desired for application to dermal , ocular, or mucosal ated disease , disorder or condition , with that in question . In surfaces . Another method of administration is via aspiration another embodiment, the term “ reducing the pathogenesis ” or aerosol formulation . Further, in another embodiment, the is to be understood to encompass reducing the number of pharmaceutical compositions may be administered topically associated diseases, disorders or conditions with the indi to body surfaces , and are thus formulated in a form suitable cated , or symptoms associated thereto . for topical administration . Suitable topical formulations include gels, ointments , creams, lotions , drops and the like. Pharmaceutical Compositions For topical administrations, the compounds of this invention [ 0617] In some embodiments , this invention provides or their physiologically tolerated derivatives such as salts , methods of use which comprise administering a composition esters , N - oxides , and the like are prepared and applied as comprising the described compounds. As used herein , “ phar solutions, suspensions , or emulsions in a physiologically maceutical composition ” means a " therapeutically effective acceptable diluent with or without a pharmaceutical carrier. amount of the active ingredient, i. e . the compound of this [0624 ] Suitable dosage forms include but are not limited to invention , together with a pharmaceutically acceptable car oral, rectal, sub -lingual , mucosal, nasal , ophthalmic , subcu rier or diluent . A " therapeutically effective amount” as used taneous, intramuscular , intravenous, transdermal, spinal, US 2019 /0040000 A1 Feb . 7 , 2019 43 intrathecal, intra -articular , intra -arterial , sub -arachinoid , Examples of non -androgenic alopecia include alopecia bronchial , lymphatic , and intra -uterile administration , and areata , alopecia due to radiotherapy or chemotherapy, scar other dosage forms for systemic delivery of active ingredi ring alopecia , stress related alopecia , etc . As used in this ents . In some embodiments , formulations suitable for oral application “ alopecia ” refers to partial or complete hair loss administration are preferred . In some applications, formu on the scalp . lations suitable for topical administration are preferred . [0632 ] Thus, the compounds of formulas I- VII , IA -IB , and [0625 ] Topical Administration : IIA - IIB can be applied topically to the scalp and hair to [0626 ] In a typical embodiment, the compounds of for prevent, or alleviate balding . Further , the compound of mulas I- VII, IA - IB , and IIA - IIB are administered topically . formulas I - VII, IA - IB , and IIA - IIB can be applied topically [0627 ] In one embodiment, the invention is directed to a in order to induce or promote the growth or regrowth of hair topical pharmaceutical composition comprising compound on the scalp . 17 0633 ] In a further embodiment of the invention , a com pound of formulas I - VII , IA - IB , and IIA - IIB is applied topically in order to prevent the growth of hair in areas 17 where such hair growth in not desired . One such use will be to alleviate hirsutism . Hirsutism is excessive hair growth in areas that typically do not have hair ( i . e . , a female face ). Such inappropriate hair growth occurs most commonly in women and is frequently seen at menopause . The topical NO administration of the compounds of formulas I - VII, IA - IB , and IIA - IIB will alleviate this condition leading to a reduc tion , or elimination of this inappropriate , or undesired , hair F3C growth . OH [ 0634 ] The compounds of formulas I - VII , IA - IB , and IIA - IIB may also be used topically to decrease sebum or its isomer , pharmaceutically acceptable salt , pharmaceu production . Sebum is composed of triglycerides, wax esters , tical product, polymorph , hydrate or any combination fatty acids , sterol esters and squalene . Sebum is produced in thereof, and a pharmaceutically acceptable carrier . the acinar cells of the sebaceous glands and accumulates as [0628 ] In one embodiment , the topical pharmaceutical these cells age . At maturation , the acinar cells lyse , releasing composition is in the form of a solution , lotion , salve, cream , sebum into the luminal duct so that it may be deposited on ointment, liposome, spray, gel, foam , roller stick , cleansing the surface of the skin . soap or bar, emulsion , mousse , aerosol, shampoo , or any [0635 ) In some individuals , an excessive quantity of combination thereof . sebum is secreted onto the skin . This can have a number of [0629 ] Topical administration is especially appropriate for adverse consequences. It can exacerbate acne , since sebum hirsutism , alopecia , acne and excess sebum . The dose will is the primary food source for Propionbacterium acnes, the vary , but as a general guideline , the compound will be causative agent of acne . It can cause the skin to have a present in a dermatologically acceptable carrier in an greasy appearance , typically considered cosmetically unap amount of from about 0 .01 to 50 w / w % , and more typically pealing . from about 0 . 1 to 10 w / w % . Typically, the dermatological [0636 ] Formation of sebum is regulated by growth factors preparation will be applied to the affected area from 1 to 4 and a variety of hormones including androgens. The cellular times daily . “ Dermatologically acceptable ” refers to a carrier and molecular mechanism by which androgens exert their which may be applied to the skin or hair, and which will influence on the sebaceous gland has not been fully eluci allow the drug to diffuse to the site of action . More specifi dated . However, clinical experience documents the impact cally , it refers to a site where inhibition of androgen receptor androgens have on sebum production . Sebum production is or degradation of androgen receptor is desired . significantly increased during puberty , when androgen levels [ 0630 ] In a further embodiment, the compounds of for are their highest. Thus, the compounds of formulas IA - IB , mulas I -VII , IA - IB , and IIA - IIB are used topically to relieve and IIA - IIB inhibit the secretion of sebum and thus reduce alopecia , especially androgenic alopecia . Androgens have a the amount of sebum on the surface of the skin . The profound effect on both hair growth and hair loss . In most compounds of formulas I - VII , IA - IB , and IIA - IIB can be body sites , such as the beard and pubic skin , androgens used to treat a variety of dermal diseases such as acne or stimulate hair growth by prolonging the growth phase of the seborrheic dermatitis . hair cycle ( anagen ) and increasing follicle size . Hair growth [0637 ] In addition to treating diseases associated with on the scalp does not require androgens but, paradoxically , excess sebum production , the compounds of formulas I -VII , androgens are necessary for the balding on the scalp in IA - IB , and IIA - IIB can also be used to achieve a cosmetic genetically predisposed individuals (androgenic alopecia ) effect . Some consumers believe that they are afflicted with where there is a progressive decline in the duration of overactive sebaceous glands . They feel that their skin is oily anagen and in hair follicle size . Androgenic alopecia is also and thus unattractive . These indivivals can utilize the com common in women where it usually presents as a diffuse hair pounds of formulas I - VII, IA - IB , and IIA - IIB to decrease the loss rather than showing the patterning seen in men . amount of sebum on their skin . Decreasing the secretion of [0631 ] While the compounds of formulas I - VII , IA - IB , sebum will alleviate oily skin in indviduals afflicted with and IIA - IIB will most typically be used to alleviate andro such conditions. genic alopecia , the invention is not limited to this specific [ 0638 ] The compounds of formulas I - VII , IA - IB , and condition . The compounds of formulas I -VII , IA - IB , and IIA - IIB of this invention will typically be administered IIA - IIB may be used to alleviate any type of alopecia . topically . As used herein , topical refers to application of the US 2019 /0040000 A1 Feb . 7 , 2019 44 compounds of formulas IA - IB , and IIA - IIB ( and optional solid formuations, a liquid carrier or diluent for liquid carrier ) directly to the skin and /or hair. The topical compo formulations, or mixtures thereof. sition according to the present invention can be in the form 10646 ) Solid carriers / diluents include , but are not limited of solutions, lotions, salves, creams, ointments , liposomes , to , a gum , a starch ( e . g . corn starch , pregeletanized starch ) , sprays , gels , foams, roller sticks, and any other formulation a sugar ( e . g ., lactose, mannitol, sucrose , dextrose ) , a cellu routinely used in dermatology . losic material ( e . g . microcrystalline cellulose ) , an acrylate [ 0639 ] Thus, a further embodiment relates to cosmetic or ( e . g . polymethylacrylate ), calcium carbonate , pharmaceutical compositions, in particular dermatological oxide, talc , or mixtures thereof. compositions , which comprise at least one of the compounds 10647 ) Oral Administration and Parenteral: corresponding to formulas I - VII, IA - IB , and IIA - IIB above . [ 0648 ] In preparing the compositions in oral dosage form , Such dermatological compositions will contain from any of the usual pharmaceutical media may be employed . 0 .001 % to 10 % w / w % of the compounds in admixture with Thus , for liquid oral preparations , such as , for example , a dermatologically acceptable carrier , and more typically , suspensions, elixirs and solutions, suitable carriers and addi from 0 . 1 to 5 w / w % of the compounds . Such compositions tives include water, glycols , oils , alcohols , flavoring agents , will typically be applied from 1 to 4 times daily . The reader ' s preservatives , coloring agents and the like . For solid oral attention is directed to Remington ' s Pharmaceutical Sci preparations such as, for example , powders , capsules and ence, Edition 17 , Mark Publishing Co ., Easton , Pa . for a tablets , suitable carriers and additives include starches, discussion of how to prepare such formulations. sugars , diluents , granulating agents , lubricants , binders , dis [ 0640 ] The compositions according to the invention can integrating agents and the like . Due to their ease in admin also consist of solid preparations constituting cleansing istration , tablets and capsules represent the most advanta soaps or bars. These compositions are prepared according to geous oral dosage unit form . If desired , tablets may be sugar the usual methods . coated or enteric coated by standard techniques . [ 0641 ] The compounds of formulas I -VII , IA - IB , and [ 0649 ] For parenteral formulations, the carrier will usually IIA - IIB can also be used for the hair in the form of aqueous, comprise sterile water , though other ingredients , for alcoholic or aqueous - alcoholic solutions, or in the form of example , ingredients that aid solubility or for preservation , creams, gels , emulsions or mousses , or alternatively in the may be included . Injectable solutions may also be prepared form of aerosol compositions also comprising a propellant in which case appropriate stabilizing agents may be under pressure . The composition according to the invention employed . can also be a hair care composition , and in particular a 10650 ] In some applications, it may be advantageous to shampoo , a hair -setting lotion , a treating lotion , a styling utilize the active agent in a “ vectorized ” form , such as by cream or gel, a dye composition , a lotion or gel for prevent encapsulation of the active agent in a liposome or other ing hair loss , etc . The amounts of the various constituents in encapsulant medium , or by fixation of the active agent, e . g . , the dermatological compositions according to the invention by covalent bonding, chelation , or associative coordination , are those conventionally used in the fields considered . on a suitable biomolecule , such as those selected from [0642 ] The medicinal and cosmetics containing the com proteins , lipoproteins , glycoproteins, and polysaccharides . pounds of formulas I - VII , IA - IB , and IIA - IIB will typically [ 0651 ] Treatment methods of the present invention using be packaged for retail distribution ( i. e ., an article of manu formulations suitable for oral administration may be pre facture ) . Such articles will be labeled and packaged in a sented as discrete units such as capsules, cachets, tablets , or manner to instruct the patient how to use the product . Such lozenges, each containing a predetermined amount of the instructions will include the condition to be treated , duration active ingredient as, for example , a powder or granules . of treatment , dosing schedule , etc . Optionally, a suspension in an aqueous liquor or a non [0643 ] Antiandrogens , such as finasteride or flutamide , aqueous liquid may be employed , such as a syrup , an elixir , have been shown to decrease androgen levels or block an emulsion , or a draught. androgen action in the skin to some extent but suffer from [0652 ] A tablet may be made by compression or molding , undesirable systemic effects . An alternative approach is to or wet granulation , optionally with one or more accessory topically apply a selective androgen receptor degrader ingredients. Compressed tablets may be prepared by com (SARD ) compound to the affected areas. In one embodi pressing in a suitable machine, with the active compound ment, such a SARD compound would exhibit potent but being in a free - flowing form such as a powder or granules local inhibition of AR activity . In another embodiment, the which optionally is mixed with , for example , a binder , SARD compound would exhibit potent but local degrada disintegrant, lubricant , inert diluent, surface active agent, or tion of AR activity . In another embodiment, the SARD discharging agent. Molded tablets comprised of a mixture of compound would not penetrate to the systemic circulation of the powdered active compound with a suitable carrier may the subject . In another embodiment, the SARD compound be made by molding in a suitable machine . would be rapidly metabolized upon entry into the blood , [0653 ] A syrup may be made by adding the active com limiting systemic exposure . pound to a concentrated aqueous solution of a sugar, for [0644 ] To prepare such pharmaceutical dosage forms, the example sucrose , to which may also be added any accessory active ingredient may be mixed with a pharmaceutical ingredient( s ) . Such accessory ingredient( s ) may include carrier according to conventional pharmaceutical com flavorings, suitable preservative , agents to retard crystalli pounding techniques. The carrier may take a wide variety of zation of the sugar, and agents to increase the solubility of forms depending on the form of preparation desired for any other ingredient, such as a polyhydroxy alcohol, for administration . example glycerol or sorbitol. [ 0645 ] As used herein " pharmaceutically acceptable car 0654 Formulations suitable for parenteral administration riers or diluents ” are well known to those skilled in the art. may comprise a sterile aqueous preparation of the active The carrier or diluent may be a solid carrier or diluent for compound , which preferably is isotonic with the blood of the US 2019 /0040000 A1 Feb . 7 , 2019 45 recipient (e .g . , physiological saline solution ). Such formu - per day, 100 - 250 mg per day , 125 - 300 mg per day, 20 - 50 mg lations may include suspending agents and thickening agents per day, 5 - 50 mg per day, 200 - 500 mg per day, 125 - 500 mg and liposomes or other microparticulate systems which are per day, 500 -1000 mg per day , 200 - 1000 mg per day , designed to target the compound to blood components or one 1000 - 2000 mg per day, 1000 - 3000 mg per day, 125 - 3000 mg or more organs . The formulations may be presented in per day, 2000 -3000 mg per day, 300 - 1500 mg per day or unit - dose or multi - dose form . 100 - 1000 mg per day. In one embodiment, a compound of [ 0655 ] Parenteral administration may comprise any suit this invention is administered at a dosage of 25 mg per day . able form of systemic delivery . Administration may for In one embodiment, a compound of this invention is admin example be intravenous , intra - arterial, intrathecal, intramus istered at a dosage of 40 mg per day. In one embodiment, a cular, subcutaneous , intramuscular , intra - abdominal ( e . g . , compound of this invention is administered at a dosage of 50 intraperitoneal) , etc ., and may be affected by infusion pumps mg per day. In one embodiment, a compound of this ( external or implantable ) or any other suitable means appro invention is administered at a dosage of 67 . 5 mg per day . In priate to the desired administration modality . one embodiment, a compound of this invention is adminis [0656 ] Nasal and other mucosal spray formulations ( e . g . tered at a dosage of 75 mg per day . In one embodiment, a inhalable forms) can comprise purified aqueous solutions of compound of this invention is administered at a dosage of 80 the active compounds with preservative agents and isotonic mg per day . In one embodiment, a compound of this agents . Such formulations are preferably adjusted to a pH invention is administered at a dosage of 100 mg per day . In and isotonic state compatible with the nasal or other mucous one embodiment , a compound of this invention is adminis membranes. Alternatively , they can be in the form of finely tered at a dosage of 125 mg per day. In one embodiment, a divided solid powders suspended in a gas carrier . Such compound of this invention is administered at a dosage of formulations may be delivered by any suitable means or 250 mg per day . In one embodiment, a compound of this method, e . g ., by nebulizer , atomizer, metered dose inhaler, invention is administered at a dosage of 300 mg per day . In or the like . one embodiment, a compound of this invention is adminis [0657 ] Formulations for rectal administration may be pre tered at a dosage of 500 mg per day . In one embodiment, a sented as a suppository with a suitable carrier such as cocoa compound of this invention is administered at a dosage of butter , hydrogenated fats , or hydrogenated fatty carboxylic 600 mg per day . In one embodiment, a compound of this acids. invention is administered at a dosage of 1000 mg per day . In [ 0658] Transdermal formulations may be prepared by one embodiment, a compound of this invention is adminis incorporating the active agent in a thixotropic or gelatinous tered at a dosage of 1500 mg per day . In one embodiment, carrier such as a cellulosic medium , e . g . , methyl cellulose or a compound of this invention is administered at a dosage of hydroxyethyl cellulose , with the resulting formulation then 2000 mg per day . In one embodiment, a compound of this being packed in a transdermal device adapted to be secured invention is administered at a dosage of 2500 mg per day. In in dermal contact with the skin of a wearer. one embodiment, a compound of this invention is adminis [ 0659 ] In addition to the aforementioned ingredients , for tered at a dosage of 3000 mg per day. In another embodi mulations of this invention may further include one or more accessory ingredient( s ) selected from , for example , diluents , ment, the compound is any one of compounds 13 - 21, 49 , 50 buffers , flavoring agents , binders, disintegrants , surface and 17a . active agents , thickeners, lubricants , preservatives ( includ [ 0664 ] In one embodiment, the methods of this invention ing antioxidants ) , and the like . may comprise administration of a compound of this inven [0660 ] The formulations of the present invention can have tion at various dosages . In one embodiment, a compound of immediate release, sustained release, delayed - onset release this invention is administered at a dosage of 3 mg . In or any other release profile known to one skilled in the art . additional embodiments , a compound of this invention is 0661] It is to be understood that this invention encom administered at a dosage of 10 mg, 30 mg, 40 mg, 50 mg, passes any embodiment of a compound as described herein , 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, which in some embodiments is referred to as " a compound 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 of this invention ” . mg, 2500 mg or 3000 mg. In another embodiment, the [ 0662 ] For administration to mammals , and particularly compound is any one of compounds 13 - 21 , 49, 50 and 17a . humans, it is expected that the physician will determine the [ 0665 ] In one embodiment, the methods of this invention actual dosage and duration of treatment, which will be most may comprise administration of a compound of this inven suitable for an individual and can vary with the age , weight tion at various dosages . In one embodiment, a compound of and response of the particular individual. this invention is administered at a dosage of 0 . 1 mg/ kg /day . 10663 ] In one embodiment, the methods of this invention In additional embodiments , a compound of this invention is may comprise administration of a compound of this inven administered at a dosage between 0 . 2 to 30 mg/ kg / day , or tion at various dosages . In one embodiment, a compound of 0 . 2 mg/ kg / day , 0 . 3 mg/ kg / day , 1 mg/ kg / day , 3 mg/kg /day , 5 this invention is administered at a dosage of 1 - 3000 mg per mg/ kg / day , 10 mg/ kg /day , 20 mg/ kg /day , 30 mg/ kg /day , 50 day. In additional embodiments , a compound of this inven mg/ kg /day or 100 mg/ kg / day . tion is administered at a dose of 1 - 10 mg per day, 3 - 26 mg [0666 ] In one embodiment, the methods of this invention per day, 3 -60 mg per day, 3 - 16 mg per day, 3 - 30 mg per day, provide for the use of a pharmaceutical composition com 10 - 26 mgper day, 15 -60 mg, 50 -100 mgper day, 50 - 200mg prising a compound of formulas I- VII, IA - IB , and IIA - IIB . US 2019 /0040000 A1 Feb . 7 , 2019 46

In additional embodiments , the methods of this invention are EXAMPLES provided for use of a pharmaceutical composition compris ing a compound of formula I, formula IA , formula IB , Example 1 formula II , formula IIA , formula IIB , formula III , formula IV , or formula V , formula VI, or formula VII, or any one of Synthesis of ( S ) - 3 - (Substituted phenyl amino ) - N - ( 4 compounds 13- 21 , 49 , 50 and 17a. nitro - or 4 - cyano - 3 - ( trifluoromethyl) phenyl) - 2 [ 0667 ] In certain embodiment, the pharmaceutical com hydroxy - 2 -methylpropanamides (Compounds position is a solid dosage form . In another embodiment, the 12 - 19 ) pharmaceutical composition is a tablet . In another embodi ment, the pharmaceutical composition is a capsule . In [0673 ] another embodiment, the pharmaceutical composition is a solution . In another embodiment, the pharmaceutical com position is a transdermal patch . Scheme 1 . Synthesis of ( S )- 3 -( substituted phenyl amino ) -N (4 - nitro - or 4 - cyano -3 -( trifluoromethyl) phenyl ) - 2 -hydroxy -2 [ 0668 ] In one embodiment, use of a compound of this methylpropanamides ( 12 - 19 ). invention or a composition comprising the same, will have utility in inhibiting , suppressing , enhancing or stimulating a desired response in a subject, as will be understood by one OH skilled in the art . In another embodiment, the compositions 2N NaOH may further comprise additional active ingredients , whose + activity is useful for the particular application for which the NH acetone compound of this invention is being administered . 1 , D -proline methacryloyl [ 0669 ] For administration to mammals , and particularly chloride humans, it is expected that the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age , weight, 11 genetics and / or response of the particular individual . ?? NBS HBr [0670 ] In some embodiments , any of the compositions of DMF this invention will comprise a compound of this invention , in any form or embodiment as described herein . In some embodiments , any of the compositions of this invention will consist of a compound of this invention , in any form or embodiment as described herein . In some embodiments , of OH the compositions of this invention will consist essentially of ?? , Br a compound of this invention , in any form or embodiment as described herein . In some embodiments , the term “ com prise ” refers to the inclusion of the indicated active agent, such as the compound of this invention , as well as inclusion of other active agents, and pharmaceutically acceptable Fzc NH2 ?? carriers, excipients, emollients , stabilizers , etc . , as are 2 HO . 1 . SOCl2 , known in the pharmaceutical industry. In some embodi Br THF ments, the term " consisting essentially of” refers to a com position , whose only active ingredient is the indicated active 2 . Et3N , ingredient, however, other compounds may be included 5 R = NO2 THF which are for stabilizing, preserving , etc . the formulation , 6 R = CN but are not involved directly in the therapeutic effect of the ? ?? K2CO3, indicated active ingredient. In some embodiments , the term Dot acetone " consisting essentially of" may refer to components which Br facilitate the release of the active ingredient. In some reflux embodiments , the term “ consisting” refers to a composition , which contains the active ingredient and a pharmaceutically acceptable carrier or excipient. 7R = NO2 [0671 ] It is to be understood that any use of any of the 8 R = CN compounds as herein described may be used in the treatment Dores of any disease , disorder or condition as described herein , and represents an embodiment of this invention . In one embodi ment, the compounds are a free base , free acid , non -charged or non -complexed compound . [ 0672 ] The following examples are presented in order to 9 R = NO2 more fully illustrate the preferred embodiments of the inven 10 R = CN tion . They should in no way, however, be construed as limiting the broad scope of the invention . US 2019 /0040000 A1 Feb . 7 , 2019 47

- continued center ), 3 .57 -3 .38 (m , 2H , CH2) , 2. 27 - 2. 12 ( 1H , CH ), 1 .97 1 .72 (m , 6H , CH2, CH , Me) ; 13C NMR (75 MHz , DMSO -do ) d for major rotamer 173 .3 , 169. 1 , 140 .9 , 116 .4 , 58 .3 , 48 .7 , 1 . NaH , THF , or DMF 28 . 9 , 24 . 7 , 19. 5 : for minor rotamer 174 . 0 , 170 . 0 , 141 . 6 , Y Y 2. 9 or 10 , 0° C . to it 115 . 2 , 60 . 3 , 45 . 9 , 31 . 0 , 22 . 3 , 19 . 7 ; IR (KBr ) 3437 (OH ) , 1737 (C = O ), 1647 (CO , COOH ), 1584 , 1508 , 1459 , 1369 , X2 1348 , 1178 cm - ? ; [ a ] D20 + 80 .8° ( c = 1 , MeOH ) ; Anal. Calcd . 11 for C , H 3NO3: C 59 .00 , H 7 . 15 , N 7 .65 . Found : C 59 .13 , H X1 or/ and X2 = H , 7 . 19 , N 7 .61 . Ph , 4 - fluorophenyl Y = H , CN ( 3R , 8aR )- 3 -Bromomethyl - 3 -methyl -tetrahydro -pyr OH CHZI rolo [2 , 1 -c ][ 1, 4 ]oxazine - 1, 4- dione (3 ) F2C or [0676 ] A solution of NBS (23 . 5 g , 0 . 132 mol) in 100 mL BnBr of DMF was added dropwise to a stirred solution of the NaCO3, (methyl - acryloyl ) - pyrrolidine ( 16 .1 g, 88 mmol ) in 70 mL of Y MW DMF under argon at RT, and the resulting mixture was stirred 3 days . The solvent was removed in vacuo , and a yellow solid was precipitated . The solid was suspended in 12 R = CN , X1 = H , X2 = H , Y = CN water , stirred overnight at RT, filtered , and dried to give 18 . 6 13 R = CN , X1 = H , X2 = Ph, Y = CN g (81 % ) ( smaller weight when dried - 34 % ) of the title 14 R = CN , X1 = H , X2 = Ph , Y = CN compound as a yellow solid : mp 158 . 1 - 160 .3° C . ; 15 R = CN , X1 = Ph , X2 = H , Y = CN [0677 ] ' H NMR (300 MHz, DMSO - do) 8 4 .69 (dd , J = 9 .6 16 R = CN , X1 = H , X2 = 4 - fluorophenyl, Y = CN Hz, J = 6 . 7 Hz, 1H , CH at the chiral center ), 4 . 02 ( d , J = 11. 4 ? ?? 2 Hz, 1H , CHH , ) , 3 . 86 ( d , J = 11 . 4 Hz, 1H , CHH , ) , 3 . 53 - 3 . 24 ( m , 4H , CH ) , 2 . 30 - 2 . 20 ( m , 1H , CH ) , 2 .04 - 1 .72 ( m , ' H , F3C , ZT CH , and CH ) , 1 .56 ( s , 2H , Me) ; 13C NMR (75 MHz , DMSO - D ) & 167. 3 , 163 . 1 , 83. 9 , 57 . 2 , 45. 4 , 37 . 8 , 29. 0 , 22 . 9 , 21 . 6 ; IR (KBr ) 3474 , 1745 ( C = O ), 1687 ( C = O ) , 1448 , NC Y CN 1377 , 1360 , 1308, 1227 , 1159 , 1062 cm - 1 ; [ a ] , 26 + 124 . 5° ( c = 1 . 3 , chloroform ) ; Anal. Calcd . for C , H , BrNOZ: C 41. 24 , H 4 .61 , N 5 .34 . Found : C 41. 46 , H 4 .64 , N 5 .32 . 17 - 19 X = H , Ph , 4 - fluorophenyl ( 2R ) - 3 - Bromo - 2 -hydroxy - 2 -methylpropanoic acid Z = CH3, Bn ( 4 ) [0678 ] A mixture of bromolactone ( 18. 5 g, 71 mmol) in 300 mL of 24 % HBr was heated at reflux for 1 h . The (2R ) -1 -Methacryloylpyrrolidin -2 -carboxylic acid (2 ) resulting solution was diluted with brine ( 200 mL ), and was [ 0674 ] D -Proline ( 14 .93 g , 0 . 13 mol ) was dissolved in 71 extracted with ethyl acetate ( 100 mLx4 ) . The combined mL of 2 N NaOH and cooled in an ice bath . The resulting extracts were washed with saturated NaHCO , ( 100 mLx4 ). alkaline solution was diluted with acetone (71 mL ) . An The aqueous solution was acidified with concentrated HCl to acetone solution (71 mL ) ofmethacryloyl chloride (13 . 56 g , pH = 1 , which , in turn , was extracted with ethyl acetate ( 100 0 .13 mol) and 2 N NaOH solution ( 71 mL ) were simulta mLx4 ) . The combined organic solution was dried over neously added over 40 min to the aqueous solution of Na2SO4, filtered through Celite® , and evaporated in vacuo D -proline in an ice bath . The temperature of the mixture was to dryness . Recrystallization from toluene afforded 10 . 2 g kept at 10 - 11° C . during the addition of the methacryloyl ( 86 % ) of the desired compound as colorless crystals : mp chloride . After stirring ( 3 h , room temperature (RT ) ) , the 110 . 3 - 113 . 8° C . ; mixture was evaporated in vacuo at a temperature at 35 - 45° [ 0679 ] ' H NMR ( 300 MHz, DMSO - do) d 3 . 63 ( d , J = 10 . 1 C . to remove acetone . The resulting solution was washed Hz , 1H , CHH ,) , 3 .52 ( d, J = 10 .1 Hz , 1H , CHH ) , 1. 35 (s , 3H , with ethyl ether and was acidified to pH 2 with concentrated Me) ; IR (KBr ) 3434 (OH ) , 3300 - 2500 (COOH ) , 1730 HCl. The acidic mixture was saturated with NaCl and was ( C = O ), 1449 , 1421 , 1380 , 1292 , 1193 , 1085 cm - 1; [ a ] , 26 + extracted with EtoAc (100 mLx3 ) . The combined extracts 10 . 5° ( c = 2 .6 , MeOH ) ; Anal. Calcd . for C _H _BrOz : C 26 . 25 , were dried over Na S04, filtered through Celite® , and H 3 .86 . Found : C 26 .28 , H 3 .75 . evaporated in vacuo to give the crude product as a colorless oil . Recrystallization of the oil from ethyl ether and hexanes ( 2R ) - 3 - Bromo - N - [ 4 -cyano - 3 - ( trifluoromethyl) phe afforded 16 . 2 g (68 % ) of the desired compound as colorless nyl] -2 -hydroxy -2 -methylpropanamide ( 8 ) crystals: mp 102 . 1 - 103 .4° C . ( lit. mp 102 . 5 - 103. 5° C . ); the [0680 ] Thionyl chloride ( 46 .02 g , 0 . 39 mol) was added NMR spectrum of this compound demonstrated the exis dropwise to a cooled solution ( less than 4° C . ) of ( R ) - 3 tence of two rotamers of the title compound . bromo - 2 -hydroxy - 2 -methylpropanoic acid (51 . 13 g , 0 . 28 10675 ) ? H NMR ( 300 MHz, DMSO -06 ) 6 5 .28 ( s ) and mol) in 300 mL of THF under an argon atmosphere . The 5 . 15 ( s ) for the first rotamer , 5 . 15 ( s ) and 5 . 03 ( s ) for the resulting mixture was stirred for 3 h under the same condi second rotamer ( totally 2H for both rotamers , vinyl CH ) , tion . To this was added Et N ( 39 . 14 g , 0 . 39 mol) and stirred 4 .48 - 4 . 44 for the first rotamer, 4 . 24 - 4 . 20 ( m ) for the second for 20 min under the same condition . After 20 min , 5 -amino rotamer ( totally 1H for both rotamers , CH at the chiral 2 -cyanobenzotrifluoride ( 40 . 0 g , 0 .21 mol) , 400 mL of THF US 2019 /0040000 A1 Feb . 7 , 2019 48 were added and then the mixture was allowed to stir over 5 -Amino -[ 1 , 1' -biphenyl ] - 2 - carbonitrile (26 ) night at RT. The solvent was removed under reduced pres sure to give a solid which was treated with 300 mL of H20 , [0685 ] extracted with EtoAc (2x400 mL ) . The combined organic extracts were washed with saturated NaHCO3 solution (2x300 mL ) and brine ( 300 mL ). The organic layer was dried over MgSO4 and concentrated under reduced pressure H?N ) – CN to give a solid which was purified from column chromatog raphy using CH2C1_ /EtOAC ( 80 : 20 ) to give a solid . This solid was recrystallized from CH C1 /hexane to give 55 . 8 g (HO )2B Pd cat ( 5 mol % ), ( 73 . 9 % ) of ( 2R ) - 3 - bromo- N - [ 4 - cyano - 3 - ( trifluoromethyl ) K2PO4 or KF phenyl] - 2 -hydroxy - 2 -methylpropanamide as a light- yellow solid . Mp 134 .0 - 136 .5° C .; dioxane , reflux [ 0681 ] " H NMR (CDC12 / TMS) 8 1 .66 ( s , PH , CH3) , 3 . 11 H2N ! CN ( s, 1H , OH ), 3 .63 (d , J = 10 .8 Hz , 1H , CH2) , 4 .05 (d , J= 10 .8 Hz , 1H , CH2) , 7 .85 (d , J = 8. 4 Hz, 1H , ArH ), 7. 99 (dd , J= 2 . 1 , 8 . 4 Hz, 1H , ArH ), 8 .12 ( d , J = 2 . 1 Hz, 1H , ArH ) , 9 . 04 (bs , 1H , Ph NH) . MS ( ESI ) 349. 0 [MH ] ; M . p : 124 - 126° C . Preparation of 4 - Cyano 2 ,3 -Substituted Anilines [0686 ] Yield 80 % ; Brown solid ; MS ( ESI) 192 . 8 [ M - H ] "; ( 26 -28 ) 217 . 1 [ M + Na ] * ; ' H NMR (CDC13 , 400 MHz) 8 7 .54 - 7 .42 [ 0682 ] ( m , 6H ) , 6 . 71 ( d , J = 3 . 2 Hz, 1H ) , 6 .66 ( dd , J = 11 . 2 , 3 . 2 Hz, 1H ) , 4 .22 (bs , 2H , NH2) . Scheme 2 . Preparation of 4 -cyano 2 , 3 - substituted anilines (26 -28 ) . 6 - Amino - [ 1 , 1 ' -biphenyl ] - 3 - carbonitrile (27 ) [ 0687 ]

H2N - CN 24 X1, X2 = H , CI (HO ) 2B Pd cat ( 5 mol % ) . K2P04 or KF (HO ) 2B Pd cat ( 5 mol% ), dioxane , reflux K2PO4 or KF X3 dioxane , reflux 25 X3 = H , F HN CN HN — CN Ph Z1 Z2 27 26 -28 Z1, Z2 = H , Ph , [0688 ] Yield 79 % ; Brown solid ; MS ( ESI) 192 . 8 [ M - H ] " ; 4 - fluorophenyl 217 . 1 [ M + Na ] * ; ' H NMR (CDC1z , 400 MHz) 8 7 .50 - 7 . 30 Pd cat (m , 7H ) , 6 . 76 (dd , J = 11. 2 , 6 . 0 Hz , 1H ) , 4 .27 ( bs, 2H , NH2) . [ 0683 ] General Procedure I : 5 - Amino - 4 '- fluoro - [ 1 , 1 '- biphenyl] - 2 -carbonitrile [0684 ] Arylaniline 24 ( 4 .46 mmol) , boric acid 25 ( 4 . 46 ( 28 ) mmol) , Pd cat (0 .224 mmol, the structure as shown in Scheme 2 ) and K , PO , ( 8 . 92 mmol) in 10 mL of 1 , 4 - dioxane [0689 ] were heated to reflux under argon overnight. The mixture was cooled to RT and poured into DCM , which was washed with water , dried over anhydrous MgSO4 , and evaporated to HON .CN dryness . The mixture was purified with flash column chro matography as an eluent EtoAc /hexane and then the con densed compounds were then recrystallized at EtOAc/ hexane to give the target products (26 ~ 28 ). US 2019 /0040000 A1 Feb . 7 , 2019 49

- continued Preparation of SARDs 12 - 19 (HO )2B Pd cat ( 5 mol % ), K2PO4 or KF [ 0695] dioxane, reflux Scheme 3 . Preparation of SARDs 12 - 19 . H2N ( ' N

NC

28

[ 0690 ] Yield 98 % ; Brown solid ; MS ( ESI) 200. 8 [ M - H ]" ; HN - CN - 'H NMR (DMSO -d6 , 400 MHz) 8 7 .50 - 7. 48 (m , 3H ), 7 . 34 - 7 . 30 ( m , 2H ) , 6 . 63 ( m , 2H ), 6 . 26 ( bs, 2H , NH2) . Xi X2 11 Preparation of several X1 = H , Ph 2 -hydroxy - 2 -methylpropanamides ( 12 -19 ) X2 = H , Ph , 4 -fluorophenyl General Procedure II : [ 0691 ] Step 1 . [ 0692] Preparation of ( S ) — N - ( 4 - cyano - 3 - ( trifluorom ethyl) phenyl) - 2 -methyloxirane - 2 - carboxamide ( 10 ) in THF: a mixture of hydroxylbromide 8 ( 1 . 0 g , 2 .84 mmol) and NC X CN potassium carbonate (790 mg, 5 .70 mmol) in 60 mL acetone Y was heated to reflux for 30 min . After complete conversion CF3 X2 of starting bromide 8 to desired epoxide 10 as monitored by 12 - 16 X = H TLC , the solvent was evaporated under reduced pressure to CH31 or BnBr 17 , 19 X = CH3 give yellowish residue, which was poured into 20 mL of 18 X = Bn anhydrous EtOAc . The solution was filtered through Celite? pad to remove K2CO3 residue and condensed under reduced pressure to give a yellowish solid of epoxide 10 , which was dissolved in 5 mL of anhydrous THF to prepare a solution ( S ) - N - ( 4 -Cyano - 3 - ( trifluoromethyl ) phenyl) - 3 - ( (4 of epoxide 10 in THF. The resulting solution was directly cyanophenyl) amino ) - 2 - hydroxy - 2 -methylpropana used as next reactant without analysis . mide ( 12 ) [0693 ] Step 2 . [0696 ] [ 0694 ] NaH of 60 % dispersion in mineral oil (228 mg, 5 . 7 mmol) was added in 30 mL of anhydrous THF solvent in 100 mL dried two necked round bottom flask equipped with a dropping funnel. Substituted aniline 11 ( 2 .84 mmol) was added to the solution under argon atmosphere at ice - water bath , and the resulting solution was stirred for 30 min at the ice -water bath . Into the flask , the prepared solution of NC CN epoxide 9 or 10 ( 2 . 84 mmol in THF ) was added through dropping funnel under argon atmosphere at the ice -water oreaCF3 bath and stirred overnight at RT. After adding 1 mL of H20 , the reaction mixture was condensed under reduced pressure , and then dispersed into 50 mL of EtoAc , washed with 50 [0697 ] Yield 58 % ; Brown solid ; MS ( ESI) 387 . 2 [ M - H ] " ; mL (x2 ) water, brine , dried over anhydrous MgSO4, and ' H NMR (DMSO - d6, 400 MHz) 8 10 .42 (bs , 1H , NH ), 8 .11 evaporated to dryness . The mixture was purified with flash ( s, 1H ), 8 .21 ( d , J= 2 .2 Hz, 1H ) , 8 .01 (d , J= 2. 2 Hz, 1H ), 7 .38 column chromatography with EtoAc/ hexane as eluent, and (d , J = 8. 7 , 2H ), 6 .75 ( d , J = 8 .7 Hz , 2H ), 6 . 12 (bs , 1H , NH ), then the condensed compounds were then recrystallized at 3 .61 ( m , 1H ), 3 .25 (m , 1H ), 2 .29 (bs , 1H , OH ), 1. 42 ( s, 3H ) ; EtOAc /hexane to give the respective target products 12 - 19 . Anal . Calcd for C19H15F3N402: C , H , N . US 2019 /0040000 A1 Feb . 7 , 2019 50

( S ) N - (4 -Cyano - 3 -( trifluoromethyl) phenyl ) -3 - (( 4 [0701 ] Yield 42 % ; Brown solid ; MS ( ESI ) 463 . 0 [ M - H ] " ; cyanonaphthalen - 1 - yl) amino ) - 2 -hydroxy - 2 -methyl ' H NMR (DMSO -do , 400 MHz) 8 10 . 50 (bs , 1H , NH ) , 8 . 46 propanamide (13 ) ( d , J = 2 . 0 Hz, 1H ), 8 . 17 (dd , J = 8 . 4 , 2 . 0 Hz, 1H ) , 8 .08 ( d , [0698 ] J = 8 . 4 Hz, 1H ) , 7 .47 ( m , 6H ) , 6 .75 ( m , 1H ) , 6 .58 ( m , 1H ) , 6 .13 (bs , 1H , NH ) , 3 .67 ( d , J = 14 . 8 Hz , 1H ) , 3 .31 ( d , J = 14 . 8 Hz , 1H ) , 2 .49 (bs , 1H , OH ), 1 . 24 ( s , 3H ); Anal. Calcd for e OH C25H19F3N402: C , H , N . (S ) N -( 4 -Cyano - 3 -( trifluoromethyl) phenyl ) - 3 -( (5 cyano - [ 1 , 1 '- biphenyl ] - 2 - yl) amino ) - 2 -hydroxy - 2 NC CN methylpropanamide ( 15 ) CF3 [ 0702 ] [0699 ] Yield 39 % ; Brown solid ; MS ( ESI ) 437 . 2 [ M - H ] " ; ' H NMR ( CDC12 , 400 MHz) 89. 14 (bs , 1H , NH ), 8 . 15 ( d , OH J = 8 . 3 Hz, 1H ) , 8 . 06 ( d , J = 1 . 8 Hz, 1H ) , 7 . 98 (dd , J = 8 . 3 , 1 . 8 Hz, 1H ), 7 . 82 -7 .71 ( m , 5H ) , 6 .70 ( d , J = 8 . 1 Hz, 1H ) , 5 .51 (bs , 1H , NH ), 3 . 95 ( m , 1H ) , 3 .57 ( m , 1H ) , 2 .29 (bs , 1H , OH ) , 1 .74 ( s , 3H ) ; Anal. Calcd for C23H?zFzN _ 02: C , H , N . NC Ph ( S ) N - (4 -Cyano - 3 -( trifluoromethyl) phenyl ) -3 - ( 6 cyano - [ 1 ,1 '- biphenyl ] -3 -yl ) amino )- 2 -hydroxy - 2 CF3 methylpropanamide ( 14 ) [0700 ] [0703 ] Yield 32 % ; Brown solid ; MS ( ESI) 462 . 9 [ M - H ] " ; 487 . 1 [ M + Na ] + ; ' H NMR (CDC12 , 400 MHz ) 8 10 .49 (bs , 1H , NH ), 8 .45 (m , 1H ), 8 . 17 - 7. 43 (m , 7H ), 7. 23 (m , 2H ), aOH 6 .52 ( m , 1H ) , 6 . 18 (bs , 1H , NH ) , 3 .67 ( d , J = 14 . 8 Hz , 1H ) , 3 .31 ( d , J = 14 . 8 Hz , 1H ), 2 .47 (bs , 1H , OH ), 1. 23 (s , 3H ); Anal. Calcd for C25H 9F3N402: C , H , N .

NC CN Scheme 4 . Preparation of SARDs 17 - 19 and 17a . CF3 Ph aOH H OH CH31, N Br X2 CH3( CH2 ) 2Br, or BnBr Acetone NCY CN N , N CF3 diisopropylethylamine , NC K2CO3 120° C . , MW presentX2 = H , Ph , 4 - fluorophenyl queCF3 ? OH?? ? Ph

HON NC CN NC ( CF3 )2CHOH CF3 ? 17 X = CH3, X2 = Ph 17a X = CH2CH2CH3, X2 = H 10 18 X = Bn , X2 = H ?? 19 X = CH3, X2 = 4 - fluorophenyl OH 17 OH CH3

NC

NC CN premo14 preso US 2019 /0040000 A1 Feb . 7 , 2019 51

-continued [0707 ] Yield 42 % ; Yellowish solid ; MS (ESI ) 501. 1 18 [ M + Na ] *; H NMR (CDC1z , 400 MHz ) : 9 .09 (bs , 1H , NH ), 8 . 06 (s , 1H ), 7 . 93 (d , v = 2 . 0 Hz, 1H ) , 7 . 90 ( d , J = 2 .0 Hz, 1H ) , 7 .79 - 7 .28 ( m , 7H ), 6 .88 (m , 2H ), 3 .98 (d , J = 15 .6 Hz , 1H ), 3 .75 ( d , J = 15 .6 Hz, 1H ), 3 .01 ( s , 3H ) , 2 . 06 (s , 1H , OH ) , 1 . 63 aOH (s , 3H ) ; Anal. Calcd for C26H2, F3N402 : C , H , N . ( S )- 3 - (Benzyl ( 4 -cyanophenyl ) amino )- N -( 4 -cyano -3 (trifluoromethyl ) phenyl) - 2 -hydroxy - 2 -methylpro NC - CN panamide ( 18 ) CF3 [0708 ]

OH CH3 Ph , ? ?? LA

NC CN

CN Cr3 NC 17a CFz

? ?? IZ [0709 ] Yield 32 % ; Brown solid ; MS ( ESI) 476 . 9 [ M - H ] "; 501 .1 [M + Na ] * ; 'H NMR (CDC13 , 400 MHz) 8 10 . 22 (bs , 1H , NH ) , 8 . 35 ( s , 1H ), 8 . 17 ( d , J = 8 . 2 Hz, 1H ), 8 .08 ( d , J = 8 . 2 NC CN Hz , 1H ), 7 .20 - 7 . 11 ( m , 5H ), 6 .75 ( m , 1H ), 6 . 91 ( m , 2H ), 6 .23 ( s , 1H ) , 4 . 90 ( s , 2H ) , 3 . 99 (d , J = 14 . 8 Hz , 1H ), 3 .89 ( d , J = 14 . 8 CF3 Hz, 1H ) , 3 .42 (bs , 1H , OH ), 1 .41 (s , 3H ) ; Anal. Calcd for C26H21F3N402: C , H , N . [0704 ] General Procedure III : [ 0705 ] A mixture of compounds 12 or 14 ( 0 .15 mmol) and (S ) - N - (4 - Cyano - 3 -( trifluoromethyl) phenyl )- 3 -( 6 0 . 5 mL of alkylhalide (methyl iodide , n -propylbromide or cyano - 4 '- fluoro - [ 1 , 1 '- biphenyl ] - 3 - yl) (methyl ) amino ) benzyl bromide ) with 1 mL of N , N - diisopropylethylamine 2 -hydroxy - 2 -methylpropanamide ( 19 ) (DIPEA , Hünig ' s base ) was loaded into a vessel with a cap . The reaction vessels were placed in a reactor block in the microwave . A programmable microwave irradiation cycle of [ 0710 ] 30 min on ( 300 W ) at 150° C . and 25 min off ( fan -cooled ) was executed irradiation time, 30 min ) . The mixture was OH transferred to round bottom flask to be concentrated under reduced pressure and poured into EtOAc, which was washed with water and dried over anhydrous MgSO4, concentrated , purified by silica gel chromatography ( EtOAc / n -hexane ) to afford to desired products ( 17 , 17a, 18 and 19 ) . NC CN ( S ) N - (4 - Cyano -3 -( trifluoromethyl) phenyl )- 3 -( 6 cyano - [ 1 , 1' - biphenyl ] - 3 - yl) (methyl ) amino )- 2 -hy droxy - 2 -methylpropanamide ( 17 ) [0706 ]

? ?? [0711 ] Yield 38 % ; Brown solid ; MS (ESI ) 495 . 2 [M - H ]" ; ' H NMR (CDC13 , 400 MHz) 8 10 . 17 (bs , 1H , NH ), 8 .15 (s , 1H ), 8 . 00 ( d , J = 2 .0 Hz, 1H ) , 8 .08 ( d , J = 2 . 0 Hz, 1H ) , NC CN 7 .49 - 7 . 48 ( m , 4H ) , 7 .34 - 7 . 30 ( m , 2H ) , 6 . 75 ( m , 1H ) , 3 . 99 ( d , CF3 Ph J = 14 . 8 Hz, 1H ), 3 .79 ( d , J = 14. 8 Hz , 1H ) , 3 . 09 (s , 3H ) , 2 . 11 (bs , 1H , OH ), 1. 61 ( s, 3H ); Anal . Calcd for C26H20F4N _02 : C , H , N . US 2019 /0040000 A1 Feb . 7 , 2019

Example 1A [0714 ] A mixture of phenyl trifluoromethanesulfonate (500 mg, 2 . 21 mmol) , palladium acetate ( II ) (50 mg, 0 .22 Synthesis of Compounds 14 and 17 mmol) , ( + ) 2 , 2 '- bis (diphenylphosphino ) - 1 , 1 '- binaphthyl Synthetic Scheme of SARDs 14 and 17 ( 317 mg, 0 .66 mmol ) and cesium carbonate ( 1 . 09 g , 3 . 31 [0712 ] mmol ) in 50 mL of toluene were inertized with argon . Then , 4 -nitroaniline ( 331mg , 2 .43 mmol) or 4 - fluoroaniline ( 2 .43 mmol) was added and the mixture was heated at 110° C . Scheme 5 . Preparation of SARDs 14 and 17 . overnight. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite? . The aOH filtrate was diluted with CH2Cl2 and water . The phases were Br separated and the aqueous phase was re - extracted 2 times with CH , C1, . The combined organic phases were dried over CN Na2SO4 and the resulting solution was dried over anhydrous NC Na, SO and purified with flash column chromatography as an eluent EtoAc/ hexane ( 1 / 6 , v / v ) to give 4 -nitro - N -phe CF2 HN Ph nylaniline or 4 - fluoro - N -phenylaniline . 26 ? ?? ZI 1. NaH , THF or DMF x 2 . 10 , 0° C . to RT NC X = F , NO2 peroCF3 02 14

OH CH3 ?? F3C

NC CN NC presoCF3 sosetaX = F , NO2 17 Reagents and conditions: (a ) NaH , THF , 0° C . ~ RT ; (b ) CH31, N , N - diisopropylethylamine , 120° C ., MW . [ 0715 ] NaH of60 % dispersion in mineral oil ( 228 mg, 5 . 7 mmol) was added in 20 mL of anhydrous THF solvent into a 100 mL dried two necked round bottom flask equipped Hydroxybromide 8 was used as an important intermediate with a dropping funnel and NH (Ph ) ( Ar ) [ Ar = 4 - fluorophe which was reacted with aniline 26 after activating by NaH nyl; 4 -nitrophenyl ] ( 2 .84 mmol) was added to the solution in THF solvent to produce 14 . N - Alkylation of 14 was a under argon atmosphere in ice -water bath , and the resulting microwave assisted reaction and performed under a basic solution was stirred for 30 min at the ice -water bath . Into the conditions in using N , N -diisopropylethylamine ( Hünig ' s flask , epoxide 10 ( 2 . 84 mmol in THF ) was added through base ) to generate 17 . dropping funnel under argon atmosphere at the ice -water Example 1B bath and stirred overnight at room temperature . After adding 1 mL of H , O , the reaction mixture was condensed under Synthesis of Compounds 49 and 50 reduced pressure , and then dispersed into 50 mL of EtoAc, General Procedure : washed with 50 mL ( x2 ) water , brine , dried over anhydrous MgSO4, and evaporated to dryness . The mixture was puri [0713 ] Preparation of compounds 49 and 50 fied with flash column chromatography as an eluent EtoAc / hexane, and then the condensed compounds were then OTf HON recrystallized in EtoAc/ hexane to give a target product 49 or ALOTEHN 50 . ( S ) - N - ( 4 - Cyano - 3 - ( trifluoromethyl) phenyl ) - 3 - ( 4 fluorophenyl) (phenyl ) amino )- 2 -hydroxy - 2 -methyl propanamide (49 ) [0716 ] Yield ; 67 % ;MS (ESI ) m /z 456 . 1 [M -H ]" ; " H NMR (400 MHz, CDC1z ) 8 8 . 85 (bs , 1H , NH ), 7 .87 ( m , 1H ) , X = F , NO2 7 .81 - 7 .73 ( m , 2H ) , 7 .65 ( dd , J= 8 . 4 , 1 . 8 Hz, 1H ) , 7 . 20 ( m , 2H ) , 7 .05 -7 .00 (m , 2H ), 6 . 94 -6 .89 ( m , 5H ), 4 .54 (d , J= 15 .2 Hz , 1H ), 3 . 84 ( d , J = 15 . 2 Hz , 1H ), 3 .61 ( s , 1H ) , 1 . 53 ( s , 3H ) . US 2019 /0040000 A1 Feb . 7 , 2019 53

Example 2 TABLE 2 DMPK Novel AR Antagonists (mouse liver Transcriptional Activation microsomes ) [0717 ] The target of this research is : Wt. W741L T877A T1/ 2 (min ) [ 0718 ] (a ) To synthesize and optimize orally bioavail Binding IC501C50 IC50 CLint able SARDs, and deduce structure -activity relationship Compound K ; (nM ) ( M ) (nM ) (nM ) (ml /min /kg ) (SAR ). DHT 1 Bicalutamide 545 . 5 420 — 557 [0719 ] ( b ) Characterize SARDs in vitro in AR ligand Enzalut 1075 . 3 489 331 . 94 binding, transactivation , and AR degradation and pro amide ARN - 509 297. 0 1939. 4 390 . 52 liferation assays in PCa cells that are dependent on ASC - J9 1008 3487 . 6 AR - FL and AR - SV for growth . 14 198 . 5 77 > 100048 See Example 6 17 28 . 4 95 101. 7 153 .51 See Example 6 [0720 ] ( c ) Determine the pharmacokinetic (PK ) prop 49 275 .41 172 .22 5 . 069 min erties , develop appropriate formulation , and character 136 . 8 ml/min /mg " ize SARDs in vivo in LNCAP and 22RV - 1 androgen dependent and CRPC PCa xenografts , respectively . # see MLM method below : [ 0721 ] The preliminary results are generated with two lead [0723 ] Metabolism Studies with Mouse LiverMicrosomes molecules , compounds 17 and 14 , selected from a library . (MLM ) [ 0722] Severalmolecules were synthesized and character Objective: ized with the intention to develop next generation AR [0724 ] To determine the relative stability of SARDs to antagonists . Interestingly , several of these AR antagonists metabolism by liver microsomal enzyme using MLM . exhibited degradation activity at concentrations comparable [0725 ) Method : to their binding and antagonistic activity . These results [ 0726 ] Determination of metabolic stability ( in vitro provided an impetus to explore the degradation activity of CL ; - ) of test compounds with regard to Phase I and Phase these molecules . I + II metabolic pathways . [0727 ] Metabolic Stability to Phase I Pathways : [0728 ] The assay was done in a final volume of 0 . 5 ml in NC . duplicates ( n = 2 ) . Test compound ( 1 uM ) was pre - incubated for 10 minutes at 37° C . in 100 mM Tris -HCl , pH 7 . 5 containing 0 . 5 mg/ ml liver micro somal protein . After pre F3C incubation , reaction was started by addition of 1 mM HITNOPOH NADPH (pre - incubated at 37° C . ) . Incubations were carried out in triplicate and at various time- points ( 0 , 5 , 10 , 15 , 30 and 60 minutes) , 100 ul aliquots were removed and quenched with 100 ul of acetonitrile containing internal TABLE 1 standard . Samples were vortex mixed and centrifuged at 4000 rpm for 10 minutes . The supernatants were transferred SARDs of this invention , binding and AR antagonistic activities to 96 well plates and submitted for LC -MS /MS analysis . As control, sample incubations done in absence of NADPH PER RK;( M ) were also included . From % PCR ( % Parent Compound DHT n / a n / a n / a 6. 62 Remaining ) , rate of compound disappearance is determined MDV - 3100 na n / a n / a 1075 . 3 ( slope ) and in vitro CLint (ul / min /mg protein ) was calcu bicalutamide SO2 FH 545 . 5 lated . Cmpd 17 N ( CH3) CN phenyl 148 . 7 [ 0729 ] Metabolic Stability in Phase I & Phase II Path Cmnd 14 NH CN phenyl 198 . 5 ways : [ 0730 ] In this assay , test compound was incubated with Transcriptional Activation ( Antagonist Mode ) liver microsomes and disappearance of drug was determined binding Wildtype W741L using discovery grade LC -MS / MS . To stimulate Phase II metabolic pathway ( glucuronidation ) , UDPGA and alame K ; IC50 % inhibition C50 % inhibition thicin ( a pore - forming peptide to increase microsomal activ Compound (NM ) (nM ) at 1 uM (nM ) at 1 uM ity ) were included in the assay. DHT 5 . 85 [0731 ] Lc -Ms /Nis Analysis : bicalutamide 545 . 5 420 91 [0732 ] The analysis of the compounds under investigation MDV - 3100 1075 . 3 489 93953 was performed using LC -MS / MS system consisting of Agi ARN -509 297 1939 . 4 lent 1100 HPLC with an MDS /Sciex 4000 Q - TrapTM mass ASC - J9 1008 3487 . 6 spectrometer. The separation was achieved using a C18 14 198 . 5 > 1000 48 analytical column ( AlltimaTM , 2 . 1x100 mm , 3 um ) protected 17 270 . 7 95 98 101. 7 87 by a C18 guard cartridge system ( SecurityGuardTM ULTRA Cartridges UHPLC for 4 . 6 mm ID columns , Phenomenex ) . Mobile phase was consisting of channel A ( 95 % acetoni US 2019 /0040000 A1 Feb . 7 , 2019 54 trile + 5 % water + 0 .1 % formic acid ) and channel C ( 95 % pounds 14 and 17 robustly bound to AR by displacing the water + 5 % acetonitrile + 0 . 1 % formic acid ) and was delivered radiolabeled from LBD in an AR -LBD binding at a flow rate of 0 . 4 mL /min . The volume ratio of acetonitrile assay . They bound at a much higher affinity than the refer and water was optimized for each of the analytes . Multiple ence standards. Consistent with potent binding , the two reaction monitoring (MRM ) scans were made with curtain molecules effectively antagonized the R1881 stimulated gas, collision gas, nebulizer gas , and auxiliary gas optimized wild type AR transcriptional activity by potencies at least for each compound , and source temperature at 550° C . five - fold greater than MDV -3100 and bicalutamide ( 77 nM Molecular ions were formed using an ion spray voltage ( IS ) and 95 nM for 14 and 17 , respectively , compared to 420 nM of - 4200 V (negative mode) . Declustering potential (DP ) , and 489 nM for bicalutamide and MDV -3100 , respectively ) entrance potential (EP ) , collision energy ( CE ) , product ion ( Table 1 and Table 2 ) . mass, and cell exit potential ( CXP ) were optimized for each [0735 ] Bicalutamide is a known agonist of AR containing compound W741L mutation , whereas MDV- 3100 retains antagonist activity though its potency is somewhat reduced (939 nM ) . [0733 ] As shown in Table 1 , the first - generation SARDS While 14 demonstrated reduced effectiveness in the W741L were generated with amino linkers. Their binding and AR mutant ( > 1 uM ) , 17 retained the ability to antagonize agonist antagonistic activities were compared to standard molecules activated W741L AR ( 101. 7 nM ). The W741L mutation was such as bicalutamide , enzalutamide (MDV3100 ) , ARN -509 , selected due to the structural similarity of SARDs to bicalu and ASC - J9 . tamide (aryl propanamide ) . The antagonist activity of 17 [0734 ] As shown in Table 1 and Table 2 , the SARDs of the was selective for the AR and did not cross - react with invention bound to AR with higher affinity than the reference progesterone receptor (PR ), mineralocorticoid receptor standards . Interestingly, two molecules in the list, com (MR ) or glucocorticoid receptors (GR ) (data not shown ). TABLE 3

NC

FzCVN 11110

WT Agonist WT Antagonist EC50 % inhibition Compound X R1 R2 R3 RBA (nM ) Emax (nM ) ICso( nM ) at 1 UM S -22 CN H H 5 . 8 1 . 8 1. 4 140 - 15 . 1 NA NA Bicalutamide SO , F H H 0 .62 + 0 .06 NA NA 22. 4 + 6 .7 90 . 9 + 0 .83 12 NH CN H H 0 . 16 + 0. 01 626 156 + 213 . 4 119 89. 9 + 0 .4 w NH CN – (CH ) 4 - 1 . 5 + 0 . 05 > 1000 48 . 3 + 7 . 4 193 63 .0 1. 2 A NH CN Ph H 0 . 56 + 0 .03 NA NA 20 . 5 88 . 2 + 1 .1 | NH CN H Ph 0. 65 + 0 . 06 > 1000 22 . 6 + 6 . 4 81. 3 92. 2 = 1 .0 NCH ( C6H6) CN H H ND NA ?? 118 . 6 92. 7 - 1 . 8 17 NCH , CH Ph H NA ?? 94 . 8

TABLE 4 W741L T877A W741L Antagonist T877A Antagonist Agonist % Agonist % EC50 Emax IC50 inhibition EC50 Emax IC50 inhibition Compound x Ri R2 (nM ) ( nM ) ( nM ) at 1 uM ( nM ) (nM ) ( nM ) at 1 uM Bicalutamide SO , F 1 . 1 + 3 . 4 273 = 37 . 9 NA NA ?? NA 229 73 . 7 + 7 . 4 12 NH CN H > 1000 24 . 8 + 7 . 2 > 1000 20 . 9 + 9 . 1 47 122 = 26 .4 NA NA 13 ?? CN - ( CH ) 2 . 4 93. 1 + 10 . 8 NA NA 3 . 4 56 . 1 + 9 . 9 784 . 4 60 . 5 7 . 8 14 NH CN Ph > 1000 26 . 8 + 1 .6 > 1000 48 . 3 + 4 . 7 > 1000 20 .6 + 3 . 6 79 . 1 85 .6 + 2 . 0 15 NH CN H 1 . 9 76 . 7 + 15 . 1 305 6 3. 8 13 . 8 > 1000 18 . 6 + 0 . 1 34 . 3 94 . 0 + 0 . 7 NCH (CH ) CN H > 1000 26 . 1 + 1 . 7 > 1000 47 . 6 + 10 . 0 > 1000 17 . 4 + 5 . 4 470 74 . 8 + 8 . 7 17 NCH3 CH Ph ?? NA 101 . 7 87 NA NA 33 . 1 95 . 6 US 2019 /0040000 A1 Feb . 7 , 2019 55

[ 0736 ] In general, compounds 12 -21 acted as antagonists at 1 uM . Unlike the HSP - 90 inhibitor 17 - AAG , 17 treatment of wildtype androgen receptor (wt - AR ) with some residual did not affect PR (FIG . 4E ) , GR (not shown ) and ERa ( FIG . agonism for 12 , 13 , and 15 . Notably , 17 was the most potent 4F ) protein levels ( FIG . 4 ) . antagonist with an IC50 value of 6 nM ( Table 3 ) . Mutant AR ' s W741L and T877A confer resistance to bicalutamide [0739 ] FIG . 9 depicts that 49 in the presence of R1881 and hydroxyflutamide , respectively . Most of the compounds degrades AR in LNCaP cells . LNCaP cells were plated in 6 12 -21 displayed mixed agonist / antagonist activity in in vitro well plates at 1 million cells /well . The cells were maintained transcriptional activation assays . However, 17 retains potent in serum free conditions for 3 days. The cells were treated pure antagonism in wildtype and both mutations ( Table 3 as indicated in the figure , harvested , protein extracted , and and Table 4 ) , demonstrating potential to overcome resistance Western blotted for AR . 49 and other SARDs of this inven to bicalutamide and / or hydroxyflutamide , independent of its tion demonstrated selective degradation of AR i . e . , SARD SARD activity ( described below ) . 14 also demonstrated activity ) in the nM range, i. e ., at concentrations comparable antagonist activity in wildtype and mutant AR 's , but was not to their antagonist IC50 values . LNCAP cells are known to a potent antagonist in all the mutants tested . express the AR mutant T877A , demonstrating the ability to [0737 ] AR transactivation assay was performed with wild degrade antiandrogen resistance conferringmutant androgen type, W741L , and T877A AR constructs . W741 mutation to receptors. leucine or cysteine ( L / C ) confers resistance to bicalutamide ( Hara , T ., Miyazaki, J. , Araki, H ., Yamaoka, M ., Kanzaki, [0740 ] FIG . 10 depicts that 49 degrades AR in RV22 - 1 N ., Kusaka , M ., and Miyamoto , M . ( 2003 ) . Novelmutations cells . 22RV - 1 cells were plated in 6 well plate at 1 - 1 . 5 of androgen receptor: a possible mechanism of bicalutamide million cells /well in growth medium (RPMI + 10 % FBS ). withdrawal syndrome. Cancer research 63 , 149 - 153 ) , while Next day, medium was changed and treated with vehicle or T877 mutation results in resistance to hydroxyflutamide a dose response of 49 . After overnight treatment ( 12 - 16 hrs ) , ( Tan , J. , Sharief, Y. , Hamil, K . G ., Gregory , C . W . , Zang, D . cells were washed in ice cold PBS and harvested by scrap Y . , Sar, M . , Gumerlock , P . H ., deVere White , R . W ., Pretlow , ping in 1 mL PBS . Cells were pelleted , protein extracted , T . G . , Harris , S . E . , et al . ( 1997) . quantified using BCA assay, and equal quantity of protein activates mutant androgen receptors expressed in the andro was fractionated on a SDS - PAGE . The proteins were trans gen - dependent human prostate cancer xenograft CWR22 ferred to nylon membrane and Western blotted with AR and LNCAP cells . Mol Endocrinol 11, 450 -459 ) . 17 potently antibody (N20 from SCBT ) and actin antibody . 49 was inhibited the R1881 - induced wildtype AR transactivation capable of degrading full - length androgen receptor ( AR -FL ) with much higher potency than enzalutamide (FIG . 13A ) . and truncated AR ( AR -SV ) in 22RV - 1 cells, suggesting that While 17 effectively antagonized both wildtype and mutant SARDs will be able to overcome AR - V7 dependent prostate ARs comparably , (FIG . 13B ). 17 inhibited glucocorticoid cancers . receptor (GR ) and mineralocorticoid receptor (MR ) trans [0741 ] LNCAP cells are known to express the AR mutant activation only at ~ 10 UM (FIG . 13C ) . T877A , demonstrating the ability of the SARDs of this invention to degrade antiandrogen resistance conferring Example 3 mutant androgen receptors (i . e . , advanced prostate cancers and CRPC ) . 14 , 17 and 49 were capable of degrading full- length androgen receptor (AR - FL ) and truncated AR AR Degradation Activity ( AR - V7) in 22RV - 1 cells , suggesting that SARDs will be [ 0738 ] Compounds 17 and 14 were tested for their effect able to overcome AR - V7 dependent prostate cancers (i . e. , on AR protein expression . While 17 drastically reduced the CRPC ). levels of AR protein following 24 hours of treatment in [0742 ] These SARD activity demonstrations suggest the LNCAP cells ( serum starved and treated with 0 . 1 nMR1881) compounds of this invention are able to degrade a variety of as measured by Western blot (FIG . 1A ) , bicalutamide or AR variants , and hence should provide the ability to inhibit enzalutamide (MDV - 3100 ) had no effect at an equal con the AR -axis activity whether it is androgen -dependent or centration (FIGS . 1E (VCP ) and 1F (LNCAP )) . Under androgen - independent . Degradation of the AR removes the identical conditions, the lowest concentration of 17 that was possibility of promiscuous activation of mutant ARs, acti capable of reducing AR protein levels in LNCAP cells was vation by intracellular processes such as signal transduction 100 nM ( FIG . 1B ) . Similar AR protein down - regulation was and kinase activation , etc . , and suggests that the SARDs observed under hormone replete conditions in LNCAP ( FIG . should also degrade the polyQ polymorphism in hyperan 1C ) , in HeLa cells infected with an adenovirus expressing drogenic dermatologic disorders ( shortened polyQ ) or Ken high levels of wt- AR ( FIG . 1D ; suggesting activity in CPRC nedy ' s disease (extended polyQ ) , providing a rationale for where AR gene has been activated ) as well as in wt- AR treating either type of diseases by destroying the AR in the expressing VCaP cells 14 (FIG . 1E ) . 14 also similarly affected tissues (skin and neuromuscular system , respec reduced the AR levels in LNCAP cells , requiring as little as tively ) . 2 hours of treatment and matching closely the time course of 17 - AAG ( FIG . 1F ) . Neither bicalutamide nor MDV - 3100 ( enzalutamide ) had any effect on AR protein levels even Example 4 after 24 hours of treatment. Likewise , 17 demonstrated more potent and complete AR degradation in LNCAP cells than the Effect on PCa Gene Expression and Cell Growth reported SARDS ASC - J9 ( not shown) and ARN -509 (FIG . 2A ) , and AR antagonist enzalutamide (not shown ) ( FIG . [0743 ] The ability of these novel antagonists to inhibit 2A ) . 17 and 14 treatment in LNCaP cells resulted in small AR -regulated gene expression was measured in LNCaj, a reductions in AR mRNA levels , but only at 10 uM and not PCa cell line known to harbor a T877A mutation ( Table 5 ) . US 2019 /0040000 A1 Feb . 7 , 2019 56

TABLE 5 TABLE 7 Effect of antagonists on AR - target gene Effect of SARDs on AR transactivation expression and growth in LNCAP cells . and growth in 22RV - 1 cells . Gene Expression + 0 .1 nM R1881 (IC50 nM ) Transactivation Growth Compound IC50 (nM ) IC50 (NM ) Gene Bicalutamide MDV - 3100 Cmpd 17 Bicalutamide 3133 . 52 > 10 ,000 PSA 783 . 7 1 ,019 . 3 198 . 5 Enzalutamide 101 . 87 > 10 , 000 NKX3 . 1 755 . 8 1 , 142 . 8 176 . 0 Cmpd 17 56 . 36 2642 FKBP51 270 . 9 76 . 8 51. 8 ARN - 509 64. 54 > 10 . 000 TMPRSS2 831. 4 823 . 7 128 . 1 ASC - J9 1026 .91 > 10 , 000 Growth 872 469 [0747 ] FIG . 4 depicts degradation of AR by SARDs under [0744 ] Consistent with binding and transcriptional activa varying conditions ( A - D ) , without degradation of other tion assays , 17 significantly inhibited agonist - stimulated receptors ( E - F ) . ( A . ) and ( B . ) LNCAP cells were serum expression of PSA , NK / 3 . 1 , FKBP51, and TMPRSS2 genes starved and treated with compound 17 ( 10 uM in panel Aand ( IC50 values of 198 .5 , 176 . 0 , 51. 8 , and 128 . 1 nM , respec a dose response in panel B ) in the presence or absence of tively ). R1881. Bicalutamide was used as a negative control . Cells TABLE 6 Cell Cmpd 17 7 Day Growth 17 -AAG 7 Day Growth Enzalutamide 7 Day Growth Line/ ( IC50 , UM ) ( IC50, UM ) ( IC50, UM ) R1881 Veh 0. 01 1 0. 1 0 Veh 0 .01 0 .1 10 Veh 0. 01 0. 1 10 VCP 2 . 99 2 . 92 2 .48 3 .82 0 .657 0 .414 0 .778 1. 06 0 . 742 1 .53 > 3 > 10 LNCAP 0 . 78 0 .490 .47 – 0 .260 0 .292 0 . 157 0 . 281 0 . 656 3 .02 PC - 3 > 10 > 10 > 10 > 10 0 . 307 0 . 221 0 .257 0 .542 > 10 > 10 > 10 > 10

[ 0745 ] Similar activity was demonstrated in LNCAP cells were harvested , protein extracted , and Western blotted for with 14 (not shown ) . Consistent with inhibition of gene AR and actin . ( C . ) LNCAP cells were plated in full serum and treated with compound 17 ( dose response ). Cells were expression , 17 inhibited growth of AR - positive , androgen harvested , protein extracted , and Western blotted for AR and dependent PCa cells (LNCAP and VCP) in both the hor actin . ( D . ) HeLa cells were infected with adenovirus con mone- deplete and hormone -replete states ( Table 6 ). Unlike taining AR and were treated with compound 17 in the the HSP - 90 inhibitor 17 - AAG , 17 had no effects in the AR presence or absence of R1881 . Cells were harvested , protein extracted , and Western blotted for AR and actin . ( E . ) and ( F .) negative PC cell line , PC - 3 ( Table 6 ) . See also FIG . 2B for SARDs do not degrade other nuclear receptors . T47D ( left a bar graph that depicts that 17 inhibited growth of LNCP panel ) and MCF - 7 ( right panel) cells were plated in full cells with comparable efficacy and potency as enzalutamide serum and treated with compound 17 (dose response ). Cells and ARN - 509 . were harvested , protein extracted , and Western blotted for PR (progesterone receptor ) or ER - a ( estrogen receptor alpha ) and actin . Example 5 [0748 ) The reproducibility of the effect of the SARD compounds of this invention on the AR expression was SARDs Degrade AR -SV in 22RV - 1 Cells evaluated under various experimental conditions (LNCAP cells in full serum , wildtype AR in HeLa cells , and others ) . [0746 ] The effect of SARD treatment on the AR levels was 17 degradation effect was captured when the Western blot also measured in androgen -refractory 22RV - 1 PCa cells . was performed for the AR with N20 antibody and actin These cells express both AR - FL and the low molecular (FIG . 14A ) . Western blot was performed with a different weight splice variant species of the AR ( AR -SV ) and depend antibody targeting the C -terminus (AR C19 ; FIG . 14B ), on the AR -SV for growth . 17 (FIGS . 3A and 3B ) and 14 indicating that the degradation is not due to the masking of ( FIG . 3C ) completely down regulated both AR - FL and the antibody binding site by the SARDs . AR - SV species (FIG . 3 ) in contrast to the limited effects of [0749 ] To exclude that the degradation effects are not due 17 - AAG only on AR - FL (not shown ) . MDV - 3100 treatment to transcriptional inhibition , LNCAP cells were treated with did not affect levels of either AR species ( FIG . 3C ) , and 17 in the presence of R1881 under conditions similar to that ASC - J9 and ARN -509 did not reduce AR - V7 levels . Growth used for Western blot. 17 failed to alter the AR mRNA assay performed in 22RV - 1 cells treated with SARDs in the expression , while it robustly inhibited the expression of the presence or absence of 0 . 1 nM R1881 demonstrated that AR - target gene , FKBP5 ( FIG . 15 ). SARDs, but not MDV - 3100 , bicalutamide , enzalutamide , or Example 6 ARN - 509 , markedly suppressed the growth of 22RV - 1 cells ( Table 7 ) . The AR -SV variant ( e . g ., AR - V7 ; Cancer Res . Liver Metabolism and Pharmacokinetic ( PK ) 2013 Jan . 15 ; 73 ( 2 ) : 483 - 489 ) lacks the LBD and so SARD Properties of SARDS activity against AR - SV must operate through an alternative [0750 ] To evaluate the metabolic stability parameters such binding and degradation domain (BDD ). as half -life and clearance , human , rat, and dog liver US 2019 /0040000 A1 Feb . 7 , 2019 57 microsomes were incubated with 17 and 14 for 60 min . Both treated 24 hrs after transfection and luciferase assay per molecules had very short half - lives between 5 and 10 min formed 48 hrs after transfection . SARDs did not inhibit and high clearance ( Table 8 ) . transactivation of other receptors until 10 UM (FIG . 6 ) . TABLE 8 DMPK studies with SARDs of the invention . Rat PK CL _ obs IV AUC all Rat LM - P1 Rat LM - P1 Rat LM - P1 Rat LM - P1 SARD (mL / min /kg ) (min * ug/ mL ) PO _ F % Half Life (min ) CL (UL /min /mg ) Half Life (min ) CL ( UL /min /mg ) 17 30 . 4 323. 4 0 . 7 4 .6 150. 9 2 . 5 281. 4 14 9 . 4 1067 . 9 0 . 4 7 .0 99 . 5 2 . 6 266 . 0

[ 0751] PK studies in rats to follow up the metabolism data Example 9 also demonstrated that the SARDs have very low bioavail ability and area under the curve ( AUC ) ( Table 8 ) , indicating SARDs Inhibit Recruitment of AR to the Promoter that their PK properties need to be improved by structural and Enhancer Elements of Androgen Responsive modifications and optimal formulation in order to obtain Genes systemic exposures necessary for oral administration and [0754 ] LNCAP cells were serum starved for 3 days and efficacy for, e . g . , prostate cancer . However , the high potency treated as indicated above with SARD (compound 17 ) or and efficacy of the selective androgen receptor degradation bicalutamide at 10 uM in the presence or absence of 0 . 1 nM coupled with the low half - lives and high metabolic clear R1881 . Proteins were cross - linked to DNA and chromatin ances suggest that topical administration of the compounds immunoprecipitation studies were conducted with AR and of this invention could exert strong ( high potency and high RNA -Pol II antibodies. 17 inhibited recruitment to the efficacy ) antiandrogenic effects when applied topically promoter or enhancer elements of androgen responsive directly to affected areas. E . g ., topical administration to genes such as PSA , FKBP, and TMPRSS2 ( FIG . 7A ) . localized skin lesions such as in acne , seborrheic dermatitis , SARDs degrade AR . LNCAP cells were serum starved for 3 hirsutism , etc . could degrade the AR in these tissues , thereby days and treated as indicated above with SARD (17 ) at 10 countering the hyperandrogenism , without risk of significant uM in the presence or absence of 0 . 1 nM R1881 . Cells were systemic exposures that could result in untoward anti fixed and immunofluorescence for AR performed . Nucleus anabolic or sexual side effects . was stained with DAPI. SARDs did not abrogate AR trans Example 7 location to the nucleus but did decrease levels of AR in the nucleus upon treatment with an agonist R1881 (FIG . 7B ) . Effects on Androgen -Dependent Tissues in Intact (0755 ) Inhibition of AR recruitment to PSA enhancer and Male Rats RNA Pol II recruitment to PSA promoter was also observed [ 0752 ] To measure in vivo antagonist activity , 17 and 14 with 17 ( FIGS . 16A , 16B ) . were administered to intact male rats via intravenous ( i . v . ) Example 10 bolus injection ( FIG . 5 ) . Due to high clearance , studies with oral administration of these molecules failed to significantly SARDs Inhibited LNCAP Cell Growth by affect any androgen -dependent tissues such as prostate , Non -Competitive Binding to AR seminal vesicles , or levator ani. Hence , the study was conducted with i . v . administration to derive evidence of in [0756 ] LNCAP cells were plated in serum free medium and vivo activity . Following 3 days of therapy, reductions in were treated with increasing concentrations of enzalutamide prostate weightnormalized to body weight were observed in or 17 in the presence of a dose range of R1881 . Seven days 1 of 2 17 - treated animals , and 3 of 4 14 - treated animals as after treatment, cells were fixed and growth measured by compared to vehicle - treated controls . Reductions of greater WST- 1 assay. SARDs inhibited LNCaP cell growth by an magnitude in seminal vesicle weight were observed in 4 of apparent non - competitive binding to AR (FIG . 8 ). As 4 animals treated with 14 with no changes in 17 animals . expected , enzalutamide IC50 values for cell growth inhibi Both compounds tested varied greatly in the exposures tion increased with increased amounts of R1881 . However, following 23 mpk 14 and 23 mpk 17 doses resulting in 32 the IC50 values for cell growth inhibition for 17 did not and 13 uM * hr exposures , respectively . These studies indi increase with amounts of R1881 , possibly indicating that cate the requirement for molecules with better bioavailabil R1881 and 17 were not competing for the same binding site ity or formulation that will enhance the oral bioavailability on AR . and efficacy in achieving systemic antiandrogenic effects . Example 11 Example 8 SARDs Bind to the AR - AF1 SARDs do not Inhibit Transactivation of Other Receptors [0757 ]. There are two tryptophan residues and up to 12 tyrosine residues in the AF1 of the AR . This has allowed the [0753 ] HEK - 293 cells were transfected with the indicated study of the folding properties of this domain using intrinsic receptors and GRE - LUC and CMV -renilla luc . Cells were steady state fluorescence emission spectra . Excitation at 287 US 2019 /0040000 A1 Feb . 7 , 2019 nm excites both tyrosine and tryptophan residues . The centration measurements were not possible because of the emission maximum (amax ) for the tryptophan is sensitive to solubility issue with the compound . the exposure to solvent. In the presence of the natural f07631 32 osmolyte TMAO there is a characteristic 'blue shift ' con [0764 ] While certain features of the invention have been sistent with the tryptophan residues being less solvent illustrated and described herein , many modifications, sub exposed and a loss of the shoulder ( ~ 307 nm ) for tyrosine as stitutions, changes , and equivalents will now occur to those there is increased energy transfer to tryptophan as the of ordinary skill in the art . It is , therefore , to be understood polypeptide folds . To test if the compounds , enobosarm that the appended claims are intended to cover all such (negative control) , and 17 interact with AF - 1 and /or alter the modifications and changes as fall within the true spirit of the folding of this domain the steady state fluorescence was invention . measured for each compound with AR - AF1 alone or the What is claimed is : presence of TMAO ( 3 M ) or urea ( 4 or 6 M ) . 1 uM of 1. A method of treating , suppressing, reducing the inci AR -AF1 and 5 uM of the individual compounds were used , dence, reducing the severity , or inhibiting the progression of and preincubated for at least 30 minutes prior to measuring a hormonal condition in a male in need thereof, comprising the emission spectra . The emission spectra were all cor administering to the subject a therapeutically effective rected for buffer alone or buffer with TMAO /urea /com amount of a selective androgen receptor degrader (SARD ) pounds as necessary . compound represented by the structure of formula IA : [ 0758 ] FIG . 11 depicts that SARDs bind to the AR - AF1 . FIG . 11A : The emission spectra were all corrected for buffer alone or buffer with TMAO /urea / compounds as necessary . IA There was no dramatic effect of enobosarm ( left panel ) on Q5 the Nma, for tryptophan , while 17 ( right panel) reduces the wavelength ( i. e ., a 'blue shift ) , indicating that 17 binds to = the AF - 1 and enobosarm does not bind to AF - 1 . FIG . 11B : Left Panel: Dose - dependent shift in the fluorescence inten sity , i. e ., fluorescent quenching , by 17 when incubated with RI R2 03 AR AF - 1 . The fluorescence shoulder observed at 307 nm , which corresponds to tyrosine residues in the AF - 1 , is wherein shifted by 17. The overall fluorescence is also markedly T is OH , OR , - NHCOCHz, or NHCOR ; altered by 17 . Z is NO2, CN , COOH , COR , NHCOR or CONHR ; [0759 ] Right Panel : Data shown in the left panel was Y is CF2 , F , I , Br, C1, CN , C ( R ) , or Sn ( R ) z; plotted as difference in fluorescence between control and R is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl , CH F , compound 17 treated samples ( fluorescence in the absence CHF2, CF3, CF2CF3, aryl, phenyl, F , C1, Br, I , alkenyl of compound - fluorescence in the presence of compound ) . or OH ; R , is CH3, CH , F , CHF2, CF3, CH2CH3, or CF2CF3; A dose dependent increase was observed in the presence of R2 is hydrogen , C . -C12 - alkyl, SO2- aryl , SO2- phenyl , 17 indicating interaction between 17 and AF1 . CO - aryl , arylalkyl, benzyl, aryl, or C3 -C7 - cy cloalkyl; Example 12 Q1, Q4, and Q5 are each independently selected from hydrogen , substituted or unsubstituted linear or AF1 Binding External Validation (VIB ) branched alkyl, substituted aryl, F , C1, Br, I, CF , CN , NO2, substituted or unsubstituted cycloalkyl, substi Target Molecule : tuted or unsubstituted heterocycloalkyl , substituted or [0760 ] Compound 17 was delivered dissolved in DMSO at unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHz, 10 uM . NHCOCF4, NHCOR , NHCONHR , NHCOOR , OCONHR , CONHR , NHCSCH?, NHCSCF , NHCSR , Experimental Setup NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , SO _ R , SR , NCS , SCN , NCO , or OCN ; [ 0761 ] Purified H . - AF1 was biotinylated with N -hydroxy Q2 and Q3 are each independently selected from hydro succinimide (NHS ) -PEG4 -biotin at an estimated protein gen , substituted or unsubstituted linear or branched biotylation ratio of 1 :1 . Bio - layer interferometry (BLI ) was alkyl, substituted aryl , F , C1, Br, I , CF3, CN , NO2, used to screen for binding of small molecule to biotinylated substituted or unsubstituted cycloalkyl, substituted or protein using the Octet 96RED system (ForteBio® ). Bioti unsubstituted heterocycloalkyl, substituted or unsubsti nylated H - AF1 was immobilized on super streptavidin tuted arylalkyl, C ( R ) 3 , N ( R ) , NHCOCH3, NHCOCF3 , ( SSA ) bio sensors at full saturation level in order to detect NHCOR, NHCONHR , NHCOOR, OCONHR , signals from binding of small molecule . Biosensors loaded CONHR , NHCSCH , , NHCSCFz , NHCSR , with AF1 were used in parallel to screen for binding of 17 . NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , SOR , SR , NCS, SCN , NCO , or OCN ; Results wherein at least two of Q?, Q2, Q3 , Q4, and Qs are not [ 0762 ) Raw data measurements from binding of Com hydrogens; or pound 17 to AF1 are shown in FIG . 12 . The data shows the Qi and Q2 are joined together to form a substituted or AF1 loaded biosensors gave a stronger signal than any of the unsubstituted C . - C , carbocyclic or heterocyclic ring, reference sensors at 50 nM concentrations. At higher con and Q3 , Q4, and Qs are as defined above ; or US 2019 /0040000 A1 Feb . 7 , 2019 59 Feb. 7, 2019 Q2 and Q3 are joined together to form a substituted or unsubstituted C5- C , carbocyclic or heterocyclic ring , 13 and Q1, Q4 , and Qs are as defined above ; and wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) - one or 1H -pyrrole ; NO or its optical isomer, its racemic mixture , pharmaceuti cally acceptable salt , pharmaceutical product , poly ?? morph , hydrate , or any combination thereof. EZ 2 . The method according to claim 1 , wherein the com pound is represented by the structure of formula III : 16 CN III Le Or

N 19 H3COH*+111110 Óz wherein Z is NO , or CN ; N Y is CF3, F , I, Br, Cl, or CN ; R2 is hydrogen , C7 - C12 - alkyl, SO2- aryl , SO2- phenyl, DlaF . - CO -aryl , arylalkyl, benzyl, aryl, or Cz -Cz - cy cloalkyl; 6 . The method according to claim 1 , wherein said condi Q is substituted or unsubstituted aryl, substituted or tion is hypergonadism , hypersexuality , sexual dysfunction , unsubstituted phenyl, substituted or unsubstituted ary - gynecomastia , precocious puberty in a male , alterations in lalkyl, F , C1, Br, I , CF3, CN , NO2, or substituted or cognition and mood , depression , hair loss , hyperandrogenic unsubstituted heterocycloalkyl ; dermatological disorders , pre -cancerous lesions of the pros Q2 is hydrogen , substituted aryl, substituted phenyl, F , C1, tate , benign prostate hyperplasia , prostate cancer and / or Br, I , CF3, CN , NO2, substituted or unsubstituted other androgen - dependent cancers. cycloalkyl, substituted or unsubstituted heterocy 7 . A method of treating prostate cancer in a subject in need cloalkyl, or substituted or unsubstituted arylalkyl; thereof, wherein said subject has AR overexpressing pros Q3 is hydrogen , substituted aryl, substituted phenyl, F , C1, tate cancer, castration -resistant prostate cancer, castration Br, I, CF3, CN , NO2, substituted or unsubstituted sensitive prostate cancer, AR - V7 expressing prostate cancer, cycloalkyl, substituted or unsubstituted heterocy or d567ES expressing prostate cancer, comprising adminis cloalkyl, or substituted or unsubstituted arylalkyl; tering to the subject a therapeutically effective amount of a wherein at least one of Q1, Q2 and Q3 is a substituted aryl, selective androgen receptor degrader ( SARD ) compound substituted phenyl, or substituted or unsubstituted ary represented by the structure of formula IA : lalkyl; or Qi and Q2 are joined together to form a substituted or unsubstituted C3 - C , carbocyclic or heterocyclic ring and Q3 is as defined above ; or Q2 and Q3 are joined together to form a substituted or Q4Q unsubstituted C3- C , non - aromatic carbocyclic or a het erocyclic ring and Q , is as defined above; and wherein said formed carbocyclic or heterocyclic ring is H not dihydropyridin - 2 ( 1H )- one , pyridin - 2 ( 1H ) - one or RIT 1H -pyrrole ; or its optical isomer , its racemic mixture , pharmaceuti wherein cally acceptable salt , pharmaceutical product, poly T is OH , OR , — NHCOCHz, or NHCOR ; morph , hydrate , or any combination thereof . Z is NO2, CN , COOH , COR , NHCOR or CONHR ; 3 . The method according to claim 1 , wherein Q , is CN . Y is CF3, F , I , Br, C1, CN , C ( R ) ; or Sn ( R ) 3 ; 4 . The method according to claim 1 , wherein Q , and Qz R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH F , are joined together to form a substituted or unsubstituted CHF2, CF3, CF CF3, aryl , phenyl, F , Cl, Br, I , alkenyl C . - C , non -aromatic carbocyclic or a substituted or unsub or OH ; stituted C3 - C , heterocyclic ring. R is CH3, CH , F , CHF2, CF3, CH2CH3, or CF CF3 ; 5 . The method according to claim 1 , wherein the com R2 is hydrogen , C , -C12 - alkyl, SO2- aryl , SO2- phenyl, pound is represented by the structure of any one of the - CO - aryl , arylalkyl, benzyl, aryl, or C3- C4- cy following compounds : cloalkyl; US 2019 /0040000 A1 Feb . 7 , 2019 60

Q1, Q2, Q3, Q4, and Qs are each independently selected 10 . The method according to claim 7 , wherein Q2 and Q3 from hydrogen , substituted or unsubstituted linear or are joined together to form a substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, sub C - C , non - aromatic carbocyclic or a substituted or unsub stituted or unsubstituted phenyl, F , Cl, Br, I , CF3, CN , stituted C .- C , heterocyclic ring . NO2, substituted or unsubstituted cycloalkyl, substi tuted or unsubstituted heterocycloalkyl, substituted or 11 . The method according to claim 7 , represented by the unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHZ, structure of any one of the following compounds: NHCOCF4 , NHCOR , NHCONHR , NHCOOR , OCONHR , CONHR , NHCSCHZ, NHCSCF3, NHCSR , NHSO , CHZ, NHSO , R , OR , COR , OCOR , OSO , R , 13 SO _ R , SR , NCS , SCN , NCO , or OCN ; or its isomer , pharmaceutically acceptable salt , pharmaceuticalprod uct , polymorph , hydrate or any combination thereof; wherein at least two of Q1, Q2, Q3, Q4, and Qs are not NC . hydrogens ; or Q , and Q , are joined together to form a substituted or NH unsubstituted C5 - Cg carbocyclic or heterocyclic ring , F3C and Q3 , Q4, and Qs are as defined above; or ZH Q2 and Q3 are joined together to form a substituted or unsubstituted C - C , carbocyclic or heterocyclic ring , 16 and Q1, Q4, and Qs are as defined above ; and NC . wherein said formed carbocyclic or heterocyclic ring is Dames not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 ( 1H ) -one or 1H -pyrrole . F3C IZ NH 8 . The method according to claim 7 , represented by the structure of formula III: or 19 NC . TII NH H3COH R , Q3 wherein 12. The method of claim 7 , wherein said castration Z is NO , or CN ; resistant prostate cancer is AR overexpressing castration Y is CF3, F , I, Br, Cl, or CN ; resistant prostate cancer, F876L mutation expressing castra R2 is hydrogen , C , -C12 - alkyl, SO2- aryl , SO2- phenyl , tion - resistant prostate cancer , F876L _ T877A double - CO - aryl, arylalkyl, benzyl, aryl, or C3 -C7 -cycloalkyl mutation expressing castration - resistant prostate cancer, Qi is substituted or unsubstituted aryl, substituted or AR - V7 expressing castration - resistant prostate cancer, unsubstituted phenyl, substituted or unsubstituted ary d567ES expressing castration - resistant prostate cancer, and / lalkyl, CN , or NOZ; or castration -resistant prostate cancer characterized by intra Q2 is hydrogen , substituted or unsubstituted aryl, substi tumoral androgen synthesis . tuted or unsubstituted phenyl, F, C1, Br, I, CF3, CN , NO , , substituted or unsubstituted cycloalkyl , substi 13. The method of claim 7, wherein said castration tuted or unsubstituted heterocycloalkyl, or substituted sensitive prostate cancer is F876L mutation expressing cas or unsubstituted arylalkyl; tration -sensitive prostate cancer, F876L _ T877A double Q , is hydrogen , substituted or unsubstituted aryl, substi mutation castration -sensitive prostate cancer, and /or castra tuted or unsubstituted phenyl, F , C1, Br, I, CF3, CN , tion - sensitive prostate cancer characterized by intratumoral NO2, substituted or unsubstituted cycloalkyl, substi androgen synthesis . tuted or unsubstituted heterocycloalkyl, or substituted 14 . The method of claim 7 , wherein said treating of or unsubstituted arylalkyl; castration - sensitive prostate cancer is conducted in a non wherein at least one of Q2 and Q3 is a substituted or castrate setting , or as monotherapy , or when castration unsubstituted aryl, substituted or unsubstituted phenyl, or substituted or unsubstituted arylalkyl; or sensitive prostate cancer tumor is resistant to enzalutamide, Q2 and Q3 are joined together to form a substituted or apalutamide, and /or abiraterone . unsubstituted C3- C , carbocyclic or heterocyclic ring 15 . A method of treating, suppressing, reducing the inci and Q , is as defined above ; dence, reducing the severity , or inhibiting triple negative or its optical isomer, its racemic mixture , pharmaceuti breast cancer in need thereof, comprising administering to cally acceptable salt , pharmaceutical product, poly the subject a therapeutically effective amount of a selective morph , hydrate , or any combination thereof. androgen receptor degrader (SARD ) compound represented 9 . The method according to claim 7 , wherein Q? is CN . by the structure of formula IA : US 2019 /0040000 A1 Feb . 7 , 2019 61

16 . The method according to claim 15 , wherein the IA compound is represented by the structure of formula III : Z III

N " OH R 03 wherein wherein T is OH , OR , - NHCOCH3, or NHCOR ; Z is NO , or CN ; Y is CF3 , F , I , Br, Cl, or CN ; Z is NO2, CN , COOH , COR , NHCOR or CONHR ; R2 is hydrogen , C1- C12 - alkyl , SO2- aryl, SO2- phenyl, - CO - aryl, arylalkyl, benzyl, aryl, or C3 -C7 -cy Y is CF3 , F , I, Br, C1, CN , C (R ), or Sn (R )z ; cloalkyl; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH , F , Qi is substituted or unsubstituted aryl, substituted or CHF2, CF3, CF2CF3, aryl, phenyl, F , C1, Br, I, alkenyl unsubstituted phenyl, substituted or unsubstituted ary or OH ; lalkyl, F , Cl, Br, I, CF3, CN , NO2, or substituted or unsubstituted heterocycloalkyl ; R is CH3, CH F , CHF2 , CF3 , CH2CH3, or CF2CF3 ; Q2 is hydrogen , substituted aryl, substituted phenyl, F , C1, R2 is hydrogen, C , - C12- alkyl , SO2- aryl, SO2- phenyl , Br, I , CF3, CN , NO2, substituted or unsubstituted - CO - aryl, arylalkyl, benzyl, aryl, or Cz -Cz - cy cycloalkyl , substituted or unsubstituted heterocy cloalkyl; cloalkyl , or substituted or unsubstituted arylalkyl; Q3 is hydrogen , substituted aryl, substituted phenyl, F , CI, Q1, Q4, and Qs are each independently selected from Br, I , CF3, CN , NO2, substituted or unsubstituted hydrogen , substituted or unsubstituted linear or cycloalkyl, substituted or unsubstituted heterocy branched alkyl, substituted aryl, F , C1, Br, I, CF3, CN , cloalkyl, or substituted or unsubstituted arylalkyl; NO2, substituted or unsubstituted cycloalkyl, substi wherein at least one of Q1, Q2 and Q3 is a substituted aryl, tuted or unsubstituted heterocycloalkyl, substituted or substituted phenyl, or substituted or unsubstituted ary unsubstituted arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCHZ, lalkyl; or NHCOCF , NHCOR , NHCONHR, NHCOOR , Q and Q , are joined together to form a substituted or OCONHR , CONHR , NHCSCH , NHCSCF4, NHCSR , unsubstituted C5 - Cg carbocyclic or heterocyclic ring NHSO , CH , , NHSO , R , OR , COR , OCOR , OSO , R , and Q , is as defined above ; or SOR, SR , NCS , SCN , NCO , or OCN ; Q2 and Qz are joined together to form a substituted or unsubstituted C5 - C , non - aromatic carbocyclic or a het Q2 and Q3 are each independently selected from hydro erocyclic ring and Q , is as defined above ; and gen , wherein said formed carbocyclic or heterocyclic ring is substituted or unsubstituted linear or branched alkyl, not dihydropyridin - 2 ( 1H ) -one , pyridin - 2 (1H ) - one or substituted aryl, F , C1, Br, I , CF3, CN , NO2, substituted 1H -pyrrole ; or unsubstituted cycloalkyl, substituted or unsubsti or its optical isomer, its racemic mixture , pharmaceuti tuted heterocycloalkyl, substituted or unsubstituted cally acceptable salt, pharmaceutical product , poly arylalkyl, C ( R ) 3 , N ( R ) 2 , NHCOCH3, NHCOCF3, morph , hydrate , or any combination thereof. NHCOR , NHCONHR, NHCOOR , OCONHR , 17 . Themethod according to claim 15 , wherein Q , is CN . CONHR , NHCSCHZ, NHCSCF3, NHCSR , 18 . Themethod according to claim 15 , wherein Q , and Qz NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , are joined together to form a substituted or unsubstituted SO _ R , SR , NCS , SCN , NCO , or OCN ; C5 - C , non -aromatic carbocyclic or a substituted or unsub wherein at least two of Q1, Q2, Q3, Q4 , and Qs are not stituted C5- C , heterocyclic ring. hydrogens; or 19 . The method according to claim 15 , wherein the compound is represented by the structure of any one of the Q? and Q2 are joined together to form a substituted or following compounds: unsubstituted C5 - C , carbocyclic or heterocyclic ring , and Q3 , Q4, and Qs are as defined above ; or Q2 and Q3 are joined together to form a substituted or 13 unsubstituted C5- Cg carbocyclic or heterocyclic ring , and Q1, Q4, and Qs are as defined above; and wherein said formed carbocyclic or heterocyclic ring is NC . not dihydropyridin - 2 ( 1H ) - one, pyridin - 2 ( 1H ) - one or 1H -pyrrole ; NH or its optical isomer , its racemic mixture , pharmaceuti FzC IZ cally acceptable salt , pharmaceutical product, poly morph , hydrate , or any combination thereof. LesUS 2019novelas /0040000 A1 *Feb* .* 7 ,* 2019 * -continued 16 17 NC .

F C or NC

FC ZI ?????20 NC NC .

F3C F C sama20 . A method of treating , suppressing , reducing the incisasa dence, reducing the severity , or inhibiting the progression of a hormonal condition in a male in need thereof; prostate cancer in a subject in need thereof, wherein said subject has NC AR overexpressing prostate cancer, castration - resistant prostate cancer, castration -sensitive prostate cancer , AR - V7 expressing prostate cancer , or d567ES expressing prostate F3C IZ cancer; triple negative breast cancer in need thereof, com prising administering to the subject a therapeutically effec tive amount of a selective androgen receptor degrader ( SARD ) compound represented by the structure : * * * * *